WO2014136905A1 - Polynuclear and multiple magnetic resonance imaging method and imaging device - Google Patents

Polynuclear and multiple magnetic resonance imaging method and imaging device Download PDF

Info

Publication number
WO2014136905A1
WO2014136905A1 PCT/JP2014/055848 JP2014055848W WO2014136905A1 WO 2014136905 A1 WO2014136905 A1 WO 2014136905A1 JP 2014055848 W JP2014055848 W JP 2014055848W WO 2014136905 A1 WO2014136905 A1 WO 2014136905A1
Authority
WO
WIPO (PCT)
Prior art keywords
magnetic resonance
pulse
nuclear magnetic
applying
probe
Prior art date
Application number
PCT/JP2014/055848
Other languages
French (fr)
Japanese (ja)
Inventor
輝幸 近藤
安宏 青山
山田　久嗣
宏彦 今井
裕生 高山
嘉則 長谷川
祐 木村
豪人 杤尾
昌宏 白川
文徳 杉原
昭夫 年光
松田　哲也
信介 山東
Original Assignee
国立大学法人京都大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人京都大学 filed Critical 国立大学法人京都大学
Priority to JP2015504398A priority Critical patent/JP6233815B2/en
Publication of WO2014136905A1 publication Critical patent/WO2014136905A1/en

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/483—NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy
    • G01R33/485—NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy based on chemical shift information [CSI] or spectroscopic imaging, e.g. to acquire the spatial distributions of metabolites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy
    • G01R33/4608—RF excitation sequences for enhanced detection, e.g. NOE, polarisation transfer, selection of a coherence transfer pathway
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Definitions

  • the present invention relates to a multinuclear multiple magnetic resonance imaging method. More particularly, the present invention relates to a multinuclear multiple magnetic resonance imaging method and a multinuclear multiple magnetic resonance imaging apparatus useful for acquiring image information for diagnosing diseases.
  • the multinuclear multiple magnetic resonance imaging method of the present invention uses a probe composed of naturally occurring atomic nuclei that do not generate radiation, and the morphological information of the specimen only with one modality of the multiple magnetic resonance imaging apparatus. As well as obtaining the positional information of the probe in the sample and visualizing the function of the probe in vivo and the metabolic reaction via the probe in vivo, it is accurate and has a low sample load. It is expected to be used for diagnostic imaging.
  • the multinuclear multiple magnetic resonance imaging apparatus of the present invention obtains not only the morphology information of the specimen but also the positional information of the probe in the specimen, and the function of the probe in the living body, the metabolic reaction via the probe in the living body. Therefore, it is expected to be used for diagnostic imaging that is accurate and has a low specimen load.
  • a magnetic resonance imaging method (hereinafter, also referred to as “ 1 H-MRI”) using the 1 H nuclear magnetic resonance phenomenon does not require the use of radiation, and non-invasively magnetizes the internal tissue or internal structure of a living body. Since a resonance image can be taken and a tissue or structure in a deep part of a living body can be imaged, it is widely used in clinical settings.
  • 1 H-MRI has a drawback that the observation frequency is narrow and a plurality of 1 H signals are detected in an overlapping manner.
  • double nuclear magnetic resonance method that utilizes the nuclear magnetic resonance phenomenon of a plurality of nuclei is a method in which magnetization is performed between adjacent nuclear magnetic resonance active nuclei having different Larmor frequencies ( This is a technique for moving (coherence) and is used for higher-order structure analysis of proteins and nucleic acids (see, for example, Non-Patent Document 1).
  • double resonance NMR has been applied to magnetic resonance spectroscopy imaging, and is used, for example, for the incorporation of ⁇ 1- 13 C ⁇ -glucose into the cat brain and the detection of its metabolites (for example, Non-patent document 2).
  • the water signal in the living body can be erased.
  • the chemical shift value of ⁇ 1- 13 C ⁇ -glucose is detected by overlapping with the chemical shift value of endogenous 13 C-lipid (natural abundance ratio 1.1%).
  • the chemical shift value of endogenous 13 C-lipid naturally abundance ratio 1.1%.
  • the present invention has been made in view of the above-described prior art, and visualizes the function of a probe in a living body, a metabolic reaction via a probe in a living body, and the like with a low load on the living body. It is an object of the present invention to provide a multinuclear multiple magnetic resonance imaging method and a multinuclear multiple magnetic resonance imaging apparatus.
  • the present invention [1] A multinuclear multiple magnetic resonance imaging method for detecting and imaging multiple resonance signals caused by probes in a specimen, (A) a bond comprising at least two nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and comprising at least three nuclear magnetic resonance active nuclei having different resonance frequencies; And (B) magnetizing transfer between the nuclei during the binding of the probe by irradiating the specimen to which the probe has been applied in step (A) with an electromagnetic wave.
  • a multi-nuclear multiple magnetic resonance imaging method comprising the step of detecting a multiple resonance signal caused by the probe using the magnetization movement, [2]
  • a probe comprising a compound having a 1 H- 13 C- 15 N bond, a 1 H- 15 N- 13 C bond, or a 1 H- 13 C- 13 C bond as a probe, and a triple nucleus based on the bond
  • the multinuclear multiple magnetic resonance imaging method according to [1], wherein a multiple resonance signal caused by the probe is detected using each pulse sequence of a magnetic resonance method and a magnetic resonance imaging method, [3]
  • the probe is Formulas (x1) to (x3):
  • R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent, and R 5 is a carbon number optionally having a substituent) 1 to 4 hydrocarbon group, * is bonded to the side chain directly or via a linker, provided that when R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one carbon in the hydrocarbon group Atoms are attached to the side chain directly or via a linker) Having a main chain having a degree of polymerization of 1 to 5000 containing at least one repeating unit selected from the group consisting of repeating units represented by formulas (y1) to (y3):
  • R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent, Z represents a monovalent functional group, and * represents the above formulas (x1) to (x3) (Directly or via a linker)
  • the side chain is a functional group represented by the formula (y1) or (y2), and Z in the formula (y1) or (y2) is represented by the formula (z1): * - 15 NH 2 (z1) [Wherein, * represents a bond bonded to the functional group represented by the formula (y1) or (y2)]
  • the linker may have a substituent and may have a hydrocarbon group having 1 to 4 carbon atoms and formulas (l1) to (l3):
  • L ′ represents an optionally substituted hydrocarbon group having 1 to 4 carbon atoms or a formula (l ′):
  • the main chain is represented by formulas (a1) to (a3):
  • R 1 to R 5 are the same as above.
  • R 7 represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may have a substituent.
  • a probe comprising a compound having A pulse applying unit for applying an RF pulse corresponding to a resonance frequency of each of at least three nuclear magnetic resonance active nuclei included in the coupling; A gradient magnetic field application unit for applying a gradient magnetic field to the probe; A detection unit for detecting a magnetic resonance signal of each of the nuclear magnetic resonance active nuclei included in the binding; A control unit that controls the pulse application unit and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
  • the predetermined pulse sequence is A magnetization transfer pulse sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization transfer between each nuclear magnetic resonance active nucleus included in the coupling; and
  • a multi-nuclear multiple magnetic resonance imaging apparatus comprising: a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal; [13]
  • the probe is magnetically coupled to the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus magnetically coupled to the first nuclear magnetic resonance active nucleus, and the second
  • a probe comprising a compound having a bond comprising the third nuclear magnetic resonance active nucleus
  • a first pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus
  • a second pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the second nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus
  • a third pulse applying unit for applying an RF pulse corresponding to the resonance frequency of the third nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus
  • a gradient magnetic field application unit for applying a gradient magnetic field to the probe
  • a detector for detecting a magnetic resonance signal of at least one nuclear magnetic resonance active nucleus selected from the group consisting of the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus, and the third nuclear magnetic resonance active nucleus
  • a magnetization transfer pulse sequence of The multinuclear multiple magnetic resonance imaging apparatus further comprising: a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal.
  • the magnetization transfer pulse sequence is the following (a1) to (a16): (A1) applying a first RF pulse of 90 degrees to the first nuclear magnetic resonance active nucleus, and further applying a second RF pulse of 180 degrees to the first nuclear magnetic resonance active nucleus; (A2) applying a third RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus simultaneously with or after applying the second RF pulse; (A3) applying a 90 degree fourth RF pulse to the first nuclear magnetic resonance active nucleus and then applying a 90 degree fifth RF pulse to the second nuclear magnetic resonance active nucleus; (A4) applying a 180 ° sixth RF pulse to the second nuclear magnetic resonance active nucleus; (A5) applying a seventh RF pulse of 180 degrees to the third nuclear magnetic resonance active nucleus simultaneously with or after applying the sixth RF pulse; (A1)
  • the multinuclear multiple magnetic resonance imaging method and multinuclear multiple magnetic resonance imaging apparatus of the present invention are accurate in terms of the function of the probe in vivo, the metabolic reaction via the probe in vivo, and the load on the living body is low. It has an excellent effect that it can be visualized with.
  • Example 1 a diagram illustrating a pulse sequence used in the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method.
  • A is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Experimental Example 1
  • (b) is a drawing-substituting photograph showing the result of imaging a 1 H- ⁇ 13 C ⁇ double magnetic resonance image.
  • (C) is a drawing-substituting photograph showing the result of imaging a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image
  • (d) is a layout of each sample in each of the images (a) to (c). is there.
  • (A) is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Experimental Example 2
  • (b) is a drawing-substituting photograph showing the result of imaging a 1 H- ⁇ 13 C ⁇ double magnetic resonance image
  • (C) is a drawing-substituting photograph showing the result of imaging a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image
  • (d) is a layout of each sample in each of the images (a) to (c). is there.
  • (A) is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Experimental Example 3, and (b) is a drawing-substituting photograph showing the result of imaging a 1 H- ⁇ 13 C ⁇ double magnetic resonance image.
  • (C) is a drawing-substituting photograph showing the result of imaging a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image, and (d) is a layout of each sample in each of the images (a) to (c). is there.
  • Example 1 is a drawing-substituting photograph showing the result of taking a 1 H-magnetic resonance image in Example 1
  • (b) is a drawing showing the result of taking a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image.
  • a substitute photograph (c) is a drawing substitute photograph showing the result of superimposing the 1 H-magnetic resonance image and the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image.
  • Example 1 it is the chart which shows the 13 C-magnetic resonance spectrum of the cancer tissue.
  • Example 2 is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Example 2, and (b) is a drawing showing the result of imaging a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image.
  • a substitute photograph (c) is a drawing substitute photograph showing the result of superimposing the 1 H-magnetic resonance image and the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image.
  • 4 is a chart showing 1 H- ⁇ 13 C- 15 N ⁇ -NMR spectrum of each structure obtained in Example 3. In Example 3, it is a graph which shows the result of having investigated the accumulation amount of 13 C / 15 N-PMPC in each structure
  • Example 4 it is a graph which shows the relationship between the density
  • the multinuclear multiple magnetic resonance imaging method of the present invention is a multinuclear multiple magnetic resonance imaging method for detecting and imaging a multiple resonance signal caused by a probe in a specimen, (A) a bond comprising at least two nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and comprising at least three nuclear magnetic resonance active nuclei having different resonance frequencies; And (B) magnetizing transfer between the nuclei during the binding of the probe by irradiating the specimen to which the probe has been applied in step (A) with an electromagnetic wave. And a step of detecting a multiple resonance signal caused by the probe using the magnetization movement.
  • the multinuclear multiple magnetic resonance imaging method of the present invention is characterized in that the probe is applied to a specimen and a multiple resonance signal caused by the probe is detected using magnetization transfer between the nuclei in the binding. It has two major features.
  • the probe is composed of naturally occurring nuclei that do not generate radiation, and has a bond having a sequence with a low abundance in living organisms. Therefore, according to the multinuclear multiple magnetic resonance imaging method of the present invention, it is possible to eliminate the detection of signals due to contaminants derived from living organisms, and to selectively detect the signal of the probe.
  • the multinuclear multiple magnetic resonance imaging method of the present invention since the probe is used, not only the morphology information of the specimen but also the probe in the specimen with only one modality of the multiple magnetic resonance imaging apparatus. It is possible to visualize the function of the probe in vivo, the metabolic reaction via the probe in vivo, and the like. Therefore, according to the multinuclear multiple magnetic resonance imaging method of the present invention, the function of the probe in the living body, the metabolic reaction through the probe in the living body, and the like can be visualized accurately and with a low load on the living body. Can do.
  • the probe used in the multinuclear multiple magnetic resonance imaging method of the present invention has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and has different resonance frequencies. It has a bond consisting of at least three nuclear magnetic resonance active nuclei.
  • the nuclear magnetic resonance active nucleus is a naturally occurring nuclear magnetic resonance active nucleus that does not generate radiation.
  • the bond has at least two types of nuclear magnetic resonance active nuclei among the nuclear magnetic resonance active nuclei and is composed of at least three nuclear magnetic resonance active nuclei having different resonance frequencies. In such coupling, multiple resonances can be caused by magnetization transfer between at least three nuclear magnetic resonance active nuclei.
  • an A 1 -A 2 -B bond (A 1 and A 2 are the same kind of nuclear magnetic resonance active nuclei, B is A 1 and A 2
  • a 1 and A 2 are the same kind of nuclear magnetic resonance active nuclei
  • B is A 1 and A 2
  • the above-mentioned bond may be any one having two or more of the same type of nuclear magnetic resonance active nuclei, which are linked so that these nuclei have different resonance frequencies.
  • Examples of the bond include a 1 H- 13 C- 15 N bond, a 1 H- 15 N- 13 C bond, and a 1 H- 13 C- 13 C bond. It is not limited. Among these bonds, 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond and 1 H- 13 are present from the viewpoint of low presence in the living body and detection with high selectivity. A C- 13 C bond is preferred, and a 1 H- 13 C- 15 N bond is more preferred.
  • the 1 H- 13 C-15 N bonds 1 H magnetization was moved to 13 C, the 13 C magnetization was moved to 15 N, and returns the magnetization of 15 N to 13 C, 1 the magnetization of 13 C It can be detected by returning to H.
  • the 1 H- 15 N-13 C coupling moves the magnetization of the 1 H to 15 N, to move the magnetization of 15 N to 13 C, returning the magnetization of 13 C to 15 N, the 15 N magnetization Can be detected by returning to 1 H.
  • 1 H- 13 C-13 C coupling moves the magnetization of the 1 H in the adjacent 13 C, the magnetization of the 13 C is moved to the adjacent 13 C, returning the magnetization of the 13 C in the adjacent 13 C
  • the 13 C magnetization can be detected by returning it to 1 H.
  • the probe preferably has a plurality of the bonds from the viewpoint of improving the detection sensitivity of the probe.
  • R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent, and R 5 is a carbon number optionally having a substituent) 1 to 4 hydrocarbon group, * is bonded to the side chain directly or via a linker, provided that when R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one carbon in the hydrocarbon group Atoms are attached to the side chain directly or via a linker) Having a main chain having a degree of polymerization of 1 to 5000 containing at least one repeating unit selected from the group consisting of repeating units represented by formulas (y1) to (y3):
  • R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent
  • Z represents a monovalent functional group
  • * represents the above formulas (x1) to (x3) (Directly or via a linker)
  • compound A also referred to as “compound A”
  • the compound A has at least one functional group selected from the group consisting of functional groups represented by the formulas (y1) to (y3) as a side chain, a 1 H- 13 C- 15 N bond, 1 H It can be detected with high selectivity using magnetization transfer between nuclei of 15 N- 13 C bond or 1 H- 13 C- 13 C bond.
  • the compound A only needs to have one or more of 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond, and 1 H- 13 C- 13 C bond.
  • the compound A preferably has at least 1 H- 13 C- 15 N.
  • the main chain of the compound A contains at least one repeating unit selected from the group consisting of repeating units represented by the formulas (x1) to (x3).
  • the degree of polymerization of the repeating unit is 1 or more, preferably 2 or more, more preferably 10 or more, still more preferably 20 or more from the viewpoint of ensuring high sensitivity, and from the viewpoint of improving the ease of application to the specimen. It is 5000 or less, preferably 1000 or less, more preferably 400 or less.
  • the main chain may be linear or branched.
  • the main chain may be composed of one type of repeating unit, or may be composed of two or more types of repeating units.
  • R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent.
  • the hydrocarbon group having 1 to 9 carbon atoms include an alkyl group having 1 to 9 carbon atoms, an alkenyl group having 2 to 9 carbon atoms, and an alkynyl group having 2 to 9 carbon atoms.
  • the present invention is not limited to such examples.
  • alkyl group having 1 to 9 carbon atoms examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and a nonyl group. It is not limited to illustration only.
  • alkenyl group having 2 to 9 carbon atoms include a vinyl group, an allyl group, a butenyl group, a pentenyl group, and a hexenyl group, but the present invention is not limited to such examples.
  • alkynyl group having 2 to 9 carbon atoms examples include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, and a hexynyl group, but the present invention is not limited to such examples.
  • Examples of the substituent include a functional group containing at least one atom selected from the group consisting of a halogen atom, an oxygen atom and a nitrogen atom, specifically, a hydroxyl group, an amino group, a dimethylamino group, a carboxyl group, Examples include an aldehyde group, a cyano group, a nitro group, and a sulfonic acid group, but the present invention is not limited to such examples.
  • R 5 is an optionally substituted hydrocarbon group having 1 to 4 carbon atoms.
  • the hydrocarbon having 1 to 4 carbon atoms include an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and an alkynyl group having 2 to 4 carbon atoms. It is not limited to only.
  • the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, and a butyl group, but the present invention is not limited only to such examples.
  • Examples of the alkenyl group having 2 to 4 carbon atoms include a vinyl group, an allyl group, and a butenyl group, but the present invention is not limited to such examples.
  • Examples of the alkynyl group having 2 to 4 carbon atoms include an ethynyl group, a propynyl group, a butynyl group, and the like, but the present invention is not limited to such examples.
  • the substituent is the same as the substituent in R 1 to R 4 .
  • * represents a moiety bonded to the side chain directly or via a linker.
  • R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one, preferably one carbon atom in the hydrocarbon group is bonded to the side chain directly or via a linker. Good.
  • R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent.
  • the hydrocarbon group having 1 to 4 carbon atoms is the same as the hydrocarbon group having 1 to 4 carbon atoms in R 5 .
  • the substituent is the same as the substituent in R 1 to R 4 .
  • * represents a moiety bonded to * in the formulas (x1) to (x3) directly or via a linker.
  • Z is a monovalent functional group.
  • the monovalent functional group include an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, an amino group, a dimethylamino group, a carboxyl group, and an aldehyde group.
  • an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and an alkynyl group having 2 to 4 carbon atoms in Z are an alkyl group having 1 to 4 carbon atoms in R 5 , an alkyl group having 2 to 4 carbon atoms, The same as the alkenyl group and the alkynyl group having 2 to 4 carbon atoms.
  • Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. The present invention is not limited to such examples.
  • the side chain is a functional group represented by the formula (y1) or (y2) and the purpose is to improve sensitivity
  • the functional group represented by can be used.
  • the side chain is a functional group represented by the formulas (y1) to (y3) and the purpose is to further bind an antibody to the probe or improve hydrophilicity, the formula (z3) :
  • * represents a bond bonded to the functional group represented by the formulas (y1) to (y3)
  • d represents an integer of 1 to 4, and the hydrogen atom of the methylene group is substituted with another atom.
  • the functional group represented by can be used.
  • * is a bond bonded to the functional groups represented by the formulas (y1) to (y3), and 13 C in the formulas (y1) to (y3), or 15 Combine with N.
  • d is 1 or more, preferably 2 or more from the viewpoint of antibody binding reactivity, and 4 or less, preferably 3 or less from the viewpoint of improving hydrophilicity.
  • the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
  • the side chain is a functional group represented by the formula (y3) and the purpose is to improve sensitivity
  • the functional group represented by the formula (z2) can be used as the Z.
  • the compound A when Z is a functional group represented by the formula (z2), the compound A has a structure having a high tumor accumulation property because it has a structure similar to choline.
  • the compound A when Z has a carboxyl group like the functional group represented by the formula (z3), the compound A has a property of easily binding a capture molecule that specifically binds to a target site such as an antibody.
  • Z has a sulfonic acid group like the functional group represented by the formula (z4) the compound A has a property of being highly hydrophilic and difficult to aggregate in vivo.
  • the linker is a substituent from the viewpoint of ensuring sufficient molecular mobility, antibody binding reactivity and hydrophilicity in the compound A.
  • L ′ is an optionally substituted hydrocarbon group having 1 to 4 carbon atoms or the formula (l ′):
  • a and b each independently represent an integer of 1 to 4, and the hydrogen atom of the methylene group may be substituted with another atom
  • * is bonded to * in the above formulas (x1) to (x3) or * in the above formulas (y1) to (y3).
  • It is preferably at least one functional group selected from the group consisting of functional groups represented by:
  • the hydrocarbon group having 1 to 4 carbon atoms is the same as the hydrocarbon group having 1 to 4 carbon atoms in R 5 .
  • the substituent is the same as the substituent in R 1 to R 4 .
  • * represents a moiety bonded to * in the formulas (x1) to (x3) or * in the formulas (y1) to (y3).
  • a and b are each independently an integer of 1 to 4, and are 1 or more, preferably 2 or more, from the viewpoint of ensuring the stability of chemical bonds, and have sufficient hydrophilicity. From the viewpoint of securing the compatibility and biocompatibility, it is 4 or less, preferably 2 or less.
  • the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
  • * represents a bond bonded to * in the formulas (x1) to (x3), a and b each independently represents an integer of 1 to 4, and methylene in the formulas (y5) to (y7)
  • the hydrogen atom of the group may be substituted with another atom
  • a structure selected from the group consisting of structures represented by When the compound A has a structure similar to choline like the structure represented by the formula (y5), it has a property of high tumor accumulation. Further, when the compound A has a structure having a carboxyl group as in the structure represented by the formula (y6), it has a property that it easily binds a capture molecule that specifically binds to a target site such as an antibody. Further, when the compound A has a sulfonic acid group as in the structure represented by the formula (y7), the compound A has a property of being highly hydrophilic and difficult to aggregate in vivo.
  • * represents a bond that is bonded to * in the formulas (x1) to (x3) as the main chain.
  • a and b are the same as a and b in the formula (l ′).
  • the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
  • Compound A is preferably represented by formulas (i1) to (i12) from the viewpoint of controlling the degree of polymerization and the degree of dispersion of the polymer compound:
  • a and b are the same as a and b in the formula (l ′).
  • the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
  • Compound A may be a copolymer having two or more types of repeating units.
  • any of an alternating copolymer, a random copolymer and a block copolymer may be used.
  • the main chain is derived from a (meth) acrylate monomer, a repeating unit derived from a (meth) acrylate monomer, in addition to the repeating units represented by the formulas (X1) to (x3) And a repeating unit selected from the group consisting of a repeating unit derived from an amino acid monomer, and a repeating unit derived from a hydroxy acid monomer.
  • repeating units include formulas (a1) to (a3):
  • R 7 represents a monovalent functional group
  • examples of the monovalent functional group represented by R 7 include a hydrogen atom and an optionally substituted hydrocarbon group having 1 to 6 carbon atoms.
  • examples of the hydrocarbon group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group, but the present invention is limited only to such examples. is not.
  • the substituent is the same as the substituent in R 1 to R 4 .
  • compound A is a copolymer
  • all of the repeating units constituting the copolymer are any functional groups represented by the formulas (y1) to (y3) in the side chain. It is preferable to have.
  • the compound is a copolymer, only a part of the repeating units constituting the copolymer is used from the viewpoint of controlling according to the purpose such as control of hydrophilicity, adsorption capacity in vivo, etc. May have any of functional groups represented by formulas (y1) to (y3).
  • the probe is added with a capture molecule that specifically binds to the target site from the viewpoint of more accurately tracking the target site's specific detection, target substance dynamics, localization, drug efficacy, metabolism, etc.
  • a capture molecule that specifically binds to the target site from the viewpoint of more accurately tracking the target site's specific detection, target substance dynamics, localization, drug efficacy, metabolism, etc.
  • the capture molecule include a substance that specifically binds to a target site such as a tumor, and a substance that specifically binds to a substance present around the target site.
  • the present invention is limited only to such examples. It is not something.
  • Specific examples of the capture molecule include antibodies, antibody fragments, enzymes, biologically active peptides, glycopeptides, sugar chains, lipids, nucleic acids, molecular recognition compounds, and the like. These capture substances may be used alone or in combination of two or more.
  • the repeating unit of Compound A has an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, It preferably has any one functional group of 2 to 4 alkynyl groups, hydroxyl groups, thiol groups, amino groups, azide groups, maleimide groups, N-hydroxysuccinimide groups and trichlorosilyl groups.
  • the terminal of compound A has, for example, any structure of formulas (b1) to (b9).
  • alkyl group having 1 to 12 carbon atoms examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Although mentioned, this invention is not limited only to this illustration.
  • alkenyl group having 2 to 12 carbon atoms examples include a vinyl group, an allyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, and the like.
  • the alkynyl group having 2 to 4 carbon atoms at the terminal of the repeating unit is the same as the alkynyl group having 2 to 4 carbon atoms in R 5 .
  • e is an integer of 1 to 11.
  • f is an integer of 0 to 17.
  • R 8 is a hydrogen atom or a methyl group.
  • * is bonded to a repeating unit of the main chain. Both ends of Compound A may have the same structure or different structures.
  • Compound A can be synthesized by polymerizing a polymerizable compound.
  • Compound A can be synthesized, for example, by polymerizing any of the compounds represented by formulas (j1) to (j12).
  • a and b are the same as a and b in formula (l ′).
  • the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
  • EPR Enhanced Permeability and Retention
  • the probe can be applied to the specimen by, for example, subcutaneous injection, oral administration, transdermal administration, intravenous administration, intraperitoneal administration, and the like, but the present invention is not limited to such examples.
  • the probe When applying the probe to a specimen, the probe can be used after being dissolved in a dispersion medium.
  • the dispersion medium may be a liquid substance for dissolving the probe, and examples thereof include physiological saline, distilled water for injection, and phosphate buffered aqueous solution (PBS), but the present invention is only such examples.
  • PBS phosphate buffered aqueous solution
  • the probe may be used together with a pharmacologically acceptable additive as necessary.
  • step (A) the specimen to which the probe is attached in the step (A) is irradiated with electromagnetic waves to move the magnetization between the binding nuclei, and the probe moves to the probe using the magnetization movement.
  • the resulting multiple resonance signal is detected [step (B)].
  • a pulse sequence of a multiple nuclear magnetic resonance method and a pulse sequence of a magnetic resonance imaging method according to the number of nuclear magnetic resonance active nuclei contained in the probe are used.
  • a probe having 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond or 1 H- 13 C- 13 C bond is used as the probe, triple nuclear magnetic resonance based on the bond (For example, 1 H- ⁇ 13 C- 15 N ⁇ triple nuclear magnetic resonance method, HNCO triple nuclear magnetic resonance method, HNCA triple nuclear magnetic resonance method, HN (CA) CO triple magnetic resonance method, HCACO triple magnetic resonance method, etc. ) Pulse sequence and magnetic resonance imaging pulse sequence.
  • the pulse sequence of the multiple nuclear magnetic resonance method includes, for example, the types of nuclear magnetic resonance active nuclei, their number, their arrangement, chemical shifts of these nuclear magnetic resonance active nuclei, coupling constants between nuclear magnetic resonance active nuclei, etc. Can be set as appropriate based on the above.
  • Examples of the pulse sequence of the multiple nuclear magnetic resonance method include INEPT, HMQC, HSQC, HMBC, HCN, HNCA, HNCO, HN (CA) CO, HCACO, etc., but the present invention is limited only to such examples. Is not to be done.
  • the pulse sequence of the magnetic resonance imaging method can be appropriately set based on, for example, the longitudinal relaxation time (T1) and transverse relaxation time (T2) of the magnetic resonance active nucleus included in the probe.
  • the pulse sequence of the magnetic resonance imaging method include a spin echo method, a fast spin echo method, an echo planar imaging method, a gradient echo method, a spoiled gradient echo method, a coherent gradient echo method, and the like.
  • the present invention is not limited to such examples.
  • the probe has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and a bond consisting of three nuclear magnetic resonance active nuclei having different resonance frequencies (ie, , A probe having a first nuclide, a second nuclide magnetically coupled to the first nuclide, and a third nuclide magnetically coupled to the second nuclide), the probe is more selective.
  • the pulse sequence used in the step (B) undergoes magnetization transfer from the first nuclide to the second nuclide, and then magnetizes from the second nuclide to the third nuclide.
  • the pulse sequence includes a sequence and a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal.
  • the multinuclear multiple magnetic resonance imaging method of the present invention can obtain not only the morphology information of the specimen but also the positional information of the probe in the specimen as well as the single magnetic modality imaging apparatus.
  • the function of the probe in the body, the metabolic reaction through the probe in the living body, etc. can be visualized, and it is expected to be used for diagnostic imaging that is accurate and has little burden on the patient.
  • the multinuclear multiple magnetic resonance imaging apparatus of the present invention is a multinuclear multiple magnetic resonance imaging apparatus for detecting and imaging a multiple resonance signal caused by a probe in a specimen,
  • the probe has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and is composed of at least three nuclear magnetic resonance active nuclei having different resonance frequencies.
  • a probe comprising a compound having A pulse applying unit for applying an RF pulse corresponding to a resonance frequency of each of at least three nuclear magnetic resonance active nuclei included in the coupling; A gradient magnetic field application unit for applying a gradient magnetic field to the probe; A detection unit for detecting a magnetic resonance signal of each of the nuclear magnetic resonance active nuclei included in the binding; A control unit that controls the pulse application unit and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
  • the predetermined pulse sequence is A magnetization transfer pulse sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization transfer between each nuclear magnetic resonance active nucleus included in the coupling; and
  • a multinuclear multiple magnetic resonance imaging apparatus comprising: a signal acquisition pulse sequence for adding position information to the magnetic resonance signal and acquiring the magnetic resonance signal.
  • the multinuclear magnetic resonance imaging apparatus of the present invention includes a pulse applying unit that applies RF pulses corresponding to the resonance frequencies of at least three nuclear magnetic resonance active nuclei included in the coupling in the probe, and a gradient magnetic field applied to the probe.
  • a control unit for controlling, and applying the RF pulse and the gradient magnetic field to the probe so that the predetermined pulse series moves the magnetization between the nuclear magnetic resonance active nuclei included in the coupling.
  • the multinuclear multiple magnetic resonance imaging apparatus of the present invention obtains not only the form information of the specimen but also the positional information of the probe in the specimen, the function of the probe in the living body, the metabolic reaction via the probe in the living body, etc. Can be visualized. Therefore, according to the multinuclear multiple magnetic resonance imaging apparatus of the present invention, the function of the probe in the living body, the metabolic reaction through the probe in the living body, and the like can be visualized accurately and with a low load on the living body. Can do.
  • the probe is magnetically coupled to a first nuclear magnetic resonance active nucleus, a second nuclear magnetic resonance active nucleus that is magnetically coupled to the first nuclear magnetic resonance active nucleus, and a third magnetically coupled to the second nuclear magnetic resonance active nucleus.
  • the multinuclear multiple magnetic resonance imaging apparatus of the present invention is A first pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus; A second pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the second nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus; A third pulse applying unit for applying an RF pulse corresponding to the resonance frequency of the third nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus; A gradient magnetic field application unit for applying a gradient magnetic field to the probe
  • the probe is magnetically applied to the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus magnetically coupled to the first nuclear magnetic resonance active nucleus, and the second nuclear magnetic resonance active nucleus.
  • An example of a multi-nuclear multiple magnetic resonance imaging apparatus in the case of a probe made of a compound having a bond consisting of a third nuclear magnetic resonance active nucleus that is bonded to the target will be described.
  • FIG. 11 is a block diagram showing a functional configuration of a multinuclear magnetic resonance imaging apparatus according to an embodiment of the present invention.
  • a multinuclear magnetic resonance imaging apparatus 1 shown in FIG. 11 includes a gantry unit 10 that applies a static magnetic field, a gradient magnetic field, and an RF pulse to a probe in a specimen arranged in an internal space serving as an imaging region, and an RF pulse that is a gantry unit. 10, a pulse applying unit 20 for applying an RF pulse to the probe in the specimen, a power supply unit 30, a pulse sequence control unit 40, a detection unit 50a for receiving and detecting an echo signal, and the echo signal A data collection unit 60 that collects data based on the computer 70 is provided.
  • the gantry unit 10 includes a cylindrical static magnetic field magnet 11 that generates a static magnetic field, a cylindrical shim coil 12 that equalizes the static magnetic field, a cylindrical gradient magnetic field coil 13 that generates a gradient magnetic field, and an RF pulse. It comprises a cylindrical RF coil 14 that irradiates a probe in the specimen and receives an echo signal resulting from the RF pulse.
  • the static magnetic field magnet 11 has a function of generating a static magnetic field in the imaging region.
  • Examples of the magnet that constitutes the static magnetic field magnet 11 include a superconducting magnet and a permanent magnet, but the present invention is not limited to such examples.
  • the static magnetic field magnet 11 is composed of a superconducting magnet, the static magnetic field magnet 11 is connected to a power source and forms a static magnetic field by a current supplied from the power source.
  • the shim coil 12 is provided coaxially with the static magnetic field magnet 11 inside the static magnetic field magnet 11.
  • the shim coil 12 is connected to a shim coil power supply 31 of the power supply unit 30.
  • the shim coil 12 is composed of component coils that generate various compensation magnetic fields.
  • the shim coil 12 adopting such a configuration can generate a compensation magnetic field that reduces non-uniformity of the static magnetic field and can make the static magnetic field uniform when current is supplied from the power supply 31.
  • the gradient magnetic field coil 13 is provided on the inner side of the shim coil 12 and coaxially with the shim coil 12.
  • the gradient magnetic field coil 13 is connected to a gradient magnetic field coil power supply 32 of the power supply unit 30.
  • the gradient magnetic field coil 13 includes an x-axis gradient magnetic field coil, a y-axis gradient magnetic field coil, and a z-axis gradient magnetic field coil (not shown).
  • the gradient magnetic field coil 13 adopting such a configuration is supplied with a current from the power supply 31, thereby causing a magnetic field gradient in the x-axis direction, a magnetic field gradient in the y-axis direction, and a magnetic field gradient in the z-axis direction, respectively. Can be generated.
  • x-axis direction is a direction orthogonal to the direction of the static magnetic field
  • y-axis direction is a direction orthogonal to the direction of the static magnetic field and is orthogonal to the x-axis
  • z “Axial direction” indicates a direction parallel to the direction of the static magnetic field and perpendicular to the y-axis and the x-axis.
  • the RF coil 14 is provided inside the gradient magnetic field coil 13 and coaxially with the gradient magnetic field coil 13.
  • the RF coil 14 is connected to the pulse application unit 20 and the detection unit 50a.
  • the RF coil 14 emits an RF pulse to the probe in the specimen, and an echo signal generated when the first nuclide, the second nuclide, and the third nuclide of the probe in the specimen are excited by the RF pulse. It is also used for reception and transmission to the detection unit 50a.
  • the RF coil 14 employing such a configuration irradiates the probe in the sample with the RF pulse transmitted from the pulse applying unit 20, and receives and detects an echo signal resulting from the RF pulse from the probe in the sample. It can transmit to the part 50a.
  • the RF pulse corresponding to the resonance frequency of each of the first nuclide, the second nuclide and the third nuclide is irradiated to the probe in the specimen, and excitation of each of the first nuclide, the second nuclide and the third nuclide by the RF pulse As a result, an echo signal is generated.
  • the pulse application unit 20 is connected to the RF coil 14 and the detection unit 50a.
  • the pulse applying unit 20 includes a first pulse applying unit 21 that applies an RF pulse corresponding to the resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus, and a second nuclear magnetic resonance active nucleus.
  • the pulse applying unit 20 generates an RF pulse corresponding to the resonance frequency of each nuclide included in the coupling in the probe in accordance with predetermined pulse sequence setting information under the control of the pulse sequence control unit 40, and Send.
  • the power supply unit 30 is connected to the pulse sequence control unit 40, the shim coil 12, and the gradient magnetic field coil 13.
  • the power supply unit 30 includes a shim coil power supply 31 that supplies current to the shim coil 12 and a gradient magnetic field coil power supply 32 that supplies current to the gradient magnetic field coil 13.
  • the shim coil power supply 31 is controlled by the pulse sequence control unit 40, supplies current to the shim coil 12 according to the pulse sequence setting information, and controls the generation of the compensation magnetic field by the shim coil 12.
  • the gradient magnetic field coil 13 is controlled by the pulse sequence control unit 40, supplies current to the gradient magnetic field coil 13 according to the pulse sequence setting information, and controls the generation of the gradient magnetic field by the gradient magnetic field coil 13.
  • the pulse series control unit 40 is connected to the computer 70, the pulse application unit 20, the gradient magnetic field coil power supply 32 of the power supply unit 30, and the data collection unit 60.
  • the pulse sequence control unit 40 is controlled by the computer 70 and controls the pulse applying unit 20 and the gradient magnetic field coil power supply 32 in accordance with predetermined pulse sequence setting information.
  • the detection unit 50a is connected to the RF coil 14 and the data collection unit.
  • the detection unit 50a receives and detects a magnetic resonance signal, which is an echo signal generated when the first nuclide, the second nuclide, and the third nuclide are excited by the RF pulse, from the RF coil 14.
  • the detection unit 50 a receives the first resonance unit 51 that receives the magnetic resonance signal of the first nuclear magnetic resonance active nucleus from the RF coil 14, and the magnetic resonance signal of the second nuclear magnetic resonance activation nucleus from the RF coil 14.
  • a third receiver 53 that receives a magnetic resonance signal of the third nuclear magnetic resonance active nucleus from the RF coil 14. Information regarding the magnetic resonance signal detected by the detection unit 50 a is transmitted to the data collection unit 60.
  • the data collection unit 60 is connected to the detection unit 50a and the computer 70.
  • the data collection unit 60 converts the magnetic resonance signal detected by the detection unit 50a into a digital signal, and obtains data related to the magnetic resonance signal. Examples of the data include data on strength, data on chemical shift, and the like, but the present invention is not limited to such examples.
  • the data collection unit 60 transmits the collected data to the computer 70.
  • the computer 70 is connected to the pulse sequence control unit 40 and the data collection unit 60.
  • the computer 70 includes an arithmetic device 71, an input device 72, an output device 73, and a storage unit 74.
  • the arithmetic device 71 executes a program for controlling the pulse sequence control unit 40 in accordance with predetermined pulse sequence setting information and a program for performing processing for imaging data. Thereby, the arithmetic unit 71 controls the operation of the pulse sequence control unit 40 and performs processing such as Fourier transform on the collected data, and image data of spins of nuclear magnetic resonance active nuclei contained in the probe in the specimen. Create The input device 72, the output device 73, and the storage unit 74 are connected to the arithmetic device 71.
  • the arithmetic device 71 is composed of, for example, a CPU.
  • the input device 72 is a device for inputting an operation command of the multinuclear multiple magnetic resonance imaging apparatus 1, sample information, and the like to the arithmetic device.
  • Examples of the input device 72 include a keyboard and a voice input device.
  • the present invention is not limited to such an example.
  • the output device 73 displays or outputs an image based on the data processed by the arithmetic device 71. Examples of the output device 73 include a display and a printer, but the present invention is not limited to such examples.
  • the storage unit 74 stores information input to the arithmetic unit 71, pulse sequence setting information and program for generating a pulse sequence, a program for performing processing for imaging data, and the like.
  • the image data created by the arithmetic device 71 is transmitted to the output device 73, and is displayed or output as an image on the output device 73.
  • FIG. 12 is a schematic explanatory diagram illustrating an example of a pulse sequence in the multinuclear multiple magnetic resonance imaging apparatus according to an embodiment of the present invention.
  • the pulse sequence shown in FIG. 12 is the same as the pulse sequence shown in FIG. FIG. 12 is different from FIG. 1 in that reference numerals for the RF pulses and reference numerals corresponding to the steps are attached.
  • the pulse sequence shown in FIG. 12 includes a magnetization transfer pulse sequence (see “triple nuclear magnetic resonance method” in FIG. 12) for applying magnetization transfer by applying an RF pulse and a gradient magnetic field to the probe, and the magnetic resonance. It includes a signal collection pulse sequence (see “Fast Spin Echo MRI” in FIG. 12) for adding position information to the signal and collecting the magnetic resonance signal.
  • the magnetization transfer pulse sequence is a sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform the following magnetization transfers (I), (II), (III), and (IV) in this order: (I) Magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus, (II) magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus; (III) Magnetization transfer from the third nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus, and (IV) Magnetization transfer from the second nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus.
  • the magnetization transfer pulse sequence includes an RF pulse application sequence which is an RF pulse application pattern and a gradient magnetic field application sequence which is a gradient magnetic field application pattern.
  • the RF pulse application sequence is processed by the pulse sequence control unit 40 in the following steps (a1) to (a16): (A1) after applying a first RF pulse P1 of 90 degrees to the first nuclear magnetic resonance active nucleus, further applying a second RF pulse P2 of 180 degrees to the first nuclear magnetic resonance active nucleus; (A2) applying a third RF pulse P3 of 180 degrees to the second nuclear magnetic resonance active nucleus at the same time as or after applying the second RF pulse P2.
  • steps (a1) to (a3) are executed by the pulse sequence controller 40, (I) magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus [the magnetization transfer ( I)] is performed.
  • steps (a4) to (a6) are executed by the pulse sequence controller 40, the magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus [the magnetization transfer ( II)] is performed.
  • the steps (a7) to (a13) are executed by the pulse sequence controller 40, whereby the magnetization transfer from the third nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus [the magnetization transfer ( III)] is performed.
  • the steps (a14) to (a16) are executed by the pulse sequence control unit 40, the magnetization transfer from the second nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus [the magnetization transfer (IV)] is performed.
  • the RF pulse application sequence is as shown in FIG. (A1-1) 90 degree first RF pulse P1 applied to the first nuclear magnetic resonance active nucleus, (A1-2) A second RF pulse P2 of 180 degrees applied to the first nuclear magnetic resonance active nucleus after the application of the first RF pulse P1, (A2) A third RF pulse P3 of 180 degrees applied to the second nuclear magnetic resonance active nucleus simultaneously with or after the application of the second RF pulse P2.
  • the RF pulses (a3-1) and (a3-2) are RF pulses generated when the step (a3) is executed by the pulse sequence control unit 40.
  • the RF pulses (a6-1) and (a6-2) are RF pulses generated by the step (a6) being executed by the pulse sequence control unit 40.
  • the RF pulses (a14-1) and (a14-2) are pulses generated when the step (a14) is executed by the pulse sequence control unit 40.
  • the RF pulses of (a2), (a4), (a5), (a7), (a9), (a10), (a11), (a12), (a13), (a15) and (a16) are respectively
  • the pulse sequence control unit 40 performs the steps (a2), (a4), (a5), (a7), (a9), (a10), (a11), (a12), (a13), (a15) and ( This is an RF pulse generated by executing a16).
  • the gradient magnetic field application sequence is performed by the pulse sequence control unit 40 in the following steps (b1) to (b12): (B1) applying a gradient magnetic field to the probe in the interval between the first RF pulse P1 and the second RF pulse P2. (B2) applying a gradient magnetic field to the probe in the interval between the third RF pulse P3 and the fourth RF pulse P4; (B3) applying a gradient magnetic field to the probe in the interval between the fourth RF pulse P4 and the fifth RF pulse P5; (B4) applying a gradient magnetic field to the probe in the interval between the eighth RF pulse P8 and the ninth RF pulse P9; (B5) applying a gradient magnetic field to the probe in the interval between the ninth RF pulse P9 and the tenth RF pulse P10; (B6) applying a gradient magnetic field to the probe in the interval between the tenth RF pulse P10 and the eleventh RF pulse P11; (B7) applying a gradient magnetic field to the probe at an interval between the twelfth RF pulse P12 and the
  • the gradient magnetic field application series is as shown in FIG. 12 (b1) a gradient magnetic field applied to the probe in the interval between the first RF pulse P1 and the second RF pulse P2, (B2) a gradient magnetic field applied to the probe in the interval between the third RF pulse P3 and the fourth RF pulse P4; (B3) a gradient magnetic field applied to the probe in the interval between the fourth RF pulse P4 and the fifth RF pulse P5; (B4) a gradient magnetic field applied to the probe in the interval between the eighth RF pulse P8 and the ninth RF pulse P9; (B5) a gradient magnetic field applied to the probe in the interval between the ninth RF pulse P9 and the tenth RF pulse P10; (B6) a gradient magnetic field applied to the probe in the interval between the tenth RF pulse P10 and the eleventh RF pulse P11; (B7) a gradient magnetic field applied to the probe in the interval between the twelfth RF pulse P12 and the thirteenth RF pulse P13; (B8) a gradient magnetic field
  • the predetermined pulse sequence setting information includes magnetization transfer pulse sequence setting information and signal collection pulse sequence setting information.
  • the RF pulse application sequence information includes the RF pulse application sequence information for causing the pulse sequence control unit 40 to execute the steps (a1) to (a16), and the pulse sequence control unit 40 for the step (b1). ) To (a12) and gradient magnetic field application sequence information for executing each step.
  • FIG. 13 is a schematic explanatory diagram showing a modification of the pulse series in the multinuclear magnetic resonance imaging apparatus according to one embodiment of the present invention.
  • the pulse sequence shown in FIG. 13 is performed after the step (a14), instead of the steps (a15) and (a16) being performed by the pulse sequence control unit 40 after the step (a14).
  • A18 The step of applying the 23rd RF pulse 23 of 180 degrees to the first nuclear magnetic resonance active nucleus, and
  • the step of applying the 24th RF pulse 24 of 90 degrees to the second nuclear magnetic resonance active nucleus is executed. This is a sequence that includes a sequence generated as a result of being applied as an RF pulse application sequence.
  • the multinuclear multiple magnetic resonance imaging apparatus of the present invention is as shown in FIG. 14 instead of the detection unit 50a including the first reception unit 51, the second reception unit 52, and the third reception unit 53.
  • a detecting unit 50b including a receiving unit 54 that receives any of the echo signals generated along with the RF coil 14 may be provided.
  • the multinuclear magnetic resonance imaging apparatus of the present invention obtains not only the form information of the specimen but also the position information of the probe in the specimen, and the function of the probe in the living body, the probe in the living body. Therefore, it is expected to be used for diagnostic imaging that is accurate and has a low load on the specimen.
  • a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) using Ltd.] by 1 H- magnetic resonance imaging method
  • 1 H- magnetic resonance imaging method we were imaged 1 H- magnetic resonance image of said sample.
  • a high-speed spin echo method is used, the number of times of integration is 2, the imaging time is 16 seconds, the repetition time (TR) is 1000 ms, the echo train number (ETL) is 8 and the imaging range (FOV) is 5 ⁇ 5 cm. Two conditions were used.
  • 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd.
  • the 1 H- ⁇ 13 C ⁇ double magnetic resonance image of the sample was imaged by the 1 H- ⁇ 13 C ⁇ double magnetic resonance imaging method.
  • an imaging method in which the fast spin echo method is extended to 1 H- ⁇ 13 C ⁇ double resonance is used, and the number of integrations is 32 times, and the imaging time is 256 seconds.
  • Conditions of time (TR) 1000 ms, echo train number (ETL) 8 and imaging range (FOV) 5 ⁇ 5 cm 2 were used.
  • an MRI apparatus for 7T animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI (manufactured by Doty Scientific)
  • the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image of the sample was imaged by the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method.
  • 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method is used to select a 1 H nucleus derived from a molecular probe, and position information is obtained with respect to the 1 H nucleus by a gradient magnetic field (G phase and G read ). Added.
  • the number of times of integration is 32
  • the imaging time is 256 seconds
  • the repetition time (TR) is 1000 ms
  • the number of echo trains (ETL) is 8
  • the imaging range (FOV) is 5 ⁇ .
  • a condition of 5 cm 2 was used.
  • 1 H- ⁇ 13 C- 15 N ⁇ Mie magnetic resonance imaging method in order to perform a plurality of signal collection needed to position information addition in a short time, high-speed spin echo method 1 H- ⁇ 13 C- 15 An imaging method extended to N ⁇ triple resonance was used.
  • FIG. 1 shows a pulse sequence used in 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method in Experimental Example 1.
  • a thin bar represents a 90 ° excitation pulse
  • a thick bar represents a 180 ° convergence pulse.
  • 1/4 1 J CN 35ms.
  • FIG. 2A shows the result of imaging a 1 H-magnetic resonance image
  • FIG. 2B shows the result of imaging 1 H- ⁇ 13 C ⁇ double magnetic resonance image
  • 1 H- ⁇ 13 the results of the captured c-15 N ⁇ triple magnetic resonance imaging FIG. 2 (c)
  • FIG. 2 (d) a layout view of each sample in each image of FIG. 2 (a) ⁇ (c) .
  • (D) (a) is 6 mg / mL 13 C / 15 N-labeled choline chloride heavy aqueous solution, (b) is 30 mg / mL 13 C / 15 N-labeled choline chloride heavy aqueous solution, (c) is 120 mg / mL 13 C / 15 N-labeled choline chloride heavy aqueous solution, (d) shows a heavy aqueous solution of 1M 13 C-labeled lactic acid, and (e) shows water.
  • 13 C / 15 N-labeled poly-2-meth represented methacryloyloxyethyl phosphorylcholine (molecular weight 44000, hereinafter, "13 C / 15 N-PMPC" hereinafter) of an aqueous solution (in 13 C / 15 N-PMPC in solution Concentration: 8 mg / mL) 0.5 mL, 13 C-labeled poly-2-methacryloyloxyethyl phosphorylcholine (molecular weight 35000, hereinafter referred to as “ 13 C-PMPC”) aqueous solution (concentration of 13 C-PMPC in the solution: 8 mg / ML) 0.5 mL, 0.5 mL of oleic acid (containing 1.1 vol% 13 C-oleic acid) and 0.5 mL of water were used as samples. Each sample was placed side by side on a cylindrical coil.
  • 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd.
  • the 1 H- ⁇ 13 C ⁇ double magnetic resonance image of the sample was imaged by the 1 H- ⁇ 13 C ⁇ double magnetic resonance imaging method.
  • an imaging method in which the spin echo method is extended to 1 H- ⁇ 13 C ⁇ double resonance is used, and the number of times of integration is 16, the imaging time is 512 seconds, and the repetition time is Conditions of (TR) 1000 ms and imaging range (FOV) 5 ⁇ 5 cm 2 were used.
  • an MRI apparatus for 7T animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI (manufactured by Doty Scientific)
  • the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image of the sample was imaged by the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method.
  • a pulse sequence combining a pulse sequence of the 1 H- ⁇ 13 C- 15 N ⁇ triple nuclear magnetic resonance method and a pulse sequence of the spin echo method is used.
  • the number of integration was 1024 times
  • the imaging time was 32768 seconds
  • the repetition time (TR) was 1000 ms
  • the imaging range (FOV) was 5 ⁇ 5 cm 2 .
  • FIG. 3A shows water
  • FIG. 3B shows a result of taking a C- 15 N ⁇ triple magnetic resonance image
  • FIG. 3 (d) shows water
  • (b) shows a 13 C / 15 N-PMPC aqueous solution
  • (c) shows a 13 C-PMPC aqueous solution
  • (d) shows oleic acid.
  • a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) using Ltd.] by 1 H- magnetic resonance imaging method
  • 1 H- magnetic resonance imaging method a high-speed spin echo method is used, the number of times of integration is 1, the imaging time is 16 seconds, the repetition time (TR) is 1000 ms, the echo train number (ETL) is 8 and the imaging range (FOV) is 5 ⁇ 5 cm. Two conditions were used.
  • 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd.
  • the 1 H- ⁇ 13 C ⁇ double magnetic resonance image of the sample was imaged by the 1 H- ⁇ 13 C ⁇ double magnetic resonance imaging method.
  • an imaging method in which the fast spin echo method is extended to 1 H- ⁇ 13 C ⁇ double resonance is used, and the number of integrations is 16 times, and the imaging time is 16 seconds.
  • Conditions of time (TR) 1000 ms, echo train number (ETL) 32, and imaging range (FOV) 5 ⁇ 5 cm 2 were used.
  • an MRI apparatus for 7T animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI (manufactured by Doty Scientific)
  • the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image of the sample was imaged by the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method.
  • the number of times of integration is 1024 times
  • the imaging time is 1024 seconds
  • the repetition time (TR) is 1000 ms
  • the number of echo trains (ETL ) 32 and an imaging range (FOV) of 5 ⁇ 5 cm 2 were used.
  • Example 1 In the right abdomen of a Balb / c nu-nu female mouse (6 weeks old), a mouse colon cancer cell colon 26 suspension (1.9 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 ⁇ L of a physiological saline solution (containing saline) was injected subcutaneously, and a mouse colon cancer cell colon 26 suspension (0.8 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) was injected into the left abdomen of the mouse. ) Containing saline solution) 50 ⁇ L was injected subcutaneously.
  • a mouse colon cancer cell colon 26 suspension 1.9 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 ⁇ L of a physiological saline solution (containing saline) was injected subcutaneously,
  • a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image of the cancer tissue was imaged by the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance imaging method.
  • the pulse sequence shown in FIG. 1 is used, the number of times of integration is 1024, the imaging time is 1065 seconds, the repetition time (TR) is 1000 ms, the number of echo trains (ETL) ) 32 and an imaging range (FOV) of 5 ⁇ 5 cm 2 were used.
  • MRI apparatus for 7T Animals [Bruker BioSpin (Bruker BioSpin Corp.)] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific ) using a manufactured] by 1 H- magnetic resonance imaging method, were imaged 1 H- magnetic resonance image of the cancerous tissue.
  • a high-speed spin echo method is used, the number of times of integration is 1, the imaging time is 80 seconds, the repetition time (TR) is 2500 ms, the number of echo trains (ETL) is 8 and the imaging range (FOV) is 5 ⁇ 5 cm. Two conditions were used.
  • Example 1 the result of imaging a 1 H-magnetic resonance image is shown in FIG. 5A, the result of imaging a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image is shown in FIG. 5B, and 1 H- The result of superimposing the magnetic resonance image and the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image is shown in FIG. 5A
  • 7T animal MRI system (manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd. ] the 13 C- magnetic resonance spectroscopy was used to measure the 13 C- magnetic resonance spectrum of the cancerous tissue.
  • Example 2 In the right abdomen of a Balb / c nu-nu female mouse (6 weeks old), a mouse colon cancer cell colon 26 suspension (1.9 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 ⁇ L of a physiological saline solution (containing saline) was injected subcutaneously, and a mouse colon cancer cell colon 26 suspension (0.8 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) was injected into the left abdomen of the mouse. ) Containing saline solution) 50 ⁇ L was injected subcutaneously.
  • a mouse colon cancer cell colon 26 suspension 1.9 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 ⁇ L of a physiological saline solution (containing saline) was injected subcutaneously,
  • the number of times of integration is 1024 times
  • the imaging time is 1024 seconds
  • the repetition time (TR) is 1000 ms
  • the number of echo trains (ETL ) 32 and an imaging range (FOV) of 5 ⁇ 5 cm 2 were used.
  • MRI apparatus for 7T Animals [Bruker BioSpin (Bruker BioSpin Corp.)] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific).
  • the 1 H-magnetic resonance image of the mouse was imaged by the 1 H-magnetic resonance imaging method.
  • a high-speed spin echo method is used, the number of times of integration is 1, the imaging time is 80 seconds, the repetition time (TR) is 2500 ms, the number of echo trains (ETL) is 8 and the imaging range (FOV) is 5 ⁇ 5 cm. Two conditions were used.
  • Example 2 the result of imaging a 1 H-magnetic resonance image is shown in FIG. 7A, the result of imaging a 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image is shown in FIG. 7B, and 1 H- FIG. 7C shows the result of superimposing the magnetic resonance image and the 1 H- ⁇ 13 C- 15 N ⁇ triple magnetic resonance image.
  • Example 3 In the right abdomen of a Balb / c nu-nu female mouse (6 weeks old), a mouse colon cancer cell colon 26 suspension (1.9 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 ⁇ L of a physiological saline solution (containing saline) was injected subcutaneously, and a mouse colon cancer cell colon 26 suspension (0.8 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) was injected into the left abdomen of the mouse. ) Containing saline solution) 50 ⁇ L was injected subcutaneously.
  • a mouse colon cancer cell colon 26 suspension 1.9 ⁇ 10 6 cells / 50 ⁇ L 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 ⁇ L of a physiological saline solution (containing saline) was injected subcutaneously,
  • the obtained lysate was subjected to centrifugation at 14000 ⁇ g for 30 minutes to obtain a supernatant.
  • the obtained supernatant was freeze-dried and then redissolved in 4 times the amount of tissue water to obtain a sample.
  • a 1 H- ⁇ 13 C- 15 N ⁇ -NMR spectrum of the sample was measured using a 600 MHz NMR apparatus (manufactured by Bruker) equipped with a cryoprobe (16 times of integration). Further, the S / N ratio of the 1 H- ⁇ 13 C- 15 N ⁇ triple resonance NMR signal was determined from the obtained 1 H- ⁇ 13 C- 15 N ⁇ -NMR spectrum, and 13 C / 15 N— in each tissue was obtained. The amount of accumulated PMPC was calculated.
  • FIG. 9 shows the results of examining the amount of 13 C / 15 N-PMPC accumulated in each tissue in Example 3. 8 and 9, “liver”, “kidney” and “heart” mean “liver tissue”, “kidney tissue” and “heart tissue”, respectively.
  • the multinuclear multiple magnetic resonance imaging method of the present invention was performed using a probe having a function of acting on a living body, such as 13 C / 15 N-PMPC that specifically accumulates in cancer tissue. This suggests that the dynamics of the probe in vivo can be examined.
  • n 60 and is 13 C / 15 N-PMPC (molecular weight: 18000) of the formula (p2) heavy water solution (in 13 C / 15 N-PMPC in solution concentration of: 0.7 [mu] M, 0.1 [mu] M , 0.07 ⁇ M, or 0.03 ⁇ M), a heavy aqueous solution of 13 C / 15 N-PMPC (molecular weight 12000) in which n in the formula (p2) is 40 ( 13 C / 15 N-PMPC in solution) Concentration: 0.6 ⁇ M, 0.1 ⁇ M, 0.06 ⁇ M, or 0.03 ⁇ M), 13 C / 15 N-PMPC (molecular weight 10,000) of heavy aqueous solution ( 13 C / in solution) where n in formula (p2) is 33 15 concentration of n-PMPC: 0.5 ⁇ M, 0.1 ⁇ M, 0.05 ⁇ M or 0.025 uM) or formula (j1) (wherein n is equivalent to the case 1 of the formula (p2)
  • FIG. 10 shows the relationship between the concentration of 13 C / 15 N-PMPC and the signal-to-noise ratio.
  • the black rectangle is 13 C / 15 N-PMPC (molecular weight 18000) where n in the formula (p2) is 60
  • the black square is 13 C / 15 N-PMPC (molecular weight where n is 40 in the formula (p2)) 12000
  • the black triangle is 13 C / 15 N-PMPC (molecular weight: 10000) where n in the formula (p2) is 33
  • the black circle is the formula (j1) equivalent to the case where n is 1 in the formula (p2)
  • the probe is composed of naturally occurring nuclei that do not generate radiation, and has a bond having a sequence with a low abundance in living bodies.
  • the multinuclear multiple magnetic resonance imaging method of the present invention using such a probe is In addition, with only one modality of multiple magnetic resonance imaging apparatus, not only the morphology information of the specimen but also the position information of the probe in the specimen is obtained, and the function of the probe in the living body, the metabolic reaction via the probe in the living body Can be visualized, and is expected to be used for diagnostic imaging that is accurate and has a low load on the specimen. In addition, the multinuclear multiple magnetic resonance imaging apparatus of the present invention obtains not only the morphology information of the specimen but also the positional information of the probe in the specimen, and the function of the probe in the living body, the metabolic reaction via the probe in the living body. Therefore, it is expected to be used for diagnostic imaging that is accurate and has a low load on the specimen.

Landscapes

  • Physics & Mathematics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

A polynuclear and multiple magnetic resonance imaging method for detecting and imaging a multiple resonance signal caused by a probe in a subject comprising: (A) a step for applying a probe composed of a compound having a bond of at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1H, 13C, and 15N; and (B) a step for irradiating the subject to which the probe is applied in the step (A) with an electromagnetic wave to perform magnetization transfer between the respective nuclei in the bond of the probe, and using the magnetization transfer to detect the multiple resonance signal caused by the probe, and a device used for this method.

Description

[規則37.2に基づきISAが決定した発明の名称]　多核多重磁気共鳴画像化方法および画像化装置[Name of Invention Determined by ISA Based on Rule 37.2] Multinuclear Multiple Magnetic Resonance Imaging Method and Imaging Apparatus
　本発明は、多核多重磁気共鳴画像化方法に関する。さらに詳しくは、疾患の診断を行なうための画像情報の取得などに有用な多核多重磁気共鳴画像化方法および多核多重磁気共鳴画像化装置に関する。
　本発明の多核多重磁気共鳴画像化方法は、放射線を発生しない天然に存在する原子核から構成されたプローブが用いられており、しかも多重磁気共鳴画像化装置という１つのモダリティのみで、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができることから、正確で、かつ検体の負荷が少ない画像診断に使用されることが期待されるものである。また、本発明の多核多重磁気共鳴画像化装置は、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができることから、正確で、かつ検体の負荷が少ない画像診断に使用されることが期待されるものである。 The present invention relates to a multinuclear multiple magnetic resonance imaging method. More particularly, the present invention relates to a multinuclear multiple magnetic resonance imaging method and a multinuclear multiple magnetic resonance imaging apparatus useful for acquiring image information for diagnosing diseases.
The multinuclear multiple magnetic resonance imaging method of the present invention uses a probe composed of naturally occurring atomic nuclei that do not generate radiation, and the morphological information of the specimen only with one modality of the multiple magnetic resonance imaging apparatus. As well as obtaining the positional information of the probe in the sample and visualizing the function of the probe in vivo and the metabolic reaction via the probe in vivo, it is accurate and has a low sample load. It is expected to be used for diagnostic imaging. In addition, the multinuclear multiple magnetic resonance imaging apparatus of the present invention obtains not only the morphology information of the specimen but also the positional information of the probe in the specimen, and the function of the probe in the living body, the metabolic reaction via the probe in the living body. Therefore, it is expected to be used for diagnostic imaging that is accurate and has a low specimen load.
　１Ｈの核磁気共鳴現象を利用する磁気共鳴画像化方法（以下、「１Ｈ－ＭＲＩ」ともいう）は、放射線を用いる必要がなく、かつ非侵襲的に生体の内部組織または内部構造の磁気共鳴画像を撮像することができ、しかも生体の深部の組織または構造を画像化することができるので、広く臨床現場で利用されている。しかし、１Ｈ－ＭＲＩには、観測周波数の幅が狭く、複数の１Ｈのシグナルが重なって検出されるという欠点がある。 A magnetic resonance imaging method (hereinafter, also referred to as “ 1 H-MRI”) using the 1 H nuclear magnetic resonance phenomenon does not require the use of radiation, and non-invasively magnetizes the internal tissue or internal structure of a living body. Since a resonance image can be taken and a tissue or structure in a deep part of a living body can be imaged, it is widely used in clinical settings. However, 1 H-MRI has a drawback that the observation frequency is narrow and a plurality of 1 H signals are detected in an overlapping manner.
　一方、複数の原子核の核磁気共鳴現象を利用する二重核磁気共鳴法（以下、「二重共鳴ＮＭＲ」ともいう）は、異なるラーモア周波数を有する隣接した核磁気共鳴活性核の間で磁化（コヒーレンス）を移動させる手法であり、タンパク質および核酸の高次構造解析に利用されている（例えば、非特許文献１参照）。また、二重共鳴ＮＭＲは、磁気共鳴スペクトロスコピーイメージングに応用されており、例えば、猫の脳への｛１－１３Ｃ｝－グルコースの取り込みおよびその代謝産物の検出に用いられている（例えば、非特許文献２参照）。前記方法によれば、生体内の水のシグナルを消去することができる。しかし、前記方法には、｛１－１３Ｃ｝－グルコースの化学シフト値が内在性の１３Ｃ－脂質（天然存在比１．１％）のケミカルシフト値と重なって検出されるため、｛１－１３Ｃ｝－グルコースのみを選択的に観測することが困難であるという欠点がある。 On the other hand, a double nuclear magnetic resonance method (hereinafter, also referred to as “double resonance NMR”) that utilizes the nuclear magnetic resonance phenomenon of a plurality of nuclei is a method in which magnetization is performed between adjacent nuclear magnetic resonance active nuclei having different Larmor frequencies ( This is a technique for moving (coherence) and is used for higher-order structure analysis of proteins and nucleic acids (see, for example, Non-Patent Document 1). In addition, double resonance NMR has been applied to magnetic resonance spectroscopy imaging, and is used, for example, for the incorporation of {1- 13 C} -glucose into the cat brain and the detection of its metabolites (for example, Non-patent document 2). According to the method, the water signal in the living body can be erased. However, in the above method, the chemical shift value of {1- 13 C} -glucose is detected by overlapping with the chemical shift value of endogenous 13 C-lipid (natural abundance ratio 1.1%). There is a drawback that it is difficult to selectively observe only 13 C} -glucose.
　本発明は、前記従来技術に鑑みてなされたものであり、生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを正確で、かつ生体に対して低負荷で可視化することができる多核多重磁気共鳴画像化方法および多核多重磁気共鳴画像化装置を提供することを課題とする。 The present invention has been made in view of the above-described prior art, and visualizes the function of a probe in a living body, a metabolic reaction via a probe in a living body, and the like with a low load on the living body. It is an object of the present invention to provide a multinuclear multiple magnetic resonance imaging method and a multinuclear multiple magnetic resonance imaging apparatus.
　本発明は、
〔１〕検体中のプローブに起因する多重共鳴シグナルを検出して画像化する多核多重磁気共鳴画像化方法であって、
（Ａ）１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブを検体に付与するステップ、および
（Ｂ）　前記ステップ（Ａ）でプローブが付与された前記検体に電磁波を照射して前記プローブの前記結合中の各核の間での磁化移動を行ない、当該磁化移動を利用して前記プローブに起因する多重共鳴シグナルを検出するステップ
を含むことを特徴とする多核多重磁気共鳴画像化方法、
〔２〕前記プローブとして、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合または１Ｈ－１３Ｃ－１３Ｃ結合を有する化合物からなるプローブと、前記結合に基づく三重核磁気共鳴法および磁気共鳴撮像法の各パルス系列とを用いて前記プローブに起因する多重共鳴シグナルを検出する前記〔１〕に記載の多核多重磁気共鳴画像化方法、
〔３〕前記プローブが、
　式（ｘ１）～（ｘ３）： The present invention
[1] A multinuclear multiple magnetic resonance imaging method for detecting and imaging multiple resonance signals caused by probes in a specimen,
(A) a bond comprising at least two nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and comprising at least three nuclear magnetic resonance active nuclei having different resonance frequencies; And (B) magnetizing transfer between the nuclei during the binding of the probe by irradiating the specimen to which the probe has been applied in step (A) with an electromagnetic wave. Performing a multi-nuclear multiple magnetic resonance imaging method comprising the step of detecting a multiple resonance signal caused by the probe using the magnetization movement,
[2] A probe comprising a compound having a 1 H- 13 C- 15 N bond, a 1 H- 15 N- 13 C bond, or a 1 H- 13 C- 13 C bond as a probe, and a triple nucleus based on the bond The multinuclear multiple magnetic resonance imaging method according to [1], wherein a multiple resonance signal caused by the probe is detected using each pulse sequence of a magnetic resonance method and a magnetic resonance imaging method,
[3] The probe is
Formulas (x1) to (x3):
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
（式中、Ｒ１～Ｒ４はそれぞれ独立して水素原子または置換基を有していてもよい炭素数１～９の炭化水素基、Ｒ５は置換基を有していてもよい炭素数１～４の炭化水素基、＊は側鎖に直接またはリンカーを介して結合する。ただし、Ｒ5が炭素数２～４の炭化水素基である場合、当該炭化水素基中の少なくとも１つの炭素原子が前記側鎖に直接またはリンカーを介して結合する）
で表わされる繰返し単位からなる群より選ばれた少なくとも１種の繰返し単位を含む重合度が１～５０００の主鎖を有し、かつ前記側鎖として式（ｙ１）～（ｙ３）： (Wherein R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent, and R 5 is a carbon number optionally having a substituent) 1 to 4 hydrocarbon group, * is bonded to the side chain directly or via a linker, provided that when R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one carbon in the hydrocarbon group Atoms are attached to the side chain directly or via a linker)
Having a main chain having a degree of polymerization of 1 to 5000 containing at least one repeating unit selected from the group consisting of repeating units represented by formulas (y1) to (y3):
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
〔式中、Ｒ６は直接結合または置換基を有していてもよい炭素数１～４の炭化水素基、Ｚは１価の官能基を示し、＊は前記式（ｘ１）～（ｘ３）における＊に直接またはリンカーを介して結合する〕
で表わされる官能基からなる群より選ばれた少なくとも１種の官能基を有する化合物である前記〔１〕または〔２〕に記載の多核多重磁気共鳴画像化方法、
〔４〕前記側鎖が、式（ｙ１）または（ｙ２）で表わされる官能基であり、前記式（ｙ１）または（ｙ２）におけるＺが式（ｚ１）：
＊－１５ＮＨ２　　（ｚ１）
〔式中、＊は前記式（ｙ１）または（ｙ２）で表わされる官能基に結合する結合手を示す〕
で表わされる官能基である前記〔３〕に記載の多核多重磁気共鳴画像化方法、
〔５〕前記式（ｙ１）～（ｙ３）におけるＺが式（ｚ２）～（ｚ４）：
＊－１３ＣＨ３　　（ｚ２） [Wherein R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent, Z represents a monovalent functional group, and * represents the above formulas (x1) to (x3) (Directly or via a linker)
The multinuclear multiple magnetic resonance imaging method according to the above [1] or [2], which is a compound having at least one functional group selected from the group consisting of functional groups represented by:
[4] The side chain is a functional group represented by the formula (y1) or (y2), and Z in the formula (y1) or (y2) is represented by the formula (z1):
* - 15 NH 2 (z1)
[Wherein, * represents a bond bonded to the functional group represented by the formula (y1) or (y2)]
The multinuclear multiple magnetic resonance imaging method according to the above [3], which is a functional group represented by
[5] Z in the formulas (y1) to (y3) represents formulas (z2) to (z4):
* - 13 CH 3 (z2)
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
〔式中、＊は前記式（ｙ１）～（ｙ３）で表わされる官能基に結合する結合手、ｄは１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい〕
で表される前記〔３〕に記載の多核多重磁気共鳴画像化方法、
〔６〕前記リンカーが、置換基を有していてもよい炭素数１～４の炭化水素基および式（ｌ１）～（ｌ３）： [In the formula, * represents a bond bonded to the functional group represented by the formulas (y1) to (y3), d represents an integer of 1 to 4, and the hydrogen atom of the methylene group is substituted with another atom. (May be)
The multinuclear multiple magnetic resonance imaging method according to the above [3] represented by:
[6] The linker may have a substituent and may have a hydrocarbon group having 1 to 4 carbon atoms and formulas (l1) to (l3):
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
〔式中、Ｌ’は置換基を有していてもよい炭素数１～４の炭化水素基または式（ｌ’）：
Figure JPOXMLDOC01-appb-C000021
[In the formula, L ′ represents an optionally substituted hydrocarbon group having 1 to 4 carbon atoms or a formula (l ′):
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
（式中、ａおよびｂはそれぞれ独立して１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい）
で表わされる官能基を示し、＊は前記式（ｘ１）～（ｘ３）における＊または前記式（ｙ１）～（ｙ３）における＊に結合する〕
で表わされる官能基からなる群より選ばれた少なくとも１種の官能基である前記〔３〕～〔５〕のいずれかに記載の多核多重磁気共鳴画像化方法、
〔７〕前記主鎖と側鎖とがリンカーを介して結合しており、前記リンカーと前記側鎖とからなる構造が、式（ｙ５）～（ｙ７）： (Wherein, a and b each independently represent an integer of 1 to 4, and the hydrogen atom of the methylene group may be substituted with another atom)
Wherein * is bonded to * in the above formulas (x1) to (x3) or * in the above formulas (y1) to (y3).
The multinuclear multiple magnetic resonance imaging method according to any one of the above [3] to [5], which is at least one functional group selected from the group consisting of functional groups represented by:
[7] The main chain and the side chain are bonded via a linker, and the structure consisting of the linker and the side chain has the formulas (y5) to (y7):
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
〔式中、＊は前記式（ｘ１）～（ｘ３）における＊に結合する結合手、ａおよびｂはそれぞれ独立して１～４の整数を示し、式（ｙ５）～（ｙ７）中のメチレン基の水素原子は他の原子で置換されていてもよい〕
で表わされる構造からなる群より選ばれた構造である前記〔３〕に記載の多核多重磁気共鳴画像化方法、
〔８〕前記主鎖が、（メタ）アクリレートモノマーに由来する繰返し単位、（メタ）アクリルアミドモノマーに由来する繰り返し単位、アミノ酸モノマーに由来する繰返し単位およびヒドロキシ酸モノマーに由来する繰返し単位からなる群より選ばれた繰返し単位をさらに有する前記〔３〕～〔７〕のいずれかに記載の多核多重磁気共鳴画像化方法、
〔９〕前記主鎖が、式（ａ１）～（ａ３）：
Figure JPOXMLDOC01-appb-C000025
[In the formula, * represents a bond bonded to * in the formulas (x1) to (x3), a and b each independently represents an integer of 1 to 4, and methylene in the formulas (y5) to (y7) The hydrogen atom of the group may be substituted with another atom)
The multinuclear multiple magnetic resonance imaging method according to the above [3], which is a structure selected from the group consisting of structures represented by:
[8] From the group consisting of a repeating unit derived from a (meth) acrylate monomer, a repeating unit derived from a (meth) acrylamide monomer, a repeating unit derived from an amino acid monomer, and a repeating unit derived from a hydroxy acid monomer. The multinuclear multiple magnetic resonance imaging method according to any one of the above [3] to [7], further comprising a selected repeating unit,
[9] The main chain is represented by formulas (a1) to (a3):
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000028
（式中、Ｒ1～Ｒ５は前記と同じ。Ｒ７は水素原子または置換基を有していてもよい炭素数１～６の炭化水素基を示す）
で表わされる繰返し単位からなる群より選ばれた繰返し単位をさらに有する前記〔３〕～〔７〕のいずれかに記載の多核多重磁気共鳴画像化方法、
〔１０〕前記繰り返し単位の末端に、炭素数１～１２のアルキル基、炭素数２～１２のアルケニル基、炭素数２～４のアルキニル基、水酸基、チオール基、アミノ基、アジド基、マレイミド基、Ｎ－ヒドロキシスクシンイミド基およびトリクロロシリル基のいずれかの官能基を有する前記〔３〕～〔９〕のいずれかに記載の多核多重磁気共鳴画像化方法、
〔１１〕前記重合体の繰り返し単位の末端に有する官能基に、標的部位に特異的に結合する捕捉分子が結合されてなる前記〔１０〕に記載の多核多重磁気共鳴画像化方法、
〔１２〕検体中のプローブに起因する多重共鳴シグナルを検出して画像化するための多核多重磁気共鳴画像化装置であって、
　前記プローブが、１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブであり、
　前記結合に含まれる少なくとも３個の核磁気共鳴活性核それぞれの共鳴周波数に相当するＲＦパルスを印加するパルス印加部と、
　前記プローブに勾配磁場を印加する勾配磁場印加部と、
　前記結合に含まれる核磁気共鳴活性核それぞれの磁気共鳴信号を検出する検出部と、
　所定のパルス系列が生成されるように前記パルス印加部と前記勾配磁場印加部とを制御する制御部と
を備えており、
　前記所定のパルス系列が、
　前記結合に含まれる各核磁気共鳴活性核間の磁化移動を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、
　前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列と
を含むことを特徴とする多核多重磁気共鳴画像化装置、
〔１３〕前記プローブが、第１核磁気共鳴活性核と当該第１核磁気共鳴活性核に磁気的に結合した第２核磁気共鳴活性核と当該第２核磁気共鳴活性核に磁気的に結合した第３核磁気共鳴活性核とからなる結合を有する化合物からなるプローブであり、
　前記第１核磁気共鳴活性核に当該第１核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第１パルス印加部と、
　前記第２核磁気共鳴活性核に当該第２核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第２パルス印加部と、
　前記第３核磁気共鳴活性核に当該第３核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第３パルス印加部と、
　前記プローブに勾配磁場を印加する勾配磁場印加部と、
　前記第１核磁気共鳴活性核、前記第２核磁気共鳴活性核および前記第３核磁気共鳴活性核からなる群より選ばれた少なくとも１つの核磁気共鳴活性核の磁気共鳴信号を検出する検出部と、
　所定のパルス系列が生成されるように前記第１パルス印加と前記第２パルス印加部と前記第３パルス印加部と前記勾配磁場印加部とを制御する制御部と
を備えており、
　前記所定のパルス系列が、
　前記第１核磁気共鳴活性核から第２核磁気共鳴活性核への磁化移動を行なった後、前記第２核磁気共鳴活性核から第３核磁気共鳴活性核への磁化移動を行ない、さらに前記第３核磁気共鳴活性核から前記第２核磁気共鳴活性核を経て前記第１核磁気共鳴活性核への磁化を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、
　前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列と
を含む、〔１２〕に記載の多核多重磁気共鳴画像化装置。
〔１４〕前記磁化移動パルス系列は、前記制御部によって下記（ａ１）～（ａ１６）：
　（ａ１）前記第１核磁気共鳴活性核に９０度の第１ＲＦパルスを印加した後、当該第１核磁気共鳴活性核に１８０度の第２ＲＦパルスをさらに印加するステップ、
　（ａ２）前記第２ＲＦパルスを印加すると同時または印加した後、前記第２核磁気共鳴活性核に１８０度の第３ＲＦパルスを印加するステップ、
　（ａ３）前記第１核磁気共鳴活性核に９０度の第４ＲＦパルスを印加した後、前記第２核磁気共鳴活性核に９０度の第５ＲＦパルスを印加するステップ、
　（ａ４）前記第２核磁気共鳴活性核に１８０度の第６ＲＦパルスを印加するステップ、
　（ａ５）前記第６ＲＦパルスを印加すると同時または印加した後、前記第３核磁気共鳴活性核に１８０度の第７ＲＦパルスを印加するステップ、
　（ａ６）前記第２核磁気共鳴活性核に９０度の第８ＲＦパルスを印加した後、前記第３核磁気共鳴活性核に９０度の第９ＲＦパルスを印加するステップ、
　（ａ７）前記第２核磁気共鳴活性核に１８０度の第１０ＲＦパルスを印加するステップ、
　（ａ８）前記第１核磁気共鳴活性核に１８０度の第１１ＲＦパルスと前記第３核磁気共鳴活性核に１８０度の第１２ＲＦパルスとを同時に印加するステップ、
　（ａ９）前記第２核磁気共鳴活性核に１８０度の第１３ＲＦパルスを印加するステップ、
　（ａ１０）前記第３核磁気共鳴活性核に９０度の第１４ＲＦパルスを印加するステップ、
　（ａ１１）前記第２核磁気共鳴活性核に９０度の第１５ＲＦパルスを印加するステップ、
　（ａ１２）前記第２核磁気共鳴活性核に１８０度の第１６ＲＦパルスを印加するステップ、
　（ａ１３）前記第１６ＲＦパルスと同時または印加後に、前記第３核磁気共鳴活性核に１８０度の第１７ＲＦパルスを印加するステップ、
　（ａ１４）前記第２核磁気共鳴活性核に９０度の第１８ＲＦパルスを印加した後、前記第１核磁気共鳴活性核に９０度の第１９ＲＦパルスを印加するステップ、および
　（ａ１５）前記第１核磁気共鳴活性核に１８０度の第２０ＲＦパルスを印加するステップ、
　（ａ１６）前記第２０ＲＦパルスを印加すると同時または印加後に、前記第２核磁気共鳴活性核に１８０度の第２１ＲＦパルスを印加するステップ
がこの順に実行されることによって生成されるＲＦパルス印加系列と、前記制御部によって下記（ｂ１）～（ｂ１２）：
　（ｂ１）前記第１ＲＦパルスと前記第２ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ２）前記第３ＲＦパルスと前記第４ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ３）前記第４ＲＦパルスと前記第５ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ４）前記第８ＲＦパルスと前記第９ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ５）前記第９ＲＦパルスと前記第１０ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ６）前記第１０ＲＦパルスと前記第１１ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ７）前記第１２ＲＦパルスと前記第１３ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ８）前記第１３ＲＦパルスと前記第１４ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ９）前記第１４ＲＦパルスと前記第１５ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ１０）前記第１８ＲＦパルスと前記第１９ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ１１）前記第１９ＲＦパルスと前記第２０ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、および
　（ｂ１２）前記第２１ＲＦパルスの印加後において、前記プローブに勾配磁場を印加するステップ
がこの順に実行されることによって生成される勾配磁場印加系列と
を含む、前記〔１３〕に記載の多核多重磁気共鳴画像化装置
に関する。
Figure JPOXMLDOC01-appb-C000028
(In the formula, R 1 to R 5 are the same as above. R 7 represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may have a substituent.)
The multinuclear multiple magnetic resonance imaging method according to any one of [3] to [7], further comprising a repeating unit selected from the group consisting of repeating units represented by:
[10] At the terminal of the repeating unit, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a hydroxyl group, a thiol group, an amino group, an azide group, and a maleimide group , The multinuclear multiple magnetic resonance imaging method according to any one of the above [3] to [9], which has any functional group of N-hydroxysuccinimide group and trichlorosilyl group,
[11] The multinuclear multiple magnetic resonance imaging method according to [10], wherein a capture molecule that specifically binds to a target site is bound to a functional group at the terminal of the repeating unit of the polymer,
[12] A multinuclear multiple magnetic resonance imaging apparatus for detecting and imaging multiple resonance signals caused by probes in a specimen,
The probe has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C, and 15 N, and is composed of at least three nuclear magnetic resonance active nuclei having different resonance frequencies. A probe comprising a compound having
A pulse applying unit for applying an RF pulse corresponding to a resonance frequency of each of at least three nuclear magnetic resonance active nuclei included in the coupling;
A gradient magnetic field application unit for applying a gradient magnetic field to the probe;
A detection unit for detecting a magnetic resonance signal of each of the nuclear magnetic resonance active nuclei included in the binding;
A control unit that controls the pulse application unit and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
The predetermined pulse sequence is
A magnetization transfer pulse sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization transfer between each nuclear magnetic resonance active nucleus included in the coupling; and
A multi-nuclear multiple magnetic resonance imaging apparatus comprising: a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal;
[13] The probe is magnetically coupled to the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus magnetically coupled to the first nuclear magnetic resonance active nucleus, and the second nuclear magnetic resonance active nucleus. A probe comprising a compound having a bond comprising the third nuclear magnetic resonance active nucleus,
A first pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus;
A second pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the second nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus;
A third pulse applying unit for applying an RF pulse corresponding to the resonance frequency of the third nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus;
A gradient magnetic field application unit for applying a gradient magnetic field to the probe;
A detector for detecting a magnetic resonance signal of at least one nuclear magnetic resonance active nucleus selected from the group consisting of the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus, and the third nuclear magnetic resonance active nucleus When,
A control unit that controls the first pulse application, the second pulse application unit, the third pulse application unit, and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
The predetermined pulse sequence is
After performing the magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus, performing the magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus, In order to perform magnetization transfer by applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization from the third nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus through the second nuclear magnetic resonance active nucleus. A magnetization transfer pulse sequence of
The multinuclear multiple magnetic resonance imaging apparatus according to [12], further comprising: a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal.
[14] The magnetization transfer pulse sequence is the following (a1) to (a16):
(A1) applying a first RF pulse of 90 degrees to the first nuclear magnetic resonance active nucleus, and further applying a second RF pulse of 180 degrees to the first nuclear magnetic resonance active nucleus;
(A2) applying a third RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus simultaneously with or after applying the second RF pulse;
(A3) applying a 90 degree fourth RF pulse to the first nuclear magnetic resonance active nucleus and then applying a 90 degree fifth RF pulse to the second nuclear magnetic resonance active nucleus;
(A4) applying a 180 ° sixth RF pulse to the second nuclear magnetic resonance active nucleus;
(A5) applying a seventh RF pulse of 180 degrees to the third nuclear magnetic resonance active nucleus simultaneously with or after applying the sixth RF pulse;
(A6) applying a 90-degree ninth RF pulse to the third nuclear magnetic resonance active nucleus after applying a 90-degree eighth RF pulse to the second nuclear magnetic resonance active nucleus;
(A7) applying a 180 degree tenth RF pulse to the second nuclear magnetic resonance active nucleus;
(A8) applying a 180 degree eleventh RF pulse to the first nuclear magnetic resonance active nucleus and a 180 degree twelfth RF pulse simultaneously to the third nuclear magnetic resonance active nucleus;
(A9) applying a 13th RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus;
(A10) applying a 14th RF pulse of 90 degrees to the third nuclear magnetic resonance active nucleus;
(A11) applying a 90 degree 15th RF pulse to the second nuclear magnetic resonance active nucleus;
(A12) applying a 180 degree sixteenth RF pulse to the second nuclear magnetic resonance active nucleus;
(A13) applying a 180 degree 17th RF pulse to the third nuclear magnetic resonance active nucleus simultaneously with or after the application of the 16th RF pulse;
(A14) applying a 90 degree 18th RF pulse to the second nuclear magnetic resonance active nucleus and then applying a 90 degree 19th RF pulse to the first nuclear magnetic resonance active nucleus; and (a15) the first nuclear magnetic resonance active nucleus Applying a 180 degree 20th RF pulse to the nuclear magnetic resonance active nucleus;
(A16) An RF pulse application sequence generated by performing a step of applying a 21st RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus in this order simultaneously with or after the application of the 20th RF pulse; The control unit performs the following (b1) to (b12):
(B1) applying a gradient magnetic field to the probe in the interval between the first RF pulse and the second RF pulse;
(B2) applying a gradient magnetic field to the probe in the interval between the third RF pulse and the fourth RF pulse;
(B3) applying a gradient magnetic field to the probe in an interval between the fourth RF pulse and the fifth RF pulse;
(B4) applying a gradient magnetic field to the probe in the interval between the eighth RF pulse and the ninth RF pulse;
(B5) applying a gradient magnetic field to the probe in the interval between the ninth RF pulse and the tenth RF pulse;
(B6) applying a gradient magnetic field to the probe in the interval between the tenth RF pulse and the eleventh RF pulse;
(B7) applying a gradient magnetic field to the probe in the interval between the twelfth RF pulse and the thirteenth RF pulse;
(B8) applying a gradient magnetic field to the probe in an interval between the thirteenth RF pulse and the fourteenth RF pulse;
(B9) applying a gradient magnetic field to the probe in an interval between the 14th RF pulse and the 15th RF pulse;
(B10) applying a gradient magnetic field to the probe in the interval between the 18th RF pulse and the 19th RF pulse;
(B11) applying a gradient magnetic field to the probe in the interval between the 19th RF pulse and the 20th RF pulse; and (b12) applying a gradient magnetic field to the probe after applying the 21st RF pulse. The multi-nuclear multiple magnetic resonance imaging apparatus according to [13], including a gradient magnetic field application sequence generated by being executed in this order.
　本発明の多核多重磁気共鳴画像化方法および多核多重磁気共鳴画像化装置は、生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを正確で、かつ生体に対して低負荷で可視化することができるという優れた効果を奏する。 The multinuclear multiple magnetic resonance imaging method and multinuclear multiple magnetic resonance imaging apparatus of the present invention are accurate in terms of the function of the probe in vivo, the metabolic reaction via the probe in vivo, and the load on the living body is low. It has an excellent effect that it can be visualized with.
実施例１において、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法で用いられたパルス系列を示す図である。In Example 1, a diagram illustrating a pulse sequence used in the 1 H- {13 C- 15 N} triple magnetic resonance imaging method. （ａ）は実験例１において、１Ｈ－磁気共鳴画像を撮像した結果を示す図面代用写真、（ｂ）は１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｃ）は１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｄ）は（ａ）～（ｃ）の各画像における各試料の配置図である。(A) is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Experimental Example 1, and (b) is a drawing-substituting photograph showing the result of imaging a 1 H- { 13 C} double magnetic resonance image. , (C) is a drawing-substituting photograph showing the result of imaging a 1 H- { 13 C- 15 N} triple magnetic resonance image, and (d) is a layout of each sample in each of the images (a) to (c). is there. （ａ）は実験例２において、１Ｈ－磁気共鳴画像を撮像した結果を示す図面代用写真、（ｂ）は１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｃ）は１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｄ）は（ａ）～（ｃ）の各画像における各試料の配置図である。(A) is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Experimental Example 2, and (b) is a drawing-substituting photograph showing the result of imaging a 1 H- { 13 C} double magnetic resonance image. , (C) is a drawing-substituting photograph showing the result of imaging a 1 H- { 13 C- 15 N} triple magnetic resonance image, and (d) is a layout of each sample in each of the images (a) to (c). is there. （ａ）は実験例３において、１Ｈ－磁気共鳴画像を撮像した結果を示す図面代用写真、（ｂ）は１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｃ）は１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｄ）は（ａ）～（ｃ）の各画像における各試料の配置図である。(A) is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Experimental Example 3, and (b) is a drawing-substituting photograph showing the result of imaging a 1 H- { 13 C} double magnetic resonance image. , (C) is a drawing-substituting photograph showing the result of imaging a 1 H- { 13 C- 15 N} triple magnetic resonance image, and (d) is a layout of each sample in each of the images (a) to (c). is there. （ａ）は実施例１において、１Ｈ－磁気共鳴画像を撮像した結果を示す図面代用写真、（ｂ）は１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｃ）は１Ｈ－磁気共鳴画像と１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像とを重ね合わせた結果を示す図面代用写真である。(A) is a drawing-substituting photograph showing the result of taking a 1 H-magnetic resonance image in Example 1, and (b) is a drawing showing the result of taking a 1 H- { 13 C- 15 N} triple magnetic resonance image. A substitute photograph (c) is a drawing substitute photograph showing the result of superimposing the 1 H-magnetic resonance image and the 1 H- { 13 C- 15 N} triple magnetic resonance image. 実施例１において、癌組織の１３Ｃ－磁気共鳴スペクトルを示すチャートである。In Example 1, it is the chart which shows the 13 C-magnetic resonance spectrum of the cancer tissue. （ａ）は実施例２において、１Ｈ－磁気共鳴画像を撮像した結果を示す図面代用写真、（ｂ）は１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を示す図面代用写真、（ｃ）は１Ｈ－磁気共鳴画像と１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像とを重ね合わせた結果を示す図面代用写真である。(A) is a drawing-substituting photograph showing the result of imaging a 1 H-magnetic resonance image in Example 2, and (b) is a drawing showing the result of imaging a 1 H- { 13 C- 15 N} triple magnetic resonance image. A substitute photograph (c) is a drawing substitute photograph showing the result of superimposing the 1 H-magnetic resonance image and the 1 H- { 13 C- 15 N} triple magnetic resonance image. 実施例３で得られた各組織の１Ｈ－｛１３Ｃ－１５Ｎ｝－ＮＭＲスペクトルを示すチャートである。4 is a chart showing 1 H- { 13 C- 15 N} -NMR spectrum of each structure obtained in Example 3. 実施例３において、各組織における１３Ｃ／１５Ｎ－ＰＭＰＣの蓄積量を調べた結果を示すグラフである。In Example 3, it is a graph which shows the result of having investigated the accumulation amount of 13 C / 15 N-PMPC in each structure | tissue. 実施例４において、１３Ｃ／１５Ｎ－ＰＭＰＣの濃度と信号対雑音比との関係を示すグラフである。In Example 4, it is a graph which shows the relationship between the density | concentration of 13 C / 15 N-PMPC, and a signal to noise ratio. 本発明の一実施形態に係る多核多重磁気共鳴画像化装置の機能構成を示すブロック図である。It is a block diagram which shows the function structure of the multinuclear multiple magnetic resonance imaging apparatus which concerns on one Embodiment of this invention. 本発明の一実施形態に係る多核多重磁気共鳴画像化装置におけるパルス系列を示す概略説明図である。It is a schematic explanatory drawing which shows the pulse series in the multinuclear multiple magnetic resonance imaging apparatus which concerns on one Embodiment of this invention. 本発明の一実施形態に係る多核多重磁気共鳴画像化装置におけるパルス系列の変形例を示す概略説明図である。It is a schematic explanatory drawing which shows the modification of the pulse series in the multinuclear multiple magnetic resonance imaging apparatus which concerns on one Embodiment of this invention. 本発明の他の実施形態に係る多核多重磁気共鳴画像化装置の機能構成を示すブロック図である。It is a block diagram which shows the function structure of the multinuclear multiple magnetic resonance imaging apparatus which concerns on other embodiment of this invention.
１．多核多重磁気共鳴画像化方法
　本発明の多核多重磁気共鳴画像化方法は、検体中のプローブに起因する多重共鳴シグナルを検出して画像化する多核多重磁気共鳴画像化方法であって、
（Ａ）１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブを検体に付与するステップ、および
（Ｂ）　前記ステップ（Ａ）でプローブが付与された前記検体に電磁波を照射して前記プローブの前記結合中の各核の間での磁化移動を行ない、当該磁化移動を利用して前記プローブに起因する多重共鳴シグナルを検出するステップ
を含むことを特徴としている。 1. Multinuclear multiple magnetic resonance imaging method The multinuclear multiple magnetic resonance imaging method of the present invention is a multinuclear multiple magnetic resonance imaging method for detecting and imaging a multiple resonance signal caused by a probe in a specimen,
(A) a bond comprising at least two nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and comprising at least three nuclear magnetic resonance active nuclei having different resonance frequencies; And (B) magnetizing transfer between the nuclei during the binding of the probe by irradiating the specimen to which the probe has been applied in step (A) with an electromagnetic wave. And a step of detecting a multiple resonance signal caused by the probe using the magnetization movement.
　本発明の多核多重磁気共鳴画像化方法は、前記プローブを検体に付与し、前記結合中の各核の間での磁化移動を利用して前記プローブに起因する多重共鳴シグナルを検出する点に１つの大きな特徴を有する。前記プローブは、放射線を発生しない天然に存在する原子核から構成され、しかも生体における存在率が低い配列を有する結合を有している。そのため、本発明の多核多重磁気共鳴画像化方法によれば、生体由来の夾雑物に起因するシグナルの検出を排除することができ、前記プローブのシグナルを選択的に検出することができる。また、本発明の多核多重磁気共鳴画像化方法によれば、前記プローブが用いられているので、多重磁気共鳴画像化装置という１つのモダリティのみで、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができる。したがって、本発明の多核多重磁気共鳴画像化方法によれば、生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを正確で、かつ生体に対して低負荷で可視化することができる。 The multinuclear multiple magnetic resonance imaging method of the present invention is characterized in that the probe is applied to a specimen and a multiple resonance signal caused by the probe is detected using magnetization transfer between the nuclei in the binding. It has two major features. The probe is composed of naturally occurring nuclei that do not generate radiation, and has a bond having a sequence with a low abundance in living organisms. Therefore, according to the multinuclear multiple magnetic resonance imaging method of the present invention, it is possible to eliminate the detection of signals due to contaminants derived from living organisms, and to selectively detect the signal of the probe. Further, according to the multinuclear multiple magnetic resonance imaging method of the present invention, since the probe is used, not only the morphology information of the specimen but also the probe in the specimen with only one modality of the multiple magnetic resonance imaging apparatus. It is possible to visualize the function of the probe in vivo, the metabolic reaction via the probe in vivo, and the like. Therefore, according to the multinuclear multiple magnetic resonance imaging method of the present invention, the function of the probe in the living body, the metabolic reaction through the probe in the living body, and the like can be visualized accurately and with a low load on the living body. Can do.
（プローブ）
　本発明の多核多重磁気共鳴画像化方法に用いられるプローブは、１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する。前記核磁気共鳴活性核は、放射線を発生しない天然に存在する核磁気共鳴活性な原子核である。前記結合は、前記核磁気共鳴活性核のうちの少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる。かかる結合では、少なくとも３個の核磁気共鳴活性核の間での磁化移動によって多重共鳴を起こすことができる。なお、少なくとも３個の核磁気共鳴活性核からなる結合においては、例えば、Ａ１－Ａ２－Ｂ結合（Ａ１およびＡ２は同じ種類の核磁気共鳴活性核、ＢはＡ１およびＡ２と異なる種類の核磁気共鳴活性核を示す）のように同じ種類の核磁気共鳴活性核（Ａ１，Ａ２）が２個隣接していても、これらの核と結合する他の核磁気共鳴活性核の種類が異なる場合には、核磁気共鳴活性核（Ａ１，Ａ２）のそれぞれ共鳴周波数は互いに異なる。したがって、前記結合は、同じ種類の核磁気共鳴活性核を２個以上有していてもこれらの核が互いに異なる共鳴周波数を有するように連結されたものであればよい。前記結合としては、例えば、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合、１Ｈ－１３Ｃ－１３Ｃ結合などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。これらの結合の中では、生体における存在率が低く、高い選択性で検出することができる観点から、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合および１Ｈ－１３Ｃ－１３Ｃ結合が好ましく、１Ｈ－１３Ｃ－１５Ｎ結合がより好ましい。前記１Ｈ－１３Ｃ－１５Ｎ結合は、１Ｈの磁化を１３Ｃに移動させ、１３Ｃの磁化を１５Ｎに移動させ、１５Ｎの磁化を１３Ｃに戻し、１３Ｃの磁化を１Ｈに戻すことによって検出することができる。また、前記１Ｈ－１５Ｎ－１３Ｃ結合は、１Ｈの磁化を１５Ｎに移動させ、１５Ｎの磁化を１３Ｃに移動させ、１３Ｃの磁化を１５Ｎに戻し、１５Ｎの磁化を１Ｈに戻すことによって検出することができる。１Ｈ－１３Ｃ－１３Ｃ結合は、１Ｈの磁化を隣接する１３Ｃに移動させ、この１３Ｃの磁化を隣接する１３Ｃに移動させ、この１３Ｃの磁化を隣接する１３Ｃに戻し、この１３Ｃの磁化を１Ｈに戻すことによって検出することができる。前記プローブは、当該プローブの検出感度を向上させる観点から、前記結合を複数個有することが好ましい。 (probe)
The probe used in the multinuclear multiple magnetic resonance imaging method of the present invention has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and has different resonance frequencies. It has a bond consisting of at least three nuclear magnetic resonance active nuclei. The nuclear magnetic resonance active nucleus is a naturally occurring nuclear magnetic resonance active nucleus that does not generate radiation. The bond has at least two types of nuclear magnetic resonance active nuclei among the nuclear magnetic resonance active nuclei and is composed of at least three nuclear magnetic resonance active nuclei having different resonance frequencies. In such coupling, multiple resonances can be caused by magnetization transfer between at least three nuclear magnetic resonance active nuclei. In the bond consisting of at least three nuclear magnetic resonance active nuclei, for example, an A 1 -A 2 -B bond (A 1 and A 2 are the same kind of nuclear magnetic resonance active nuclei, B is A 1 and A 2 Even if two of the same type of nuclear magnetic resonance active nuclei (A 1 , A 2 ) are adjacent to each other as shown in FIG. When the types of active nuclei are different, the resonance frequencies of the nuclear magnetic resonance active nuclei (A 1 , A 2 ) are different from each other. Therefore, the above-mentioned bond may be any one having two or more of the same type of nuclear magnetic resonance active nuclei, which are linked so that these nuclei have different resonance frequencies. Examples of the bond include a 1 H- 13 C- 15 N bond, a 1 H- 15 N- 13 C bond, and a 1 H- 13 C- 13 C bond. It is not limited. Among these bonds, 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond and 1 H- 13 are present from the viewpoint of low presence in the living body and detection with high selectivity. A C- 13 C bond is preferred, and a 1 H- 13 C- 15 N bond is more preferred. The 1 H- 13 C-15 N bonds, 1 H magnetization was moved to 13 C, the 13 C magnetization was moved to 15 N, and returns the magnetization of 15 N to 13 C, 1 the magnetization of 13 C It can be detected by returning to H. Further, the 1 H- 15 N-13 C coupling moves the magnetization of the 1 H to 15 N, to move the magnetization of 15 N to 13 C, returning the magnetization of 13 C to 15 N, the 15 N magnetization Can be detected by returning to 1 H. 1 H- 13 C-13 C coupling moves the magnetization of the 1 H in the adjacent 13 C, the magnetization of the 13 C is moved to the adjacent 13 C, returning the magnetization of the 13 C in the adjacent 13 C The 13 C magnetization can be detected by returning it to 1 H. The probe preferably has a plurality of the bonds from the viewpoint of improving the detection sensitivity of the probe.
　前記プローブとしては、例えば、
　式（ｘ１）～（ｘ３）： As the probe, for example,
Formulas (x1) to (x3):
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（式中、Ｒ１～Ｒ４はそれぞれ独立して水素原子または置換基を有していてもよい炭素数１～９の炭化水素基、Ｒ５は置換基を有していてもよい炭素数１～４の炭化水素基、＊は側鎖に直接またはリンカーを介して結合する。ただし、Ｒ5が炭素数２～４の炭化水素基である場合、当該炭化水素基中の少なくとも１つの炭素原子が前記側鎖に直接またはリンカーを介して結合する）
で表わされる繰返し単位からなる群より選ばれた少なくとも１種の繰返し単位を含む重合度が１～５０００の主鎖を有し、かつ前記側鎖として式（ｙ１）～（ｙ３）： (Wherein R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent, and R 5 is a carbon number optionally having a substituent) 1 to 4 hydrocarbon group, * is bonded to the side chain directly or via a linker, provided that when R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one carbon in the hydrocarbon group Atoms are attached to the side chain directly or via a linker)
Having a main chain having a degree of polymerization of 1 to 5000 containing at least one repeating unit selected from the group consisting of repeating units represented by formulas (y1) to (y3):
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
〔式中、Ｒ６は直接結合または置換基を有していてもよい炭素数１～４の炭化水素基、Ｚは１価の官能基を示し、＊は前記式（ｘ１）～（ｘ３）における＊に直接またはリンカーを介して結合する〕
で表わされる官能基からなる群より選ばれた少なくとも１種の官能基を有する化合物（以下、「化合物Ａ」ともいう）などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。 [Wherein R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent, Z represents a monovalent functional group, and * represents the above formulas (x1) to (x3) (Directly or via a linker)
A compound having at least one functional group selected from the group consisting of functional groups represented by the following (hereinafter, also referred to as “compound A”), and the like. However, the present invention is not limited to such examples. Absent.
　前記化合物Ａは、側鎖として式（ｙ１）～（ｙ３）で表わされる官能基からなる群より選ばれた少なくとも１種の官能基を有するため、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合または１Ｈ－１３Ｃ－１３Ｃ結合の各核の間での磁化移動を利用して高い選択性で検出することができる。前記化合物Ａは、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合および１Ｈ－１３Ｃ－１３Ｃ結合のうちのいずれか１種類以上を有していればよい。なかでも、前記化合物Ａは、少なくとも１Ｈ－１３Ｃ－１５Ｎを有していることが好ましい。 Since the compound A has at least one functional group selected from the group consisting of functional groups represented by the formulas (y1) to (y3) as a side chain, a 1 H- 13 C- 15 N bond, 1 H It can be detected with high selectivity using magnetization transfer between nuclei of 15 N- 13 C bond or 1 H- 13 C- 13 C bond. The compound A only needs to have one or more of 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond, and 1 H- 13 C- 13 C bond. Among them, the compound A preferably has at least 1 H- 13 C- 15 N.
　前記化合物Ａの主鎖は、式（ｘ１）～（ｘ３）で表わされる繰返し単位からなる群より選ばれた少なくとも１種の繰返し単位を含んでいる。前記繰返し単位の重合度は、高い感度を確保する観点から、１以上、好ましくは２以上、より好ましくは１０以上、さらに好ましくは２０以上であり、検体への付与の容易性を向上させる観点から、５０００以下、好ましくは１０００以下、より好ましくは４００以下である。前記主鎖は、直鎖状でもよく、分岐鎖状であってもよい。また、前記主鎖は、１種類の繰返し単位からなるものであってもよく、２種類以上の繰返し単位からなるものであってもよい。 The main chain of the compound A contains at least one repeating unit selected from the group consisting of repeating units represented by the formulas (x1) to (x3). The degree of polymerization of the repeating unit is 1 or more, preferably 2 or more, more preferably 10 or more, still more preferably 20 or more from the viewpoint of ensuring high sensitivity, and from the viewpoint of improving the ease of application to the specimen. It is 5000 or less, preferably 1000 or less, more preferably 400 or less. The main chain may be linear or branched. The main chain may be composed of one type of repeating unit, or may be composed of two or more types of repeating units.
　式（ｘ１）～（ｘ３）において、Ｒ１～Ｒ４は、それぞれ独立して水素原子または置換基を有していてもよい炭素数１～９の炭化水素基である。前記炭素数１～９の炭化水素基としては、例えば、炭素数１～９のアルキル基、炭素数２～９のアルケニル基、炭素数２～９のアルキニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数１～９のアルキル基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数２～９のアルケニル基としては、例えば、ビニル基、アリル基、ブテニル基、ペンテニル基、ヘキセニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数２～９のアルキニル基としては、エチニル基、プロピニル基、ブチニル基、ペンチニル基、ヒキシニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。前記置換基としては、例えば、ハロゲン原子、酸素原子および窒素原子からなる群より選ばれた少なくとも１種の原子を含む官能基、具体的には、水酸基、アミノ基、ジメチルアミノ基、カルボキシル基、アルデヒド基、シアノ基、ニトロ基、スルホン酸基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。 In formulas (x1) to (x3), R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent. Examples of the hydrocarbon group having 1 to 9 carbon atoms include an alkyl group having 1 to 9 carbon atoms, an alkenyl group having 2 to 9 carbon atoms, and an alkynyl group having 2 to 9 carbon atoms. However, the present invention is not limited to such examples. Examples of the alkyl group having 1 to 9 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and a nonyl group. It is not limited to illustration only. Examples of the alkenyl group having 2 to 9 carbon atoms include a vinyl group, an allyl group, a butenyl group, a pentenyl group, and a hexenyl group, but the present invention is not limited to such examples. Examples of the alkynyl group having 2 to 9 carbon atoms include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, and a hexynyl group, but the present invention is not limited to such examples. Examples of the substituent include a functional group containing at least one atom selected from the group consisting of a halogen atom, an oxygen atom and a nitrogen atom, specifically, a hydroxyl group, an amino group, a dimethylamino group, a carboxyl group, Examples include an aldehyde group, a cyano group, a nitro group, and a sulfonic acid group, but the present invention is not limited to such examples.
　式（ｘ１）～（ｘ３）において、Ｒ５は、置換基を有していてもよい炭素数１～４の炭化水素基である。前記炭素数１～４の炭化水素としては、炭素数１～４のアルキル基、炭素数２～４のアルケニル基、炭素数２～４のアルキニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数１～４のアルキル基としては、例えば、メチル基、エチル基、プロピル基、ブチル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数２～４のアルケニル基としては、例えば、ビニル基、アリル基、ブテニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数２～４のアルキニル基としては、例えば、エチニル基、プロピニル基、ブチニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。前記置換基は、Ｒ１～Ｒ４における置換基と同様である。 In the formulas (x1) to (x3), R 5 is an optionally substituted hydrocarbon group having 1 to 4 carbon atoms. Examples of the hydrocarbon having 1 to 4 carbon atoms include an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and an alkynyl group having 2 to 4 carbon atoms. It is not limited to only. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, and a butyl group, but the present invention is not limited only to such examples. Examples of the alkenyl group having 2 to 4 carbon atoms include a vinyl group, an allyl group, and a butenyl group, but the present invention is not limited to such examples. Examples of the alkynyl group having 2 to 4 carbon atoms include an ethynyl group, a propynyl group, a butynyl group, and the like, but the present invention is not limited to such examples. The substituent is the same as the substituent in R 1 to R 4 .
　式（ｘ１）～（ｘ３）において、＊は、側鎖に直接またはリンカーを介して結合する部分を示す。なお、Ｒ5が炭素数２～４の炭化水素基である場合、当該炭化水素基中の少なくとも１つ、好ましくは１つの炭素原子が前記側鎖に直接またはリンカーを介して結合していればよい。 In the formulas (x1) to (x3), * represents a moiety bonded to the side chain directly or via a linker. When R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one, preferably one carbon atom in the hydrocarbon group is bonded to the side chain directly or via a linker. Good.
　式（ｙ１）～（ｙ３）において、Ｒ６は、直接結合または置換基を有していてもよい炭素数１～４の炭化水素基である。前記炭素数１～４の炭化水素基は、Ｒ５における炭素数１～４の炭化水素基と同様である。また、前記置換基は、Ｒ１～Ｒ４における置換基と同様である。 In formulas (y1) to (y3), R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent. The hydrocarbon group having 1 to 4 carbon atoms is the same as the hydrocarbon group having 1 to 4 carbon atoms in R 5 . The substituent is the same as the substituent in R 1 to R 4 .
　式（ｙ１）～（ｙ３）において、＊は、式（ｘ１）～（ｘ３）における＊に直接またはリンカーを介して結合する部分を示す。 In the formulas (y1) to (y3), * represents a moiety bonded to * in the formulas (x1) to (x3) directly or via a linker.
　式（ｙ１）～（ｙ３）において、前記Ｚは、１価の官能基である。前記１価の官能基としては、例えば、炭素数１～４のアルキル基、炭素数２～４のアルケニル基、炭素数２～４のアルキニル基、アミノ基、ジメチルアミノ基、カルボキシル基、アルデヒド基、水酸基、炭素数１～４のアルコキシ基；チオール基；シアノ基などが挙げられる。なお、Ｚにおける炭素数１～４のアルキル基、炭素数２～４のアルケニル基および炭素数２～４のアルキニル基は、Ｒ5における炭素数１～４のアルキル基、炭素数２～４のアルケニル基および炭素数２～４のアルキニル基と同じである。また、炭素数１～４のアルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などが挙げられるが。本発明は、かかる例示のみに限定されるものではない。 In the formulas (y1) to (y3), Z is a monovalent functional group. Examples of the monovalent functional group include an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, an amino group, a dimethylamino group, a carboxyl group, and an aldehyde group. , A hydroxyl group, an alkoxy group having 1 to 4 carbon atoms; a thiol group; a cyano group, and the like. Note that an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and an alkynyl group having 2 to 4 carbon atoms in Z are an alkyl group having 1 to 4 carbon atoms in R 5 , an alkyl group having 2 to 4 carbon atoms, The same as the alkenyl group and the alkynyl group having 2 to 4 carbon atoms. Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. The present invention is not limited to such examples.
　前記側鎖が式（ｙ１）または（ｙ２）で表わされる官能基であって、感度を向上させることを目的とする場合には、前記Ｚとして、式（ｚ１）：
＊－１５ＮＨ２　　（ｚ１）
〔式中、＊は前記式（ｙ１）または（ｙ２）で表わされる官能基に結合する結合手を示す〕
または、式（ｚ２）：
＊－１３ＣＨ３　　（ｚ２）
〔式中、＊は前記式（ｙ１）または（ｙ２）で表わされる官能基に結合する結合手を示す〕
で表わされる官能基を用いることができる。 In the case where the side chain is a functional group represented by the formula (y1) or (y2) and the purpose is to improve sensitivity, as Z, the formula (z1):
* - 15 NH 2 (z1)
[Wherein, * represents a bond bonded to the functional group represented by the formula (y1) or (y2)]
Or the formula (z2):
* - 13 CH 3 (z2)
[Wherein, * represents a bond bonded to the functional group represented by the formula (y1) or (y2)]
The functional group represented by can be used.
　また、前記側鎖が式（ｙ１）～（ｙ３）で表わされる官能基であって、プローブに抗体をさらに結合させることまたは親水性を向上させることを目的とする場合には、式（ｚ３）： In the case where the side chain is a functional group represented by the formulas (y1) to (y3) and the purpose is to further bind an antibody to the probe or improve hydrophilicity, the formula (z3) :
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
〔式中、＊は前記式（ｙ１）～（ｙ３）で表わされる官能基に結合する結合手、ｄは１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい〕
で表わされる官能基、または式（ｚ４）： [In the formula, * represents a bond bonded to the functional group represented by the formulas (y1) to (y3), d represents an integer of 1 to 4, and the hydrogen atom of the methylene group is substituted with another atom. (May be)
Or a functional group represented by formula (z4):
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
〔式中、＊は前記式（ｙ１）～（ｙ３）で表わされる官能基に結合する結合手、ｄは１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい〕
で表わされる官能基を用いることができる。式（ｚ３）および（ｚ４）において、＊は、前記式（ｙ１）～（ｙ３）で表わされる官能基に結合する結合手であり、前記式（ｙ１）～（ｙ３）の１３Ｃ、または１５Ｎと結合する。また、式（ｚ３）および（ｚ４）において、ｄは、抗体結合反応性の観点から、１以上、好ましくは２以上であり、親水性向上の観点から、４以下、好ましくは３以下である。なお、式（ｚ３）および（ｚ４）において、メチレン基の水素原子は、ハロゲン原子、酸素原子、窒素原子などの他の原子で置換されていてもよい。 [In the formula, * represents a bond bonded to the functional group represented by the formulas (y1) to (y3), d represents an integer of 1 to 4, and the hydrogen atom of the methylene group is substituted with another atom. (May be)
The functional group represented by can be used. In the formulas (z3) and (z4), * is a bond bonded to the functional groups represented by the formulas (y1) to (y3), and 13 C in the formulas (y1) to (y3), or 15 Combine with N. In the formulas (z3) and (z4), d is 1 or more, preferably 2 or more from the viewpoint of antibody binding reactivity, and 4 or less, preferably 3 or less from the viewpoint of improving hydrophilicity. In formulas (z3) and (z4), the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
　前記側鎖が式（ｙ３）で表わされる官能基であって、感度を向上させることを目的とする場合には、前記Ｚとして、式（ｚ２）で表わされる官能基を用いることができる。 When the side chain is a functional group represented by the formula (y3) and the purpose is to improve sensitivity, the functional group represented by the formula (z2) can be used as the Z.
　なお、前記Ｚが式（ｚ２）で表わされる官能基である場合、化合物Ａは、コリンに類似する構造を有することから、腫瘍集積性が高いという性質を有する。また、前記Ｚが式（ｚ３）で表わされる官能基のようにカルボキシル基を有する場合、化合物Ａは、抗体などのように標的部位に特異的に結合する捕捉分子を結合させやすいという性質を有する。さらに、前記Ｚが式（ｚ４）で表わされる官能基のように、スルホン酸基を有する場合、化合物Ａは、親水性が高く、生体内で凝集しにくいという性質を有する。 In addition, when Z is a functional group represented by the formula (z2), the compound A has a structure having a high tumor accumulation property because it has a structure similar to choline. In addition, when Z has a carboxyl group like the functional group represented by the formula (z3), the compound A has a property of easily binding a capture molecule that specifically binds to a target site such as an antibody. . Further, when Z has a sulfonic acid group like the functional group represented by the formula (z4), the compound A has a property of being highly hydrophilic and difficult to aggregate in vivo.
　化合物Ａが、主鎖と側鎖とがリンカーを介して結合した化合物である場合、前記リンカーは、化合物Ａにおける十分な分子運動性、抗体結合反応性および親水性を確保する観点から、置換基を有していてもよい炭素数１～４の炭化水素基および式（ｌ１）～（ｌ３）： When the compound A is a compound in which the main chain and the side chain are bonded via a linker, the linker is a substituent from the viewpoint of ensuring sufficient molecular mobility, antibody binding reactivity and hydrophilicity in the compound A. A hydrocarbon group having 1 to 4 carbon atoms and formulas (l1) to (l3):
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
〔式中、Ｌ’は置換基を有していてもよい炭素数１～４の炭化水素基または式（ｌ’）： [In the formula, L ′ is an optionally substituted hydrocarbon group having 1 to 4 carbon atoms or the formula (l ′):
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（式中、ａおよびｂはそれぞれ独立して１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい）
で表わされる官能基を示し、＊は前記式（ｘ１）～（ｘ３）における＊または前記式（ｙ１）～（ｙ３）における＊に結合する〕
で表わされる官能基からなる群より選ばれた少なくとも１種の官能基であることが好ましい。前記炭素数１～４の炭化水素基は、Ｒ５における炭素数１～４の炭化水素基と同様である。また、前記置換基は、Ｒ１～Ｒ４における置換基と同様である。式（ｌ１）～（ｌ３）および式（ｌ’）において、＊は、前記式（ｘ１）～（ｘ３）における＊または前記式（ｙ１）～（ｙ３）における＊に結合する部分を示す。また、式（ｌ’）において、ａおよびｂは、それぞれ独立して１～４の整数であり、化学結合の安定性を確保する観点から、１以上、好ましくは２以上であり、十分な親水性および生体適合性を確保する観点から、４以下、好ましくは２以下である。なお、式（ｌ’）において、メチレン基の水素原子は、ハロゲン原子、酸素原子、窒素原子などの他の原子で置換されていてもよい。 (Wherein, a and b each independently represent an integer of 1 to 4, and the hydrogen atom of the methylene group may be substituted with another atom)
Wherein * is bonded to * in the above formulas (x1) to (x3) or * in the above formulas (y1) to (y3).
It is preferably at least one functional group selected from the group consisting of functional groups represented by: The hydrocarbon group having 1 to 4 carbon atoms is the same as the hydrocarbon group having 1 to 4 carbon atoms in R 5 . The substituent is the same as the substituent in R 1 to R 4 . In the formulas (l1) to (l3) and the formula (l ′), * represents a moiety bonded to * in the formulas (x1) to (x3) or * in the formulas (y1) to (y3). In formula (l ′), a and b are each independently an integer of 1 to 4, and are 1 or more, preferably 2 or more, from the viewpoint of ensuring the stability of chemical bonds, and have sufficient hydrophilicity. From the viewpoint of securing the compatibility and biocompatibility, it is 4 or less, preferably 2 or less. In the formula (l ′), the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
　前記主鎖と側鎖とがリンカーを介して結合している場合、前記リンカーと前記側鎖とからなる構造は、式（ｙ５）～（ｙ７）： When the main chain and the side chain are bonded via a linker, the structure composed of the linker and the side chain has the formulas (y5) to (y7):
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
〔式中、＊は前記式（ｘ１）～（ｘ３）における＊に結合する結合手、ａおよびｂはそれぞれ独立して１～４の整数を示し、式（ｙ５）～（ｙ７）中のメチレン基の水素原子は他の原子で置換されていてもよい〕
で表わされる構造からなる群より選ばれた構造であることが好ましい。化合物Ａは、式（ｙ５）で表わされる構造のようにコリンに類似する構造を有する場合、腫瘍集積性が高いという性質を有する。また、化合物Ａは、式（ｙ６）で表わされる構造のようにカルボキシル基を有する構造を有する場合、抗体などのように標的部位に特異的に結合する捕捉分子を結合させやすいという性質を有する。また、化合物Ａは、式（ｙ７）で表わされる構造のようにスルホン酸基を有する場合、化合物Ａは、親水性が高く、生体内で凝集しにくいという性質を有する。 [In the formula, * represents a bond bonded to * in the formulas (x1) to (x3), a and b each independently represents an integer of 1 to 4, and methylene in the formulas (y5) to (y7) The hydrogen atom of the group may be substituted with another atom)
A structure selected from the group consisting of structures represented by When the compound A has a structure similar to choline like the structure represented by the formula (y5), it has a property of high tumor accumulation. Further, when the compound A has a structure having a carboxyl group as in the structure represented by the formula (y6), it has a property that it easily binds a capture molecule that specifically binds to a target site such as an antibody. Further, when the compound A has a sulfonic acid group as in the structure represented by the formula (y7), the compound A has a property of being highly hydrophilic and difficult to aggregate in vivo.
　式（ｙ５）～（ｙ７）において、＊は、主鎖である前記式（ｘ１）～（ｘ３）における＊に結合する結合手を示す。また、式（ｙ５）～（ｙ７）において、ａおよびｂは、式（ｌ’）におけるａおよびｂと同じである。なお、式（ｙ５）～（ｙ７）において、メチレン基の水素原子は、ハロゲン原子、酸素原子、窒素原子などの他の原子で置換されていてもよい。 In the formulas (y5) to (y7), * represents a bond that is bonded to * in the formulas (x1) to (x3) as the main chain. In the formulas (y5) to (y7), a and b are the same as a and b in the formula (l ′). In formulas (y5) to (y7), the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
　化合物Ａは、重合度制御および高分子化合物の分散度制御の観点から、好ましくは式（ｉ１）～（ｉ１２）： Compound A is preferably represented by formulas (i1) to (i12) from the viewpoint of controlling the degree of polymerization and the degree of dispersion of the polymer compound:
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
で表わされる構造からなる群より選ばれた少なくとも１種の構造を有することが好ましい。なお、式（ｉ１）～（ｉ１２）において、ａおよびｂは、式（ｌ’）におけるａおよびｂと同じである。また、式（ｉ１）～（ｉ１２）において、メチレン基の水素原子は、ハロゲン原子、酸素原子、窒素原子などの他の原子で置換されていてもよい。 It preferably has at least one structure selected from the group consisting of structures represented by: In the formulas (i1) to (i12), a and b are the same as a and b in the formula (l ′). In formulas (i1) to (i12), the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
　化合物Ａは、２種類以上の繰返し単位を有する共重合体であってもよい。化合物Ａが共重合体である場合、交互共重合体、ランダム共重合体およびブロック共重合体のいずれでもよい。 Compound A may be a copolymer having two or more types of repeating units. When compound A is a copolymer, any of an alternating copolymer, a random copolymer and a block copolymer may be used.
　化合物Ａが共重合体である場合、前記主鎖は、式（Ｘ１）～（ｘ３）で表わされる繰返し単位の他に、（メタ）アクリレートモノマーに由来する繰返し単位、（メタ）アクリルアミドモノマーに由来する繰り返し単位、アミノ酸モノマーに由来する繰返し単位およびヒドロキシ酸モノマーに由来する繰返し単位からなる群より選ばれた繰返し単位をさらに有していてもよい。かかる繰返し単位としては、例えば、式（ａ１）～（ａ３）：  When compound A is a copolymer, the main chain is derived from a (meth) acrylate monomer, a repeating unit derived from a (meth) acrylate monomer, in addition to the repeating units represented by the formulas (X1) to (x3) And a repeating unit selected from the group consisting of a repeating unit derived from an amino acid monomer, and a repeating unit derived from a hydroxy acid monomer. Examples of such repeating units include formulas (a1) to (a3):
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
〔式（ａ１）～（ａ３）において、Ｒ７は１価の官能基を示す〕
で表わされる繰返し単位などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。式式（ａ１）～（ａ３）において、Ｒ７の１価の官能基としては、例えば、水素原子、置換基を有していてもよい炭素数１～６の炭化水素基などが挙げられる。前記炭素数１～６の炭化水素基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。前記置換基は、Ｒ１～Ｒ４における置換基と同様である。 [In formulas (a1) to (a3), R 7 represents a monovalent functional group]
However, the present invention is not limited to such examples. In the formulas (a1) to (a3), examples of the monovalent functional group represented by R 7 include a hydrogen atom and an optionally substituted hydrocarbon group having 1 to 6 carbon atoms. Examples of the hydrocarbon group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group, but the present invention is limited only to such examples. is not. The substituent is the same as the substituent in R 1 to R 4 .
　なお、化合物Ａが共重合体である場合、高い感度を得る観点から、共重合体を構成する繰返し単位のすべてがその側鎖に式（ｙ１）～（ｙ３）で表わされる官能基のいずれかを有することが好ましい。また、化合物が共重合体である場合、親水性の制御、生体内での吸着能の制御などのように目的に応じた制御を行なう観点から、共重合体を構成する繰返し単位の一部のみが式（ｙ１）～（ｙ３）で表わされる官能基のいずれかを有していてもよい。 When compound A is a copolymer, from the viewpoint of obtaining high sensitivity, all of the repeating units constituting the copolymer are any functional groups represented by the formulas (y1) to (y3) in the side chain. It is preferable to have. In addition, when the compound is a copolymer, only a part of the repeating units constituting the copolymer is used from the viewpoint of controlling according to the purpose such as control of hydrophilicity, adsorption capacity in vivo, etc. May have any of functional groups represented by formulas (y1) to (y3).
　前記プローブは、標的部位の特異的な検出、標的物質の動態、局在、薬効、代謝などの追跡をより的確に行なう観点から、標的部位に特異的に結合する捕捉分子が付加されていることが好ましい。前記捕捉分子としては、腫瘍などの標的部位に特異的に結合する物質、標的部位の周辺に存在する物質に特異的に結合する物質などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。前記捕捉分子の具体例としては、抗体、抗体フラグメント、酵素、生物活性ペプチド、グリコペプチド、糖鎖、脂質、核酸、分子認識化合物などが挙げられる。これらの捕捉物質は、単独で用いてもよく、２種類以上を組み合わせて用いてもよい。 The probe is added with a capture molecule that specifically binds to the target site from the viewpoint of more accurately tracking the target site's specific detection, target substance dynamics, localization, drug efficacy, metabolism, etc. Is preferred. Examples of the capture molecule include a substance that specifically binds to a target site such as a tumor, and a substance that specifically binds to a substance present around the target site. However, the present invention is limited only to such examples. It is not something. Specific examples of the capture molecule include antibodies, antibody fragments, enzymes, biologically active peptides, glycopeptides, sugar chains, lipids, nucleic acids, molecular recognition compounds, and the like. These capture substances may be used alone or in combination of two or more.
　標的部位に特異的に結合する捕捉分子を化合物Ａに付加させて用いる場合、化合物Ａの繰返し単位の末端には、炭素数１～１２のアルキル基、炭素数２～１２のアルケニル基、炭素数２～４のアルキニル基、水酸基、チオール基、アミノ基、アジド基、マレイミド基、Ｎ－ヒドロキシスクシンイミド基およびトリクロロシリル基のいずれかの官能基を有することが好ましい。この場合、化合物Ａの末端は、例えば、式（ｂ１）～（ｂ９）のいずれかの構造を有する。炭素数１～１２のアルキル基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。炭素数２～１２のアルケニル基としては、例えば、例えば、ビニル基、アリル基、ブテニル基、ペンテニル基、ヘキセニル基、ヘプテニル基、オクテニル基、ノネニル基、デセニル基、ウンデセニル基、ドデセニル基などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。繰返し単位の末端における炭素数２～４のアルキニル基は、Ｒ5における炭素数２～４のアルキニル基と同じである。 When a capture molecule that specifically binds to a target site is added to Compound A and used, the repeating unit of Compound A has an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, It preferably has any one functional group of 2 to 4 alkynyl groups, hydroxyl groups, thiol groups, amino groups, azide groups, maleimide groups, N-hydroxysuccinimide groups and trichlorosilyl groups. In this case, the terminal of compound A has, for example, any structure of formulas (b1) to (b9). Examples of the alkyl group having 1 to 12 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Although mentioned, this invention is not limited only to this illustration. Examples of the alkenyl group having 2 to 12 carbon atoms include a vinyl group, an allyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, and the like. However, the present invention is not limited to such examples. The alkynyl group having 2 to 4 carbon atoms at the terminal of the repeating unit is the same as the alkynyl group having 2 to 4 carbon atoms in R 5 .
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　なお、式（ｂ１）～（ｂ９）において、ｅは、１～１１の整数である。また、式（ｂ１）～（ｂ９）において、ｆは、０～１７の整数である。式（ｂ１）～（ｂ９）において、Ｒ８は、水素原子またはメチル基である。式（ｂ１）～（ｂ９）において、＊は、主鎖の繰返し単位に結合する。化合物Ａの両末端は、同じ構造を有していてもよく、異なる構造を有していていもよい。 In the formulas (b1) to (b9), e is an integer of 1 to 11. In the formulas (b1) to (b9), f is an integer of 0 to 17. In formulas (b1) to (b9), R 8 is a hydrogen atom or a methyl group. In formulas (b1) to (b9), * is bonded to a repeating unit of the main chain. Both ends of Compound A may have the same structure or different structures.
　化合物Ａは、重合性化合物を重合させることで合成することができる。化合物Ａは、例えば、式（ｊ１）～（ｊ１２）で表わされる化合物のいずれかを重合させることで合成することができる。 Compound A can be synthesized by polymerizing a polymerizable compound. Compound A can be synthesized, for example, by polymerizing any of the compounds represented by formulas (j1) to (j12).
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　なお、式（ｊ１）～（ｊ１２）において、ａおよびｂは、式（ｌ’）におけるａおよびｂと同じである。また、式（ｊ１）～（ｊ１２）において、メチレン基の水素原子は、ハロゲン原子、酸素原子、窒素原子などの他の原子で置換されていてもよい。 In formulas (j1) to (j12), a and b are the same as a and b in formula (l ′). In formulas (j1) to (j12), the hydrogen atom of the methylene group may be substituted with another atom such as a halogen atom, an oxygen atom, or a nitrogen atom.
　化合物Ａのうち、特に、式（ｃｌ）： Among the compounds A, in particular, the formula (cl):
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
で表わされる１３Ｃ／１５Ｎ－ラベル化塩化コリン、式（ｐ２）： 13 C / 15 N-labelled choline chloride represented by the formula (p2):
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
で表わされる１３Ｃ／１５Ｎ－ラベル化ポリ－２－メタクリロイルオキシエチルホスホリルコリンなどのコリンに類似した構造を有する化合物からなるプローブは、捕捉分子が付加されていない場合でも、ＥＰＲ（Ｅｎｈａｎｃｅｄ　Ｐｅｒｍｅａｂｉｌｉｔｙ　ａｎｄ　Ｒｅｔｅｎｔｉｏｎ）効果により、生体内の正常部位と比べて腫瘍部位により多く集積する。したがって、これらの化合物からなるプローブを用い、生体内で集積したプローブを検出することによって、腫瘍の有無または腫瘍部位の特異的なイメージングが可能である。 A probe composed of a compound having a structure similar to choline such as 13 C / 15 N-labeled poly-2-methacryloyloxyethyl phosphorylcholine represented by the formula: EPR (Enhanced Permeability and Retention) ) Due to the effect, it accumulates more in the tumor site than in the normal site in the body. Therefore, the presence or absence of a tumor or specific imaging of a tumor site is possible by detecting probes accumulated in vivo using probes comprising these compounds.
（多核多重磁気共鳴画像化方法の操作手順）
　本発明の多核多重磁気共鳴画像化方法では、まず、前記プローブを検体に付与する〔ステップ（Ａ）〕。 (Operation procedure of multinuclear multiple magnetic resonance imaging method)
In the multinuclear magnetic resonance imaging method of the present invention, first, the probe is applied to a specimen [step (A)].
　検体への前記プローブの付与は、例えば、皮下注射、経口投与、経皮投与、静脈投与、腹腔内投与などによって行なうことができるが、本発明は、かかる例示に限定されるものではない。 The probe can be applied to the specimen by, for example, subcutaneous injection, oral administration, transdermal administration, intravenous administration, intraperitoneal administration, and the like, but the present invention is not limited to such examples.
　前記プローブを検体に付与する際には、当該プローブを分散媒に溶解させて用いることができる。前記分散媒は、プローブを溶解させるための液状の物質であればよく、例えば、生理食塩水、注射用蒸留水、リン酸緩衝水溶液（ＰＢＳ）などが挙げられるが、本発明は、かかる例示のみに。また、前記プローブは、分散媒の他に、必要に応じて薬理上許容できる添加物とともに用いてもよい。 When applying the probe to a specimen, the probe can be used after being dissolved in a dispersion medium. The dispersion medium may be a liquid substance for dissolving the probe, and examples thereof include physiological saline, distilled water for injection, and phosphate buffered aqueous solution (PBS), but the present invention is only such examples. To. In addition to the dispersion medium, the probe may be used together with a pharmacologically acceptable additive as necessary.
　つぎに、前記ステップ（Ａ）でプローブが付与された前記検体に電磁波を照射して前記プローブの前記結合中の各核の間での磁化移動を行ない、当該磁化移動を利用して前記プローブに起因する多重共鳴シグナルを検出する〔ステップ（Ｂ）〕。 Next, the specimen to which the probe is attached in the step (A) is irradiated with electromagnetic waves to move the magnetization between the binding nuclei, and the probe moves to the probe using the magnetization movement. The resulting multiple resonance signal is detected [step (B)].
　電磁波の照射に際しては、プローブに含まれる核磁気共鳴活性核の個数に応じた多重核磁気共鳴法のパルス系列と磁気共鳴撮像法のパルス系列とを用いる。例えば、前記プローブとして、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合または１Ｈ－１３Ｃ－１３Ｃ結合を有するプローブを用いる場合、前記結合に基づく三重核磁気共鳴法（例えば、１Ｈ－｛１３Ｃ－１５Ｎ｝三重核磁気共鳴法、ＨＮＣＯ三重核磁気共鳴法、ＨＮＣＡ三重核磁気共鳴法、ＨＮ（ＣＡ）ＣＯ三重磁気共鳴法、ＨＣＡＣＯ三重磁気共鳴法など）のパルス系列と磁気共鳴撮像法のパルス系列とを用いることができる。 When irradiating electromagnetic waves, a pulse sequence of a multiple nuclear magnetic resonance method and a pulse sequence of a magnetic resonance imaging method according to the number of nuclear magnetic resonance active nuclei contained in the probe are used. For example, when a probe having 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond or 1 H- 13 C- 13 C bond is used as the probe, triple nuclear magnetic resonance based on the bond (For example, 1 H- { 13 C- 15 N} triple nuclear magnetic resonance method, HNCO triple nuclear magnetic resonance method, HNCA triple nuclear magnetic resonance method, HN (CA) CO triple magnetic resonance method, HCACO triple magnetic resonance method, etc. ) Pulse sequence and magnetic resonance imaging pulse sequence.
　前記多重核磁気共鳴法のパルス系列は、例えば、核磁気共鳴活性核の種類、その個数、その配列、それらの核磁気共鳴活性核の化学シフト、核磁気共鳴活性核同士のカップリング定数、などに基づいて適宜設定することができる。前記多重核磁気共鳴法のパルス系列としては、例えば、ＩＮＥＰＴ、ＨＭＱＣ、ＨＳＱＣ、ＨＭＢＣ、ＨＣＮ、ＨＮＣＡ、ＨＮＣＯ、ＨＮ（ＣＡ）ＣＯ、ＨＣＡＣＯなどが挙げられるが、本発明は、かかる例示のみに限定されるものではない。 The pulse sequence of the multiple nuclear magnetic resonance method includes, for example, the types of nuclear magnetic resonance active nuclei, their number, their arrangement, chemical shifts of these nuclear magnetic resonance active nuclei, coupling constants between nuclear magnetic resonance active nuclei, etc. Can be set as appropriate based on the above. Examples of the pulse sequence of the multiple nuclear magnetic resonance method include INEPT, HMQC, HSQC, HMBC, HCN, HNCA, HNCO, HN (CA) CO, HCACO, etc., but the present invention is limited only to such examples. Is not to be done.
　また、前記磁気共鳴撮像法のパルス系列は、例えば、プローブに含まれる磁気共鳴活性核の縦緩和時間（Ｔ１）、横緩和時間（Ｔ２）などに基づいて適宜設定することができる。前記磁気共鳴撮像法のパルス系列としては、例えば、スピンエコー法、高速スピンエコー法、エコープラナーイメージング法、グラジエントエコー法、スポイルドグラジエントエコー法、コヒーレントグラジエントエコー法などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。 In addition, the pulse sequence of the magnetic resonance imaging method can be appropriately set based on, for example, the longitudinal relaxation time (T1) and transverse relaxation time (T2) of the magnetic resonance active nucleus included in the probe. Examples of the pulse sequence of the magnetic resonance imaging method include a spin echo method, a fast spin echo method, an echo planar imaging method, a gradient echo method, a spoiled gradient echo method, a coherent gradient echo method, and the like. However, the present invention is not limited to such examples.
　前記プローブが１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する３個の核磁気共鳴活性核からなる結合（すなわち、第１核種と当該第１核種に磁気的に結合した第２核種と当該第２核種に磁気的に結合した第３核種とからなる結合）を有するプローブである場合、前記プローブをより選択的、かつ高感度で検出する観点から、前記ステップ（Ｂ）に用いられるパルス系列は、前記第１核種から第２核種への磁化移動を行なった後、前記第２核種から第３核種への磁化移動を行ない、さらに前記第３核種から前記第２核種を経て前記第１核種への磁化を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列とを含むパルス系列であることが好ましい。 The probe has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and a bond consisting of three nuclear magnetic resonance active nuclei having different resonance frequencies (ie, , A probe having a first nuclide, a second nuclide magnetically coupled to the first nuclide, and a third nuclide magnetically coupled to the second nuclide), the probe is more selective. In addition, from the viewpoint of detecting with high sensitivity, the pulse sequence used in the step (B) undergoes magnetization transfer from the first nuclide to the second nuclide, and then magnetizes from the second nuclide to the third nuclide. Magnetization transfer pulse system for performing magnetization transfer by applying an RF pulse and a gradient magnetic field to the probe so as to move and further magnetize from the third nuclide to the first nuclide via the second nuclide Preferably, the pulse sequence includes a sequence and a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal.
　電磁波を照射して前記プローブの前記結合中の各核の間での磁化移動を行なうことによって、前記プローブの前記結合中の各核に由来する多重共鳴シグナルの出現、消失、強度変化などに基づき、プローブの位置、存在量、構造などの情報を得、かかる情報に基づき画像を構築することができる。 Based on the appearance, disappearance, intensity change, etc. of multiple resonance signals derived from each nucleus of the probe in the coupling by irradiating electromagnetic waves to perform magnetization transfer between the nucleus of the probe in the coupling Information such as the position, abundance, and structure of the probe can be obtained, and an image can be constructed based on the information.
　以上説明したように、本発明の多核多重磁気共鳴画像化方法は、多重磁気共鳴画像化装置という１つのモダリティのみで、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができ、正確で、かつ患者への負荷が少ない画像診断に使用されることが期待されるものである。 As described above, the multinuclear multiple magnetic resonance imaging method of the present invention can obtain not only the morphology information of the specimen but also the positional information of the probe in the specimen as well as the single magnetic modality imaging apparatus. The function of the probe in the body, the metabolic reaction through the probe in the living body, etc. can be visualized, and it is expected to be used for diagnostic imaging that is accurate and has little burden on the patient.
２．多核多重磁気共鳴画像化装置
　本発明の多核多重磁気共鳴画像化装置は、検体中のプローブに起因する多重共鳴シグナルを検出して画像化するための多核多重磁気共鳴画像化装置であって、
　前記プローブが、1Ｈ、13Ｃおよび15Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブであり、
　前記結合に含まれる少なくとも３個の核磁気共鳴活性核それぞれの共鳴周波数に相当するＲＦパルスを印加するパルス印加部と、
　前記プローブに勾配磁場を印加する勾配磁場印加部と、
　前記結合に含まれる核磁気共鳴活性核それぞれの磁気共鳴信号を検出する検出部と、
　所定のパルス系列が生成されるように前記パルス印加部と前記勾配磁場印加部とを制御する制御部と
を備えており、
　前記所定のパルス系列が、
　前記結合に含まれる各核磁気共鳴活性核間の磁化移動を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、
　前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列と
を含むことを特徴とする多核多重磁気共鳴画像化装置である。 2. Multinuclear multiple magnetic resonance imaging apparatus The multinuclear multiple magnetic resonance imaging apparatus of the present invention is a multinuclear multiple magnetic resonance imaging apparatus for detecting and imaging a multiple resonance signal caused by a probe in a specimen,
The probe has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and is composed of at least three nuclear magnetic resonance active nuclei having different resonance frequencies. A probe comprising a compound having
A pulse applying unit for applying an RF pulse corresponding to a resonance frequency of each of at least three nuclear magnetic resonance active nuclei included in the coupling;
A gradient magnetic field application unit for applying a gradient magnetic field to the probe;
A detection unit for detecting a magnetic resonance signal of each of the nuclear magnetic resonance active nuclei included in the binding;
A control unit that controls the pulse application unit and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
The predetermined pulse sequence is
A magnetization transfer pulse sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization transfer between each nuclear magnetic resonance active nucleus included in the coupling; and
A multinuclear multiple magnetic resonance imaging apparatus comprising: a signal acquisition pulse sequence for adding position information to the magnetic resonance signal and acquiring the magnetic resonance signal.
　本発明の多核多重磁気共鳴画像装置は、プローブ中の結合に含まれる少なくとも３個の核磁気共鳴活性核それぞれの共鳴周波数に相当するＲＦパルスを印加するパルス印加部と、前記プローブに勾配磁場を印加する勾配磁場印加部と前記結合に含まれる核磁気共鳴活性核それぞれの磁気共鳴信号を検出する検出部と所定のパルス系列が生成されるように前記パルス印加部と前記勾配磁場印加部とを制御する制御部とを備え、前記所定のパルス系列が、前記結合に含まれる各核磁気共鳴活性核間の磁化移動を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列とを含むように構成されている点に１つの大きな特徴を有する。したがって、本発明の多核多重磁気共鳴画像装置は、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができる。したがって、本発明の多核多重磁気共鳴画像化装置によれば、生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを正確で、かつ生体に対して低負荷で可視化することができる。 The multinuclear magnetic resonance imaging apparatus of the present invention includes a pulse applying unit that applies RF pulses corresponding to the resonance frequencies of at least three nuclear magnetic resonance active nuclei included in the coupling in the probe, and a gradient magnetic field applied to the probe. A gradient magnetic field application unit to be applied; a detection unit for detecting a magnetic resonance signal of each of the nuclear magnetic resonance active nuclei included in the coupling; and the pulse application unit and the gradient magnetic field application unit so as to generate a predetermined pulse sequence. A control unit for controlling, and applying the RF pulse and the gradient magnetic field to the probe so that the predetermined pulse series moves the magnetization between the nuclear magnetic resonance active nuclei included in the coupling. And a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal. It has one significant feature in that there. Therefore, the multinuclear multiple magnetic resonance imaging apparatus of the present invention obtains not only the form information of the specimen but also the positional information of the probe in the specimen, the function of the probe in the living body, the metabolic reaction via the probe in the living body, etc. Can be visualized. Therefore, according to the multinuclear multiple magnetic resonance imaging apparatus of the present invention, the function of the probe in the living body, the metabolic reaction through the probe in the living body, and the like can be visualized accurately and with a low load on the living body. Can do.
　前記プローブが、第１核磁気共鳴活性核と当該第１核磁気共鳴活性核に磁気的に結合した第２核磁気共鳴活性核と当該第２核磁気共鳴活性核に磁気的に結合した第３核磁気共鳴活性核とからなる結合を有する化合物からなるプローブである場合、前記プローブをより選択的、かつ高感度で検出する観点から、本発明の多核多重磁気共鳴画像装置は、
　前記第１核磁気共鳴活性核に当該第１核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第１パルス印加部と、
　前記第２核磁気共鳴活性核に当該第２核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第２パルス印加部と、
　前記第３核磁気共鳴活性核に当該第３核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第３パルス印加部と、
　前記プローブに勾配磁場を印加する勾配磁場印加部と、
　前記第１核磁気共鳴活性核、前記第２核磁気共鳴活性核および前記第３核磁気共鳴活性核からなる群より選ばれた少なくとも１つの核磁気共鳴活性核の磁気共鳴信号を検出する検出部と、
　所定のパルス系列が生成されるように前記第１パルス印加と前記第２パルス印加部と前記第３パルス印加部と前記勾配磁場印加部とを制御する制御部と
を備えており、
　前記所定のパルス系列が、
　前記第１核磁気共鳴活性核から第２核磁気共鳴活性核への磁化移動を行なった後、前記第２核磁気共鳴活性核から第３核磁気共鳴活性核への磁化移動を行ない、さらに前記第３核磁気共鳴活性核から前記第２核磁気共鳴活性核を経て前記第１核磁気共鳴活性核への磁化を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、
　前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列と
を含むことが好ましい。 The probe is magnetically coupled to a first nuclear magnetic resonance active nucleus, a second nuclear magnetic resonance active nucleus that is magnetically coupled to the first nuclear magnetic resonance active nucleus, and a third magnetically coupled to the second nuclear magnetic resonance active nucleus. In the case of a probe comprising a compound having a bond comprising a nuclear magnetic resonance active nucleus, from the viewpoint of detecting the probe more selectively and with high sensitivity, the multinuclear multiple magnetic resonance imaging apparatus of the present invention is
A first pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus;
A second pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the second nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus;
A third pulse applying unit for applying an RF pulse corresponding to the resonance frequency of the third nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus;
A gradient magnetic field application unit for applying a gradient magnetic field to the probe;
A detector for detecting a magnetic resonance signal of at least one nuclear magnetic resonance active nucleus selected from the group consisting of the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus, and the third nuclear magnetic resonance active nucleus When,
A control unit that controls the first pulse application, the second pulse application unit, the third pulse application unit, and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
The predetermined pulse sequence is
After performing the magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus, performing the magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus, In order to perform magnetization transfer by applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization from the third nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus through the second nuclear magnetic resonance active nucleus. A magnetization transfer pulse sequence of
It is preferable that position information is added to the magnetic resonance signal and a signal acquisition pulse series for acquiring the magnetic resonance signal is included.
　以下、添付の図面を参照しながら、より詳細に説明するが、本発明は、かかる実施形態のみに限定されるものではない。なお、以下においては、前記プローブが、第１核磁気共鳴活性核と当該第１核磁気共鳴活性核に磁気的に結合した第２核磁気共鳴活性核と当該第２核磁気共鳴活性核に磁気的に結合した第３核磁気共鳴活性核とからなる結合を有する化合物からなるプローブである場合の多核多重磁気共鳴画像化装置を例として挙げて説明する。
　図１１は、本発明の一実施形態に係る多核多重磁気共鳴画像化装置の機能構成を示すブロック図である。 Hereinafter, although it demonstrates in detail, referring an accompanying drawing, this invention is not limited only to this embodiment. In the following, the probe is magnetically applied to the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus magnetically coupled to the first nuclear magnetic resonance active nucleus, and the second nuclear magnetic resonance active nucleus. An example of a multi-nuclear multiple magnetic resonance imaging apparatus in the case of a probe made of a compound having a bond consisting of a third nuclear magnetic resonance active nucleus that is bonded to the target will be described.
FIG. 11 is a block diagram showing a functional configuration of a multinuclear magnetic resonance imaging apparatus according to an embodiment of the present invention.
　図１１に示される多核多重磁気共鳴画像化装置１は、撮像領域としての内部空間に配置された検体中のプローブに静磁場、勾配磁場およびＲＦパルスを与えるガントリー部１０と、ＲＦパルスをガントリー部１０に送信し前記検体中のプローブにＲＦパルスを印加させるパルス印加部２０と、電源部３０と、パルス系列制御部４０と、エコー信号を受信して検出する検出部５０ａと、前記エコー信号に基づくデータを収集するデータ収集部６０と、コンピュータ７０とを備えている。 A multinuclear magnetic resonance imaging apparatus 1 shown in FIG. 11 includes a gantry unit 10 that applies a static magnetic field, a gradient magnetic field, and an RF pulse to a probe in a specimen arranged in an internal space serving as an imaging region, and an RF pulse that is a gantry unit. 10, a pulse applying unit 20 for applying an RF pulse to the probe in the specimen, a power supply unit 30, a pulse sequence control unit 40, a detection unit 50a for receiving and detecting an echo signal, and the echo signal A data collection unit 60 that collects data based on the computer 70 is provided.
　ガントリー部１０は、静磁場を発生させる筒状の静磁場磁石１１と、前記静磁場を均一化させる筒状のシムコイル１２と、勾配磁場を発生させる筒状の勾配磁場コイル１３と、ＲＦパルスを検体中のプローブに照射するとともに当該ＲＦパルスに起因するエコー信号を受信する筒状のＲＦコイル１４とから構成されている。 The gantry unit 10 includes a cylindrical static magnetic field magnet 11 that generates a static magnetic field, a cylindrical shim coil 12 that equalizes the static magnetic field, a cylindrical gradient magnetic field coil 13 that generates a gradient magnetic field, and an RF pulse. It comprises a cylindrical RF coil 14 that irradiates a probe in the specimen and receives an echo signal resulting from the RF pulse.
　静磁場磁石１１は、撮像領域に静磁場を発生させる機能を有している。静磁場磁石１１を構成する磁石としては、例えば、超電導磁石、永久磁石などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。静磁場磁石１１が超電導磁石から構成されたものである場合、当該静磁場磁石１１は、電源と接続され、当該電源から供給された電流によって静磁場を形成させる。 The static magnetic field magnet 11 has a function of generating a static magnetic field in the imaging region. Examples of the magnet that constitutes the static magnetic field magnet 11 include a superconducting magnet and a permanent magnet, but the present invention is not limited to such examples. In the case where the static magnetic field magnet 11 is composed of a superconducting magnet, the static magnetic field magnet 11 is connected to a power source and forms a static magnetic field by a current supplied from the power source.
　シムコイル１２は、静磁場磁石１１の内側に、当該静磁場磁石１１と同軸上に設けられている。また、シムコイル１２は、電源部３０のシムコイル電源３１と接続されている。シムコイル１２は、種々の補償磁場を発生させる成分コイルから構成されている。このような構成が採用されたシムコイル１２は、電源３１から電流が供給されることにより、静磁場の不均一を低減する補償磁場を発生させ、静磁場を均一化させることができる。 The shim coil 12 is provided coaxially with the static magnetic field magnet 11 inside the static magnetic field magnet 11. The shim coil 12 is connected to a shim coil power supply 31 of the power supply unit 30. The shim coil 12 is composed of component coils that generate various compensation magnetic fields. The shim coil 12 adopting such a configuration can generate a compensation magnetic field that reduces non-uniformity of the static magnetic field and can make the static magnetic field uniform when current is supplied from the power supply 31.
　勾配磁場コイル１３は、シムコイル１２の内側に、当該シムコイル１２と同軸上に設けられている。また、勾配磁場コイル１３は、電源部３０の勾配磁場コイル電源３２に接続されている。かかる勾配磁場コイル１３は、図示しないｘ軸勾配磁場コイルとｙ軸勾配磁場コイルとｚ軸勾配磁場コイルとから構成されている。このような構成が採用された勾配磁場コイル１３は、電源３１から電流が供給されることにより、ｘ軸方向への磁場勾配、ｙ軸方向への磁場勾配およびｚ軸方向への磁場勾配のそれぞれを発生させることができる。なお、本明細書において、「ｘ軸方向」は静磁場の方向に対し直交する方向、「ｙ軸方向」は静磁場の方向に対し直交方向であり、かつｘ軸と直交する方向、「ｚ軸方向」は、静磁場の方向に対し平行であり、y軸とｘ軸と直交する方向を示す。 The gradient magnetic field coil 13 is provided on the inner side of the shim coil 12 and coaxially with the shim coil 12. The gradient magnetic field coil 13 is connected to a gradient magnetic field coil power supply 32 of the power supply unit 30. The gradient magnetic field coil 13 includes an x-axis gradient magnetic field coil, a y-axis gradient magnetic field coil, and a z-axis gradient magnetic field coil (not shown). The gradient magnetic field coil 13 adopting such a configuration is supplied with a current from the power supply 31, thereby causing a magnetic field gradient in the x-axis direction, a magnetic field gradient in the y-axis direction, and a magnetic field gradient in the z-axis direction, respectively. Can be generated. In this specification, “x-axis direction” is a direction orthogonal to the direction of the static magnetic field, “y-axis direction” is a direction orthogonal to the direction of the static magnetic field and is orthogonal to the x-axis, “z” “Axial direction” indicates a direction parallel to the direction of the static magnetic field and perpendicular to the y-axis and the x-axis.
　ＲＦコイル１４は、勾配磁場コイル１３の内側に、当該勾配磁場コイル１３と同軸上に設けられている。また、ＲＦコイル１４は、パルス印加部２０と検出部５０ａとに接続されている。かかるＲＦコイル１４は、検体中のプローブへのＲＦパルスの照射と、検体中のプローブの第１核種、第２核種および第３核種が前記ＲＦパルスによって励起することに伴って発生したエコー信号の受信および検出部５０ａへの送信に兼用される。このような構成が採用されたＲＦコイル１４は、パルス印加部２０から送信されたＲＦパルスを検体中のプローブに照射するとともに当該ＲＦパルスに起因するエコー信号を検体中のプローブから受信して検出部５０ａに送信することができる。これにより、第１核種、第２核種および第３核種それぞれの共鳴周波数に相当するＲＦパルスが検体中のプローブに照射され、当該ＲＦパルスによる第１核種、第２核種および第３核種それぞれの励起に伴ってエコー信号が発生する。 The RF coil 14 is provided inside the gradient magnetic field coil 13 and coaxially with the gradient magnetic field coil 13. The RF coil 14 is connected to the pulse application unit 20 and the detection unit 50a. The RF coil 14 emits an RF pulse to the probe in the specimen, and an echo signal generated when the first nuclide, the second nuclide, and the third nuclide of the probe in the specimen are excited by the RF pulse. It is also used for reception and transmission to the detection unit 50a. The RF coil 14 employing such a configuration irradiates the probe in the sample with the RF pulse transmitted from the pulse applying unit 20, and receives and detects an echo signal resulting from the RF pulse from the probe in the sample. It can transmit to the part 50a. Thereby, the RF pulse corresponding to the resonance frequency of each of the first nuclide, the second nuclide and the third nuclide is irradiated to the probe in the specimen, and excitation of each of the first nuclide, the second nuclide and the third nuclide by the RF pulse As a result, an echo signal is generated.
　パルス印加部２０は、ＲＦコイル１４および検出部５０ａに接続されている。パルス印加部２０は、第１核磁気共鳴活性核に当該第１核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第１パルス印加部２１と、前記第２核磁気共鳴活性核に当該第２核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第２パルス印加部２２と、前記第３核磁気共鳴活性核に当該第３核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第３パルス印加部２３とから構成されている。かかるパルス印加部２０は、パルス系列制御部４０の制御下で、所定のパルス系列設定情報にしたがってプローブ中の結合に含まれる各核種の共鳴周波数に相当するＲＦパルスを生成し、ＲＦコイル１４に送信する。 The pulse application unit 20 is connected to the RF coil 14 and the detection unit 50a. The pulse applying unit 20 includes a first pulse applying unit 21 that applies an RF pulse corresponding to the resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus, and a second nuclear magnetic resonance active nucleus. A second pulse applying unit 22 for applying an RF pulse corresponding to the resonance frequency of the second nuclear magnetic resonance active nucleus; and a resonance frequency of the third nuclear magnetic resonance active nucleus corresponding to the third nuclear magnetic resonance active nucleus. It is comprised from the 3rd pulse application part 23 which applies RF pulse. The pulse applying unit 20 generates an RF pulse corresponding to the resonance frequency of each nuclide included in the coupling in the probe in accordance with predetermined pulse sequence setting information under the control of the pulse sequence control unit 40, and Send.
　電源部３０は、パルス系列制御部４０、シムコイル１２および勾配磁場コイル１３と接続されている。電源部３０は、シムコイル１２に電流を供給するシムコイル電源３１と、勾配磁場コイル１３に電流を供給する勾配磁場コイル電源３２とから構成されている。シムコイル電源３１は、パルス系列制御部４０に制御されており、パルス系列設定情報にしたがってシムコイル１２に電流を供給し、当該シムコイル１２による補償磁場の発生を制御する。また、勾配磁場コイル１３は、パルス系列制御部４０に制御されており、パルス系列設定情報にしたがって勾配磁場コイル１３に電流を供給し、当該勾配磁場コイル１３による勾配磁場の発生を制御する。 The power supply unit 30 is connected to the pulse sequence control unit 40, the shim coil 12, and the gradient magnetic field coil 13. The power supply unit 30 includes a shim coil power supply 31 that supplies current to the shim coil 12 and a gradient magnetic field coil power supply 32 that supplies current to the gradient magnetic field coil 13. The shim coil power supply 31 is controlled by the pulse sequence control unit 40, supplies current to the shim coil 12 according to the pulse sequence setting information, and controls the generation of the compensation magnetic field by the shim coil 12. Further, the gradient magnetic field coil 13 is controlled by the pulse sequence control unit 40, supplies current to the gradient magnetic field coil 13 according to the pulse sequence setting information, and controls the generation of the gradient magnetic field by the gradient magnetic field coil 13.
　パルス系列制御部４０は、コンピュータ７０、パルス印加部２０、電源部３０の勾配磁場コイル電源３２およびデータ収集部６０と接続されている。かかるパルス系列制御部４０は、コンピュータ７０に制御されており、所定のパルス系列設定情報にしたがってパルス印加部２０および勾配磁場コイル電源３２を制御する。 The pulse series control unit 40 is connected to the computer 70, the pulse application unit 20, the gradient magnetic field coil power supply 32 of the power supply unit 30, and the data collection unit 60. The pulse sequence control unit 40 is controlled by the computer 70 and controls the pulse applying unit 20 and the gradient magnetic field coil power supply 32 in accordance with predetermined pulse sequence setting information.
　検出部５０ａは、ＲＦコイル１４およびデータ収集部と接続されている。検出部５０ａは、第１核種、第２核種および第３核種が前記ＲＦパルスによって励起することに伴って発生したエコー信号である磁気共鳴信号をＲＦコイル１４から受信し、検出する。かかる検出部５０ａは、ＲＦコイル１４から前記第１核磁気共鳴活性核の磁気共鳴信号を受信する第１受信部５１と、ＲＦコイル１４から前記第２核磁気共鳴活性核の磁気共鳴信号を受信する第２受信部５２と、ＲＦコイル１４から前記第３核磁気共鳴活性核の磁気共鳴信号を受信する第３受信部５３とから構成されている。検出部５０ａで検出された磁気共鳴信号に関する情報は、データ収集部６０に送信される。 The detection unit 50a is connected to the RF coil 14 and the data collection unit. The detection unit 50a receives and detects a magnetic resonance signal, which is an echo signal generated when the first nuclide, the second nuclide, and the third nuclide are excited by the RF pulse, from the RF coil 14. The detection unit 50 a receives the first resonance unit 51 that receives the magnetic resonance signal of the first nuclear magnetic resonance active nucleus from the RF coil 14, and the magnetic resonance signal of the second nuclear magnetic resonance activation nucleus from the RF coil 14. And a third receiver 53 that receives a magnetic resonance signal of the third nuclear magnetic resonance active nucleus from the RF coil 14. Information regarding the magnetic resonance signal detected by the detection unit 50 a is transmitted to the data collection unit 60.
　データ収集部６０は、検出部５０ａおよびコンピュータ７０と接続されている。データ収集部６０は、検出部５０ａで検出された磁気共鳴信号をデジタル信号に変換し、磁気共鳴信号に関するデータを得る。前記データとしては、例えば、強度に関するデータ、ケミカルシフトに関するデータなどが挙げられるが、本発明は、かかる例示のみに限定されるものではない。かかるデータ収集部６０は、収集したデータをコンピュータ７０に送信する。 The data collection unit 60 is connected to the detection unit 50a and the computer 70. The data collection unit 60 converts the magnetic resonance signal detected by the detection unit 50a into a digital signal, and obtains data related to the magnetic resonance signal. Examples of the data include data on strength, data on chemical shift, and the like, but the present invention is not limited to such examples. The data collection unit 60 transmits the collected data to the computer 70.
　コンピュータ７０は、パルス系列制御部４０およびデータ収集部６０に接続されている。コンピュータ７０は、演算装置７１と、入力装置７２と、出力装置７３と、記憶部７４とから構成されている。かかる演算装置７１は、所定のパルス系列設定情報にしたがってパルス系列制御部４０を制御するためのプログラム、データを画像化する処理を行なうためのプログラムを実行する。これにより、演算装置７１は、パルス系列制御部４０の動作を制御するとともに、収集されたデータについてフーリエ変換などの処理を行ない、検体中のプローブに含まれる核磁気共鳴活性核のスピンの画像データを作成する。入力装置７２、出力装置７３および記憶部７４は、演算装置７１に接続されている。演算装置７１は、例えば、ＣＰＵなどから構成されている。入力装置７２は、多核多重磁気共鳴画像化装置１の操作の指令、検体の情報などを演算装置に入力するための装置である。入力装置７２としては、例えば、キーボード、音声入力装置などが挙げられるが、本発明は、かかる例示のみに限定されるものではない。出力装置７３は、演算装置７１によって処理されたデータに基づく画像を表示または出力する。出力装置７３としては、例えば、ディスプレイ、プリンタなどが挙げられるが、本発明は、かかる例示のみに限定されるものではない。記憶部７４は、演算装置７１に入力された情報、パルス系列を生成させるためのパルス系列設定情報およびプログラム、データを画像化する処理を行なうためのプログラムなどを記憶する。かかるコンピュータ７０では、演算装置７１によって作成された画像データが出力装置７３に送信されることにより、出力装置７３で画像として表示または出力される。 The computer 70 is connected to the pulse sequence control unit 40 and the data collection unit 60. The computer 70 includes an arithmetic device 71, an input device 72, an output device 73, and a storage unit 74. The arithmetic device 71 executes a program for controlling the pulse sequence control unit 40 in accordance with predetermined pulse sequence setting information and a program for performing processing for imaging data. Thereby, the arithmetic unit 71 controls the operation of the pulse sequence control unit 40 and performs processing such as Fourier transform on the collected data, and image data of spins of nuclear magnetic resonance active nuclei contained in the probe in the specimen. Create The input device 72, the output device 73, and the storage unit 74 are connected to the arithmetic device 71. The arithmetic device 71 is composed of, for example, a CPU. The input device 72 is a device for inputting an operation command of the multinuclear multiple magnetic resonance imaging apparatus 1, sample information, and the like to the arithmetic device. Examples of the input device 72 include a keyboard and a voice input device. However, the present invention is not limited to such an example. The output device 73 displays or outputs an image based on the data processed by the arithmetic device 71. Examples of the output device 73 include a display and a printer, but the present invention is not limited to such examples. The storage unit 74 stores information input to the arithmetic unit 71, pulse sequence setting information and program for generating a pulse sequence, a program for performing processing for imaging data, and the like. In the computer 70, the image data created by the arithmetic device 71 is transmitted to the output device 73, and is displayed or output as an image on the output device 73.
　パルス系列としては、例えば、図１２に示されるパルス系列などが挙げられる。以下、前記パルス系列を詳細に説明する。図１２は本発明の一実施形態に係る多核多重磁気共鳴画像化装置におけるパルス系列の一例を示す概略説明図である。なお、図１２に示されるパルス系列は、図１に示されるパルス系列と同じである。図１２は、各ＲＦパルスに対する符号および各ステップに対応する符号が付されている点で図１と異なっている。図１２に示されるパルス系列は、ＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列（図１２中、「三重核磁気共鳴法」参照）と、前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列（図１２中、「高速スピンエコーＭＲＩ」参照）とを含んでいる。 Examples of the pulse sequence include the pulse sequence shown in FIG. Hereinafter, the pulse sequence will be described in detail. FIG. 12 is a schematic explanatory diagram illustrating an example of a pulse sequence in the multinuclear multiple magnetic resonance imaging apparatus according to an embodiment of the present invention. The pulse sequence shown in FIG. 12 is the same as the pulse sequence shown in FIG. FIG. 12 is different from FIG. 1 in that reference numerals for the RF pulses and reference numerals corresponding to the steps are attached. The pulse sequence shown in FIG. 12 includes a magnetization transfer pulse sequence (see “triple nuclear magnetic resonance method” in FIG. 12) for applying magnetization transfer by applying an RF pulse and a gradient magnetic field to the probe, and the magnetic resonance. It includes a signal collection pulse sequence (see “Fast Spin Echo MRI” in FIG. 12) for adding position information to the signal and collecting the magnetic resonance signal.
　前記磁化移動パルス系列は、下記（Ｉ）、（ＩＩ）、（ＩＩＩ）および（ＩＶ）の磁化移動をこの順で行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加するための系列である：
（Ｉ）前記第１核磁気共鳴活性核から第２核磁気共鳴活性核への磁化移動、
（ＩＩ）前記第２核磁気共鳴活性核から第３核磁気共鳴活性核への磁化移動、
（ＩＩＩ）前記第３核磁気共鳴活性核から前記第２核磁気共鳴活性核への磁化移動、および
（ＩＶ）前記第２核磁気共鳴活性核から前記第１核磁気共鳴活性核への磁化移動。 The magnetization transfer pulse sequence is a sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform the following magnetization transfers (I), (II), (III), and (IV) in this order:
(I) Magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus,
(II) magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus;
(III) Magnetization transfer from the third nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus, and (IV) Magnetization transfer from the second nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus. .
　前記磁化移動パルス系列は、ＲＦパルスの印加パターンであるＲＦパルス印加系列と、勾配磁場の印加パターンである勾配磁場印加系列とを含む。 The magnetization transfer pulse sequence includes an RF pulse application sequence which is an RF pulse application pattern and a gradient magnetic field application sequence which is a gradient magnetic field application pattern.
　前記ＲＦパルス印加系列は、パルス系列制御部４０によって下記ステップ（ａ１）～（ａ１６）：
　（ａ１）前記第１核磁気共鳴活性核に９０度の第１ＲＦパルスＰ１を印加した後、当該第１核磁気共鳴活性核に１８０度の第２ＲＦパルスＰ２をさらに印加するステップ、
　（ａ２）前記第２ＲＦパルスＰ２を印加すると同時または印加した後、前記第２核磁気共鳴活性核に１８０度の第３ＲＦパルスＰ３を印加するステップ、
　（ａ３）前記第１核磁気共鳴活性核に９０度の第４ＲＦパルスＰ４を印加した後、前記第２核磁気共鳴活性核に９０度の第５ＲＦパルスＰ５を印加するステップ、
　（ａ４）前記第２核磁気共鳴活性核に１８０度の第６ＲＦパルスＰ６を印加するステップ、
　（ａ５）前記第６ＲＦパルスＰ６を印加すると同時または印加した後、前記第３核磁気共鳴活性核に１８０度の第７ＲＦパルスＰ７を印加するステップ、
　（ａ６）前記第２核磁気共鳴活性核に９０度の第８ＲＦパルスＰ８を印加した後、前記第３核磁気共鳴活性核に９０度の第９ＲＦパルスＰ９を印加するステップ、
　（ａ７）前記第２核磁気共鳴活性核に１８０度の第１０ＲＦパルスＰ１０を印加するステップ、
　（ａ８）前記第１核磁気共鳴活性核に１８０度の第１１ＲＦパルスＰ１１と前記第３核磁気共鳴活性核に１８０度の第１２ＲＦパルスＰ１２とを同時に印加するステップ、
　（ａ９）前記第２核磁気共鳴活性核に１８０度の第１３ＲＦパルスＰ１３を印加するステップ、
　（ａ１０）前記第３核磁気共鳴活性核に９０度の第１４ＲＦパルスＰ１４を印加するステップ、
　（ａ１１）前記第２核磁気共鳴活性核に９０度の第１５ＲＦパルスＰ１５を印加するステップ、
　（ａ１２）前記第２核磁気共鳴活性核に１８０度の第１６ＲＦパルスＰ１６を印加するステップ、
　（ａ１３）前記第１６ＲＦパルスＰ１６と同時または印加後に、前記第３核磁気共鳴活性核に１８０度の第１７ＲＦパルスＰ１７を印加するステップ、
　（ａ１４）前記第２核磁気共鳴活性核に９０度の第１８ＲＦパルスＰ１８を印加した後、前記第１核磁気共鳴活性核に９０度の第１９ＲＦパルスＰ１９を印加するステップ、
　（ａ１５）前記第１核磁気共鳴活性核に１８０度の第２０ＲＦパルスＰ２０を印加するステップ、および
　（ａ１６）前記第２０ＲＦパルスＰ２０を印加すると同時または印加後に、前記第２核磁気共鳴活性核に１８０度の第２１ＲＦパルスＰ２１を印加するステップ
がこの順に実行されることによって生成される系列である。パルス系列制御部４０によって前記ステップ（ａ１）～（ａ３）が実行されることにより、（Ｉ）前記第１核磁気共鳴活性核から第２核磁気共鳴活性核への磁化移動〔前記磁化移動（Ｉ）〕が行なわれる。つぎに、パルス系列制御部４０によって前記ステップ（ａ４）～（ａ６）が実行されることにより、前記第２核磁気共鳴活性核から第３核磁気共鳴活性核への磁化移動〔前記磁化移動（ＩＩ）〕が行なわれる。その後、パルス系列制御部４０によって前記ステップ（ａ７）～（ａ１３）が実行されることにより、前記第３核磁気共鳴活性核から前記第２核磁気共鳴活性核への磁化移動〔前記磁化移動（ＩＩＩ）〕が行なわれる。最後に、パルス系列制御部４０によって前記ステップ（ａ１４）～（ａ１６）が実行されることにより、前記第２核磁気共鳴活性核から前記第１核磁気共鳴活性核への磁化移動〔前記磁化移動（ＩＶ）〕が行なわれる。 The RF pulse application sequence is processed by the pulse sequence control unit 40 in the following steps (a1) to (a16):
(A1) after applying a first RF pulse P1 of 90 degrees to the first nuclear magnetic resonance active nucleus, further applying a second RF pulse P2 of 180 degrees to the first nuclear magnetic resonance active nucleus;
(A2) applying a third RF pulse P3 of 180 degrees to the second nuclear magnetic resonance active nucleus at the same time as or after applying the second RF pulse P2.
(A3) applying a 90 degree fourth RF pulse P5 to the first nuclear magnetic resonance active nucleus and then applying a 90 degree fifth RF pulse P5 to the second nuclear magnetic resonance active nucleus;
(A4) applying a sixth RF pulse P6 of 180 degrees to the second nuclear magnetic resonance active nucleus;
(A5) applying a seventh RF pulse P7 of 180 degrees to the third nuclear magnetic resonance active nucleus at the same time as or after applying the sixth RF pulse P6;
(A6) applying a 90 degree eighth RF pulse P8 to the second nuclear magnetic resonance active nucleus and then applying a 90 degree ninth RF pulse P9 to the third nuclear magnetic resonance active nucleus;
(A7) applying a 180 degree tenth RF pulse P10 to the second nuclear magnetic resonance active nucleus;
(A8) simultaneously applying an eleventh RF pulse P11 of 180 degrees to the first nuclear magnetic resonance active nucleus and a twelfth RF pulse P12 of 180 degrees to the third nuclear magnetic resonance active nucleus;
(A9) applying a 180-degree 13th RF pulse P13 to the second nuclear magnetic resonance active nucleus,
(A10) applying a 14th RF pulse P14 of 90 degrees to the third nuclear magnetic resonance active nucleus;
(A11) applying a 90-degree 15th RF pulse P15 to the second nuclear magnetic resonance active nucleus,
(A12) applying a 180-degree 16th RF pulse P16 to the second nuclear magnetic resonance active nucleus,
(A13) applying a 17th RF pulse P17 of 180 degrees to the third nuclear magnetic resonance active nucleus simultaneously with or after application of the 16th RF pulse P16;
(A14) applying a 90 degree nineteenth RF pulse P19 to the first nuclear magnetic resonance active nucleus after applying a ninety degree eighteenth RF pulse P18 to the second nuclear magnetic resonance active nucleus;
(A15) applying a 180-degree 20th RF pulse P20 to the first nuclear magnetic resonance active nucleus; and (a16) applying to the second nuclear magnetic resonance active nucleus simultaneously with or after applying the 20th RF pulse P20. This is a sequence generated by executing the steps of applying the 21st RF pulse P21 of 180 degrees in this order. When the steps (a1) to (a3) are executed by the pulse sequence controller 40, (I) magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus [the magnetization transfer ( I)] is performed. Next, when the steps (a4) to (a6) are executed by the pulse sequence controller 40, the magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus [the magnetization transfer ( II)] is performed. Thereafter, the steps (a7) to (a13) are executed by the pulse sequence controller 40, whereby the magnetization transfer from the third nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus [the magnetization transfer ( III)] is performed. Finally, when the steps (a14) to (a16) are executed by the pulse sequence control unit 40, the magnetization transfer from the second nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus [the magnetization transfer (IV)] is performed.
　前記ＲＦパルス印加系列は、具体的には、図１２に示されるように、
　（ａ１－１）前記第１核磁気共鳴活性核に印加される９０度の第１ＲＦパルスＰ１、
　（ａ１－２）前記第１ＲＦパルスＰ１の印加後に、前記第１核磁気共鳴活性核に印加される１８０度の第２ＲＦパルスＰ２、
　（ａ２）前記第２ＲＦパルスＰ２の印加と同時または印加後に、前記第２核磁気共鳴活性核に印加される１８０度の第３ＲＦパルスＰ３、
　（ａ３－１）前記第３ＲＦパルスＰ３の印加後に、前記第１核磁気共鳴活性核に印加される９０度の第４ＲＦパルスＰ４、
　（ａ３－２）前記第４ＲＦパルスＰ４の印加後に、前記第２核磁気共鳴活性核に印加される９０度の第５ＲＦパルスＰ５、
　（ａ４）前記第５ＲＦパルスＰ５の印加後に、前記第２核磁気共鳴活性核に印加される１８０度の第６ＲＦパルスＰ６、
　（ａ５）前記第６ＲＦパルスＰ６の印加と同時または印加後に、前記第３核磁気共鳴活性核に印加される１８０度の第７ＲＦパルスＰ７、
　（ａ６－１）前記第７ＲＦパルスＰ７の印加後に、前記第２核磁気共鳴活性核に印加される９０度の第８ＲＦパルスＰ８、
　（ａ６－２）前記第８ＲＦパルスＰ８の印加後に、前記第３核磁気共鳴活性核に印加される９０度の第９ＲＦパルスＰ９、
　（ａ７）前記第９ＲＦパルスＰ９の印加後に、前記第２核磁気共鳴活性核に印加される１８０度の第１０ＲＦパルスＰ１０、
　（ａ８－１）前記第１０ＲＦパルスＰ１０の印加後に、前記第１核磁気共鳴活性核に印加される１８０度の第１１ＲＦパルスＰ１１、
　（ａ８－２）前記第１１ＲＦパルスＰ１１の印加と同時に、前記第３核磁気共鳴活性核に印加される１８０度の第１２ＲＦパルスＰ１２、
　（ａ９）前記第１１ＲＦパルスＰ１１および第１２ＲＦパルスＰ１２の印加後に、前記第２核磁気共鳴活性核に印加される１８０度の第１３ＲＦパルスＰ１３、
　（ａ１０）前記第１３ＲＦパルスＰ１３の印加後に、前記第３核磁気共鳴活性核に印加される９０度の第１４ＲＦパルスＰ１４、
　（ａ１１）前記第１４ＲＦパルスＰ１４の印加後に、前記第２核磁気共鳴活性核に印加される９０度の第１５ＲＦパルスＰ１５、
　（ａ１２）前記第１５ＲＦパルスＰ１５の印加後に、前記第２核磁気共鳴活性核に印加される１８０度の第１６ＲＦパルスＰ１６、
　（ａ１３）前記第１６ＲＦパルスＰ１６の印加と同時または印加後に、前記第３核磁気共鳴活性核に印加される１８０度の第１７ＲＦパルスＰ１７、
　（ａ１４－１）前記第１７ＲＦパルスＰ１７の印加後に、前記第２核磁気共鳴活性核に印加される９０度の第１８ＲＦパルスＰ１８、
　（ａ１４－２）前記第１８ＲＦパルスＰ１８の印加後に、前記第１核磁気共鳴活性核に印加される９０度の第１９ＲＦパルスＰ１９、
　（ａ１５）前記第１９ＲＦパルスＰ１９の印加後に、前記第１核磁気共鳴活性核に印加される１８０度の第２０ＲＦパルスＰ２０、および
　（ａ１６）前記第２０ＲＦパルスＰ２０の印加と同時または印加後に、前記第２核磁気共鳴活性核に印加される１８０度の第２１ＲＦパルスＰ２１
を含む系列である。ここで、前記（ａ１－１）および（ａ１－２）のＲＦパルスは、パルス系列制御部４０によって前記ステップ（ａ１）が実行されることによって発生するパルスである。前記（ａ３－１）および（ａ３－２）のＲＦパルスは、パルス系列制御部４０によって前記ステップ（ａ３）が実行されることによって発生するＲＦパルスである。前記（ａ６－１）および（ａ６－２）のＲＦパルスは、パルス系列制御部４０によって前記ステップ（ａ６）が実行されることによって発生するＲＦパルスである。前記（ａ１４－１）および（ａ１４－２）のＲＦパルスは、パルス系列制御部４０によって前記ステップ（ａ１４）が実行されることによって発生するパルスである。前記（ａ２）、（ａ４）、（ａ５）、（ａ７）、（ａ９）、（ａ１０）、（ａ１１）、（ａ１２）、（ａ１３）、（ａ１５）および（ａ１６）のＲＦパルスは、それぞれ、パルス系列制御部４０によって前記ステップ（ａ２）、（ａ４）、（ａ５）、（ａ７）、（ａ９）、（ａ１０）、（ａ１１）、（ａ１２）、（ａ１３）、（ａ１５）および（ａ１６）が実行されることによって発生するＲＦパルスである。 Specifically, the RF pulse application sequence is as shown in FIG.
(A1-1) 90 degree first RF pulse P1 applied to the first nuclear magnetic resonance active nucleus,
(A1-2) A second RF pulse P2 of 180 degrees applied to the first nuclear magnetic resonance active nucleus after the application of the first RF pulse P1,
(A2) A third RF pulse P3 of 180 degrees applied to the second nuclear magnetic resonance active nucleus simultaneously with or after the application of the second RF pulse P2.
(A3-1) After applying the third RF pulse P3, a 90 degree fourth RF pulse P4 applied to the first nuclear magnetic resonance active nucleus,
(A3-2) a 90 degree fifth RF pulse P5 applied to the second nuclear magnetic resonance active nucleus after the application of the fourth RF pulse P4;
(A4) a 180 degree sixth RF pulse P6 applied to the second nuclear magnetic resonance active nucleus after the application of the fifth RF pulse P5;
(A5) A 180 degree seventh RF pulse P7 applied to the third nuclear magnetic resonance active nucleus simultaneously with or after the application of the sixth RF pulse P6,
(A6-1) After applying the seventh RF pulse P7, a 90 degree eighth RF pulse P8 applied to the second nuclear magnetic resonance active nucleus,
(A6-2) A 90 degree ninth RF pulse P9 applied to the third nuclear magnetic resonance active nucleus after application of the eighth RF pulse P8,
(A7) A tenth RF pulse P10 of 180 degrees applied to the second nuclear magnetic resonance active nucleus after application of the ninth RF pulse P9,
(A8-1) An eleventh RF pulse P11 of 180 degrees applied to the first nuclear magnetic resonance active nucleus after the application of the tenth RF pulse P10,
(A8-2) A 180 degree twelfth RF pulse P12 applied to the third nuclear magnetic resonance active nucleus simultaneously with the application of the eleventh RF pulse P11,
(A9) After applying the eleventh RF pulse P11 and the twelfth RF pulse P12, a 180-degree thirteenth RF pulse P13 applied to the second nuclear magnetic resonance active nucleus,
(A10) After application of the thirteenth RF pulse P13, a fourteenth RF pulse P14 of 90 degrees applied to the third nuclear magnetic resonance active nucleus,
(A11) A 90-degree 15th RF pulse P15 applied to the second nuclear magnetic resonance active nucleus after the application of the 14th RF pulse P14,
(A12) A 180 degree sixteenth RF pulse P16 applied to the second nuclear magnetic resonance active nucleus after application of the fifteenth RF pulse P15,
(A13) A 180 degree seventeenth RF pulse P17 applied to the third nuclear magnetic resonance active nucleus simultaneously with or after the application of the sixteenth RF pulse P16,
(A14-1) After applying the 17th RF pulse P17, a 90 degree 18th RF pulse P18 applied to the second nuclear magnetic resonance active nucleus,
(A14-2) A 90-degree nineteenth RF pulse P19 applied to the first nuclear magnetic resonance active nucleus after the application of the eighteenth RF pulse P18,
(A15) After the application of the 19th RF pulse P19, the 180th 20th RF pulse P20 applied to the first nuclear magnetic resonance active nucleus, and (a16) at the same time as or after the application of the 20th RF pulse P20, 180 degree 21st RF pulse P21 applied to the second nuclear magnetic resonance active nucleus
Is a series including Here, the RF pulses (a1-1) and (a1-2) are pulses generated by the step (a1) being executed by the pulse sequence control unit 40. The RF pulses (a3-1) and (a3-2) are RF pulses generated when the step (a3) is executed by the pulse sequence control unit 40. The RF pulses (a6-1) and (a6-2) are RF pulses generated by the step (a6) being executed by the pulse sequence control unit 40. The RF pulses (a14-1) and (a14-2) are pulses generated when the step (a14) is executed by the pulse sequence control unit 40. The RF pulses of (a2), (a4), (a5), (a7), (a9), (a10), (a11), (a12), (a13), (a15) and (a16) are respectively The pulse sequence control unit 40 performs the steps (a2), (a4), (a5), (a7), (a9), (a10), (a11), (a12), (a13), (a15) and ( This is an RF pulse generated by executing a16).
　また、前記勾配磁場印加系列は、パルス系列制御部４０によって下記ステップ（ｂ１）～（ｂ１２）：
　（ｂ１）前記第１ＲＦパルスＰ１と前記第２ＲＦパルスＰ２とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ２）前記第３ＲＦパルスＰ３と前記第４ＲＦパルスＰ４とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ３）前記第４ＲＦパルスＰ４と前記第５ＲＦパルスＰ５とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ４）前記第８ＲＦパルスＰ８と前記第９ＲＦパルスＰ９とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ５）前記第９ＲＦパルスＰ９と前記第１０ＲＦパルスＰ１０とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ６）前記第１０ＲＦパルスＰ１０と前記第１１ＲＦパルスＰ１１とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ７）前記第１２ＲＦパルスＰ１２と前記第１３ＲＦパルスＰ１３とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ８）前記第１３ＲＦパルスＰ１３と前記第１４ＲＦパルスＰ１４とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ９）前記第１４ＲＦパルスＰ１４と前記第１５ＲＦパルスＰ１５とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ１０）前記第１８ＲＦパルスＰ１８と前記第１９ＲＦパルスＰ１９とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
　（ｂ１１）前記第１９ＲＦパルスＰ１９と前記第２０ＲＦパルスＰ２０とのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、および
　（ｂ１２）前記第２１ＲＦパルスＰ２１の印加後において、前記プローブに勾配磁場を印加するステップ
がこの順に実行されることによって生成される系列である。 Further, the gradient magnetic field application sequence is performed by the pulse sequence control unit 40 in the following steps (b1) to (b12):
(B1) applying a gradient magnetic field to the probe in the interval between the first RF pulse P1 and the second RF pulse P2.
(B2) applying a gradient magnetic field to the probe in the interval between the third RF pulse P3 and the fourth RF pulse P4;
(B3) applying a gradient magnetic field to the probe in the interval between the fourth RF pulse P4 and the fifth RF pulse P5;
(B4) applying a gradient magnetic field to the probe in the interval between the eighth RF pulse P8 and the ninth RF pulse P9;
(B5) applying a gradient magnetic field to the probe in the interval between the ninth RF pulse P9 and the tenth RF pulse P10;
(B6) applying a gradient magnetic field to the probe in the interval between the tenth RF pulse P10 and the eleventh RF pulse P11;
(B7) applying a gradient magnetic field to the probe at an interval between the twelfth RF pulse P12 and the thirteenth RF pulse P13;
(B8) applying a gradient magnetic field to the probe in an interval between the thirteenth RF pulse P13 and the fourteenth RF pulse P14;
(B9) applying a gradient magnetic field to the probe in an interval between the fourteenth RF pulse P14 and the fifteenth RF pulse P15;
(B10) applying a gradient magnetic field to the probe at an interval between the 18th RF pulse P18 and the 19th RF pulse P19;
(B11) applying a gradient magnetic field to the probe at an interval between the 19th RF pulse P19 and the 20th RF pulse P20; and (b12) applying a gradient magnetic field to the probe after the application of the 21st RF pulse P21. This is a sequence generated by executing the steps to be executed in this order.
　前記勾配磁場印加系列は、具体的には、図１２に示されるように
　（ｂ１）前記第１ＲＦパルスＰ１と前記第２ＲＦパルスＰ２とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ２）前記第３ＲＦパルスＰ３と前記第４ＲＦパルスＰ４とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ３）前記第４ＲＦパルスＰ４と前記第５ＲＦパルスＰ５とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ４）前記第８ＲＦパルスＰ８と前記第９ＲＦパルスＰ９とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ５）前記第９ＲＦパルスＰ９と前記第１０ＲＦパルスＰ１０とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ６）前記第１０ＲＦパルスＰ１０と前記第１１ＲＦパルスＰ１１とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ７）前記第１２ＲＦパルスＰ１２と前記第１３ＲＦパルスＰ１３とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ８）前記第１３ＲＦパルスＰ１３と前記第１４ＲＦパルスＰ１４とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ９）前記第１４ＲＦパルスＰ１４と前記第１５ＲＦパルスＰ１５とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ１０）前記第１８ＲＦパルスＰ１８と前記第１９ＲＦパルスＰ１９とのインターバルに、前記プローブに印加される勾配磁場、
　（ｂ１１）前記第１９ＲＦパルスＰ１９と前記第２０ＲＦパルスＰ２０とのインターバルに、前記プローブに印加される勾配磁場、および
　（ｂ１２）前記第２１ＲＦパルスＰ２１の印加後に、前記プローブに印加される勾配磁場
を含む系列である。前記（ｂ１）～（ｂ１２）の勾配磁場は、それぞれ、パルス系列制御部４０によって前記ステップ（ｂ１）～（ｂ１２）が実行されることによって発生する勾配磁場である。 Specifically, the gradient magnetic field application series is as shown in FIG. 12 (b1) a gradient magnetic field applied to the probe in the interval between the first RF pulse P1 and the second RF pulse P2,
(B2) a gradient magnetic field applied to the probe in the interval between the third RF pulse P3 and the fourth RF pulse P4;
(B3) a gradient magnetic field applied to the probe in the interval between the fourth RF pulse P4 and the fifth RF pulse P5;
(B4) a gradient magnetic field applied to the probe in the interval between the eighth RF pulse P8 and the ninth RF pulse P9;
(B5) a gradient magnetic field applied to the probe in the interval between the ninth RF pulse P9 and the tenth RF pulse P10;
(B6) a gradient magnetic field applied to the probe in the interval between the tenth RF pulse P10 and the eleventh RF pulse P11;
(B7) a gradient magnetic field applied to the probe in the interval between the twelfth RF pulse P12 and the thirteenth RF pulse P13;
(B8) a gradient magnetic field applied to the probe in the interval between the thirteenth RF pulse P13 and the fourteenth RF pulse P14;
(B9) a gradient magnetic field applied to the probe in the interval between the fourteenth RF pulse P14 and the fifteenth RF pulse P15;
(B10) A gradient magnetic field applied to the probe in the interval between the 18th RF pulse P18 and the 19th RF pulse P19,
(B11) A gradient magnetic field applied to the probe at an interval between the 19th RF pulse P19 and the 20th RF pulse P20, and (b12) a gradient magnetic field applied to the probe after the application of the 21st RF pulse P21. It is a series including. The gradient magnetic fields (b1) to (b12) are gradient magnetic fields generated by executing the steps (b1) to (b12) by the pulse sequence control unit 40, respectively.
　前記所定のパルス系列設定情報は、磁化移動パルス系列設定情報と信号収集パルス系列設定情報とを含んでいる。また、前記ＲＦパルス印加系列情報は、パルス系列制御部４０に前記ステップ（ａ１）～（ａ１６）の各ステップを実行させるためのＲＦパルス印加系列情報と、パルス系列制御部４０に前記ステップ（ｂ１）～（ａ１２）の各ステップを実行させるための勾配磁場印加系列情報とを含んでいる。 The predetermined pulse sequence setting information includes magnetization transfer pulse sequence setting information and signal collection pulse sequence setting information. The RF pulse application sequence information includes the RF pulse application sequence information for causing the pulse sequence control unit 40 to execute the steps (a1) to (a16), and the pulse sequence control unit 40 for the step (b1). ) To (a12) and gradient magnetic field application sequence information for executing each step.
　図１３は、本発明の一実施形態に係る多核多重磁気共鳴画像化装置におけるパルス系列の変形例を示す概略説明図である。図１３に示されるパルス系列は、パルス系列制御部４０によって前記ステップ（ａ１４）の後に、前記ステップ（a１５）および前記ステップ（a１６）が実行される代わりに、前記ステップ（ａ１４）の後に、
（ａ１７）前記第２核磁気共鳴活性核に９０度の第２２ＲＦパルスＰ２２を印加するステップ、
（ａ１８）前記第１核磁気共鳴活性核に１８０度の第２３ＲＦパルス２３を印加するステップ、および
（ａ１９）前記第２核磁気共鳴活性核に９０度の第２４ＲＦパルス２４を印加するステップ
が実行されることによって生成される系列をＲＦパルス印加系列として含む系列である。 FIG. 13 is a schematic explanatory diagram showing a modification of the pulse series in the multinuclear magnetic resonance imaging apparatus according to one embodiment of the present invention. The pulse sequence shown in FIG. 13 is performed after the step (a14), instead of the steps (a15) and (a16) being performed by the pulse sequence control unit 40 after the step (a14).
(A17) applying a 90-degree 22nd RF pulse P22 to the second nuclear magnetic resonance active nucleus;
(A18) The step of applying the 23rd RF pulse 23 of 180 degrees to the first nuclear magnetic resonance active nucleus, and (a19) The step of applying the 24th RF pulse 24 of 90 degrees to the second nuclear magnetic resonance active nucleus is executed. This is a sequence that includes a sequence generated as a result of being applied as an RF pulse application sequence.
　なお、本発明の多核多重磁気共鳴画像化装置は、第１受信部５１と第２受信部５２と第３受信部５３とから構成される検出部５０ａの代わりに、図１４に示されるように、第１核種が前記ＲＦパルスによって励起することに伴って発生したエコー信号、第２核種が前記ＲＦパルスによって励起することに伴って発生したエコー信号および第３核種が前記ＲＦパルスによって励起することに伴って発生したエコー信号のいずれかをＲＦコイル１４から受信する受信部５４から構成された検出部５０ｂを備えていてもよい。 Note that the multinuclear multiple magnetic resonance imaging apparatus of the present invention is as shown in FIG. 14 instead of the detection unit 50a including the first reception unit 51, the second reception unit 52, and the third reception unit 53. The echo signal generated when the first nuclide is excited by the RF pulse, the echo signal generated when the second nuclide is excited by the RF pulse, and the third nuclide is excited by the RF pulse. A detecting unit 50b including a receiving unit 54 that receives any of the echo signals generated along with the RF coil 14 may be provided.
　以上説明したように、本発明の多核多重磁気共鳴画像化装置は、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができ、正確で、かつ検体への負荷が少ない画像診断に使用されることが期待されるものである。 As described above, the multinuclear magnetic resonance imaging apparatus of the present invention obtains not only the form information of the specimen but also the position information of the probe in the specimen, and the function of the probe in the living body, the probe in the living body. Therefore, it is expected to be used for diagnostic imaging that is accurate and has a low load on the specimen.
実験例１
　式（ｃｌ）： Experimental example 1
Formula (cl):
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
で表わされる１３Ｃ／１５Ｎ－ラベル化塩化コリンの重水溶液（溶液中における１３Ｃ／１５Ｎ－ラベル化塩化コリンの濃度：６ｍｇ／ｍＬ、３０ｍｇ／ｍＬまたは１２０ｍｇ／ｍＬ）１ｍＬ、１Ｍ１３Ｃ－ラベル化乳酸の重水溶液１ｍＬおよび水１ｍＬそれぞれを試料として用いた。各試料を７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル上に並べて配置した。 13 C / 15 N-labeled choline chloride in water (concentration of 13 C / 15 N-labeled choline chloride in solution: 6 mg / mL, 30 mg / mL or 120 mg / mL) 1 mL, 1M 13 C -1 mL of a labeled aqueous solution of lactic acid and 1 mL of water were used as samples. Each sample was arranged side by side on a 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI.
　つぎに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－磁気共鳴画像化方法により、前記試料の１Ｈ－磁気共鳴画像を撮像した。１Ｈ－磁気共鳴画像化方法では、高速スピンエコー法を用い、積算回数２回、撮像時間１６秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Next, a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) using Ltd.] by 1 H- magnetic resonance imaging method, we were imaged 1 H- magnetic resonance image of said sample. In the 1 H-magnetic resonance imaging method, a high-speed spin echo method is used, the number of times of integration is 2, the imaging time is 16 seconds, the repetition time (TR) is 1000 ms, the echo train number (ETL) is 8 and the imaging range (FOV) is 5 × 5 cm. Two conditions were used.
　また、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像化方法により、前記試料の１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ｝二重磁気共鳴画像化方法では、高速スピンエコー法を１Ｈ－｛１３Ｃ｝二重共鳴に拡張した撮像法を用い、積算回数３２回、撮像時間２５６秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Further, 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd. The 1 H- { 13 C} double magnetic resonance image of the sample was imaged by the 1 H- { 13 C} double magnetic resonance imaging method. In the 1 H- { 13 C} double magnetic resonance imaging method, an imaging method in which the fast spin echo method is extended to 1 H- { 13 C} double resonance is used, and the number of integrations is 32 times, and the imaging time is 256 seconds. Conditions of time (TR) 1000 ms, echo train number (ETL) 8 and imaging range (FOV) 5 × 5 cm 2 were used.
　さらに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法により、前記試料の１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した。なお、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法で分子プローブ由来の１Ｈ核を選択し、その１Ｈ核に対して傾斜磁場（ＧｐｈａｓｅおよびＧｒｅａｄ）で位置情報を付加した。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法では、積算回数３２回、撮像時間２５６秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法では、位置情報付加に必要な複数回の信号収集を短時間で行なうために、高速スピンエコー法を１Ｈ－｛１３Ｃ－１５Ｎ｝三重共鳴に拡張した撮像法を用いた。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なう際のパルス系列として、１Ｈ－｛１３Ｃ－１５Ｎ｝三重核磁気共鳴法のパルス系列と高速スピンエコー法のパルス系列とを組み合わせたパルス系列を用いた。実験例１において、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法で用いられたパルス系列を図１に示す。図中、細いバーは９０°励起パルス、太いバーは１８０°収束パルスを示す。遅延間隔は、１／４１ＪＣＨ＝１．９６７ｍｓ、および１／４１ＪＣＮ＝３５ｍｓに設定した。また、位相サイクルは、φ１＝ｘ，－ｘ、φ２＝２（ｘ），２（－ｘ）、φ３＝４（ｙ）, ４（-ｙ）、レシーバー＝２（－ｙ），４（－ｙ）、２（ｙ）に設定した。 Furthermore, an MRI apparatus for 7T animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI (manufactured by Doty Scientific) The 1 H- { 13 C- 15 N} triple magnetic resonance image of the sample was imaged by the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method. In addition, 1 H- { 13 C- 15 N} triple magnetic resonance imaging method is used to select a 1 H nucleus derived from a molecular probe, and position information is obtained with respect to the 1 H nucleus by a gradient magnetic field (G phase and G read ). Added. In the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method, the number of times of integration is 32, the imaging time is 256 seconds, the repetition time (TR) is 1000 ms, the number of echo trains (ETL) is 8 and the imaging range (FOV) is 5 ×. A condition of 5 cm 2 was used. 1 H- {13 C- 15 N} Mie magnetic resonance imaging method, in order to perform a plurality of signal collection needed to position information addition in a short time, high-speed spin echo method 1 H- {13 C- 15 An imaging method extended to N} triple resonance was used. 1 H- { 13 C- 15 N} Triple Magnetic Resonance Imaging Pulse Sequence for Performing 1 H- { 13 C- 15 N} Triple Magnetic Resonance Method Pulse Sequence and Fast Spin Echo Method Pulse Sequence And a pulse sequence combined with. FIG. 1 shows a pulse sequence used in 1 H- { 13 C- 15 N} triple magnetic resonance imaging method in Experimental Example 1. In the figure, a thin bar represents a 90 ° excitation pulse, and a thick bar represents a 180 ° convergence pulse. Delay interval was set to 1/4 1 J CH = 1.967ms , and 1/4 1 J CN = 35ms. Also, the phase cycle is φ1 = x, −x, φ2 = 2 (x), 2 (−x), φ3 = 4 (y), 4 (−y), receiver = 2 (−y), 4 (− y) Set to 2 (y).
　実験例１において、１Ｈ－磁気共鳴画像を撮像した結果を図２（ａ）、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した結果を図２（ｂ）、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を図２（ｃ）、図２（ａ）～（ｃ）の各画像における各試料の配置図を図２（ｄ）に示す。図（ｄ）中、（ａ）は６ｍｇ／ｍＬ１３Ｃ／１５Ｎ－ラベル化塩化コリン重水溶液、（ｂ）は３０ｍｇ／ｍＬ１３Ｃ／１５Ｎ－ラベル化塩化コリン重水溶液、（ｃ）は１２０ｍｇ／ｍＬ１３Ｃ／１５Ｎ－ラベル化塩化コリン重水溶液、（ｄ）は１Ｍ１３Ｃ－ラベル化乳酸の重水溶液、（ｅ）は水を示す。 In Experimental Example 1, FIG. 2A shows the result of imaging a 1 H-magnetic resonance image, FIG. 2B shows the result of imaging 1 H- { 13 C} double magnetic resonance image, and 1 H- { 13 the results of the captured c-15 N} triple magnetic resonance imaging FIG. 2 (c), the shown in FIG. 2 (d) a layout view of each sample in each image of FIG. 2 (a) ~ (c) . In FIG. (D), (a) is 6 mg / mL 13 C / 15 N-labeled choline chloride heavy aqueous solution, (b) is 30 mg / mL 13 C / 15 N-labeled choline chloride heavy aqueous solution, (c) is 120 mg / mL 13 C / 15 N-labeled choline chloride heavy aqueous solution, (d) shows a heavy aqueous solution of 1M 13 C-labeled lactic acid, and (e) shows water.
　図２（ａ）に示された結果から、１Ｈ－磁気共鳴画像化方法を行なった場合、すべての試料中の１Ｈに起因するシグナルが検出されることがわかる。また、図２（ｂ）に示された結果から、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像法を行なった場合、水中の１Ｈに起因するシグナルが検出されないが、１３Ｃ／１５Ｎ－ラベル化塩化コリン中の１Ｈ－｛１３Ｃ｝および１３Ｃ－ラベル化乳酸中の１Ｈ－｛１３Ｃ｝それぞれに起因するシグナルが検出されることがわかる。 From the results shown in FIG. 2 (a), it can be seen that when the 1 H-magnetic resonance imaging method is performed, signals due to 1 H in all samples are detected. Further, from the result shown in FIG. 2 (b), when 1 H- { 13 C} double magnetic resonance imaging is performed, a signal due to 1 H in water is not detected, but 13 C / 15 N It can be seen that signals due to 1 H- { 13 C} in the labeled choline chloride and 1 H- { 13 C} in the 13 C-labeled lactic acid, respectively, are detected.
　これに対して、図２（ｃ）に示された結果から、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なった場合、水の１Ｈに起因するシグナルおよび１３Ｃ－ラベル化乳酸の１Ｈ－｛１３Ｃ｝に起因するシグナルが検出されず、１３Ｃ／１５Ｎ－ラベル化塩化コリンの１Ｈ－｛１３Ｃ－１５Ｎ｝に起因するシグナルのみが特異的に検出されることがわかる。 On the other hand, from the results shown in FIG. 2 (c), when the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method is performed, the signal due to 1 H of water and 13 C- No signal due to 1 H- { 13 C} of labeled lactic acid was detected, and only the signal due to 1 H- { 13 C- 15 N} of 13 C / 15 N-labeled choline chloride was specifically detected It can be seen that it is detected.
　これらの結果から、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なうことにより、１３Ｃ／１５Ｎ－ラベル化塩化コリンの１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を得ることができることができることがわかる。
実験例２
　式（ｐ２）： These results, by performing 1 H- {13 C- 15 N} triple magnetic resonance imaging method, 13 C / 15 N-labeled of choline chloride 1 H- {13 C- 15 N} triple magnetic resonance It can be seen that an image can be obtained.
Experimental example 2
Formula (p2):
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
で表わされる１３Ｃ／１５Ｎ－ラベル化ポリ－２－メタクリロイルオキシエチルホスホリルコリン（分子量４４０００、以下、「１３Ｃ／１５Ｎ－ＰＭＰＣ」という）の水溶液（溶液中における１３Ｃ／１５Ｎ－ＰＭＰＣの濃度：８ｍｇ／ｍＬ）０．５ｍＬ、１３Ｃ－ラベル化ポリ－２－メタクリロイルオキシエチルホスホリルコリン（分子量３５０００、以下、「１３Ｃ－ＰＭＰＣ」という）水溶液（溶液中における１３Ｃ－ＰＭＰＣの濃度：８ｍｇ／ｍＬ）０．５ｍＬ、脂肪酸の一つであるオレイン酸（１．１体積％１３Ｃ－オレイン酸を含有する）０．５ｍＬおよび水０．５ｍＬそれぞれを試料として用いた。各試料を円筒型コイル上に並べて配置した。 In 13 C / 15 N-labeled poly-2-meth represented methacryloyloxyethyl phosphorylcholine (molecular weight 44000, hereinafter, "13 C / 15 N-PMPC" hereinafter) of an aqueous solution (in 13 C / 15 N-PMPC in solution Concentration: 8 mg / mL) 0.5 mL, 13 C-labeled poly-2-methacryloyloxyethyl phosphorylcholine (molecular weight 35000, hereinafter referred to as “ 13 C-PMPC”) aqueous solution (concentration of 13 C-PMPC in the solution: 8 mg / ML) 0.5 mL, 0.5 mL of oleic acid (containing 1.1 vol% 13 C-oleic acid) and 0.5 mL of water were used as samples. Each sample was placed side by side on a cylindrical coil.
　つぎに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－磁気共鳴画像化方法により、前記試料の１Ｈ－磁気共鳴画像を撮像した。１Ｈ－磁気共鳴画像化方法では、スピンエコー法を用い、積算回数１回、撮像時間１６秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Next, a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) using Ltd.] by 1 H- magnetic resonance imaging method, we were imaged 1 H- magnetic resonance image of said sample. In the 1 H-magnetic resonance imaging method, spin echo method is used, the number of times of integration is 1, the imaging time is 16 seconds, the repetition time (TR) is 1000 ms, the echo train number (ETL) is 8 and the imaging range (FOV) is 5 × 5 cm 2. The following conditions were used.
　また、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像化方法により、前記試料の１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ｝二重磁気共鳴画像化方法では、スピンエコー法を１Ｈ－｛１３Ｃ｝二重共鳴に拡張した撮像法を用い、積算回数１６回、撮像時間５１２秒間、繰り返し時間（ＴＲ）１０００ｍｓおよび撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Further, 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd. The 1 H- { 13 C} double magnetic resonance image of the sample was imaged by the 1 H- { 13 C} double magnetic resonance imaging method. In the 1 H- { 13 C} double magnetic resonance imaging method, an imaging method in which the spin echo method is extended to 1 H- { 13 C} double resonance is used, and the number of times of integration is 16, the imaging time is 512 seconds, and the repetition time is Conditions of (TR) 1000 ms and imaging range (FOV) 5 × 5 cm 2 were used.
　さらに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法により、前記試料の１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法では、１Ｈ－｛１３Ｃ－１５Ｎ｝三重核磁気共鳴法のパルス系列とスピンエコー法のパルス系列とを組み合わせたパルス系列を用いて、積算回数１０２４回、撮像時間３２７６８秒間、繰り返し時間（ＴＲ）１０００ｍｓおよび撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Furthermore, an MRI apparatus for 7T animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI (manufactured by Doty Scientific) The 1 H- { 13 C- 15 N} triple magnetic resonance image of the sample was imaged by the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method. In the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method, a pulse sequence combining a pulse sequence of the 1 H- { 13 C- 15 N} triple nuclear magnetic resonance method and a pulse sequence of the spin echo method is used. Using the conditions, the number of integration was 1024 times, the imaging time was 32768 seconds, the repetition time (TR) was 1000 ms, and the imaging range (FOV) was 5 × 5 cm 2 .
　実験例２において、１Ｈ－磁気共鳴画像を撮像した結果を図３（ａ）、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した結果を図３（ｂ）、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を図３（ｃ）、（ａ）～（ｃ）の各画像における各試料の配置図を図３（ｄ）に示す。図３（ｄ）中、（ａ）は水、（ｂ）は１３Ｃ／１５Ｎ－ＰＭＰＣ水溶液、（ｃ）は１３Ｃ－ＰＭＰＣ水溶液、（ｄ）はオレイン酸を示す。 In Experimental Example 2, the result of imaging a 1 H-magnetic resonance image is shown in FIG. 3A, the result of imaging a 1 H- { 13 C} double magnetic resonance image is shown in FIG. 3B, and 1 H- { 13 FIG. 3 (d) shows the arrangement of each sample in each of the images of FIGS. 3 (c) and (a) to (c), as a result of taking a C- 15 N} triple magnetic resonance image. In FIG. 3 (d), (a) shows water, (b) shows a 13 C / 15 N-PMPC aqueous solution, (c) shows a 13 C-PMPC aqueous solution, and (d) shows oleic acid.
　図３（ａ）に示された結果から、１Ｈ－磁気共鳴画像化方法を行なった場合、すべての試料中の１Ｈに起因するシグナルが検出されることがわかる。また、図３（ｂ）に示された結果から、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像法を行なった場合、１３Ｃ／１５Ｎ－ＰＭＰＣ、１３Ｃ－ＰＭＰＣおよびオレイン酸それぞれの１Ｈ－｛１３Ｃ｝に起因するシグナルが検出されることがわかる。 From the results shown in FIG. 3 (a), it can be seen that when the 1 H-magnetic resonance imaging method is performed, signals due to 1 H in all samples are detected. Further, from the results shown in FIG. 3 (b), when 1 H- { 13 C} double magnetic resonance imaging is performed, each of 13 C / 15 N-PMPC, 13 C-PMPC and oleic acid 1 It can be seen that a signal due to H- { 13 C} is detected.
　これに対して、図３（ｃ）に示された結果から、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なった場合、１３Ｃ／１５Ｎ－ラベル化ＰＭＰＣの１Ｈ－｛１３Ｃ－１５Ｎ｝に起因するシグナルのみが特異的に検出されることがわかる。 In contrast, from the results shown in FIG. 3 (c), when the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method is performed, 1 H of 13 C / 15 N-labeled PMPC is obtained. It can be seen that only the signal due to-{ 13 C- 15 N} is specifically detected.
　これらの結果から、１Ｈ－１３Ｃ－１５Ｎ結合を有する化合物からなるプローブを用いて１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なうことにより、従来の１Ｈ－磁気共鳴画像化方法の欠点であった内在性の水、脂質などに起因する内在性ノイズシグナルを除去することができ、１Ｈ－１３Ｃ－１５Ｎ結合を有する化合物からなるプローブのみを高い選択性で画像化できることがわかる。 From these results, by performing a 1 H- { 13 C- 15 N} triple magnetic resonance imaging method using a probe made of a compound having a 1 H- 13 C- 15 N bond, the conventional 1 H-magnetic The intrinsic noise signal caused by endogenous water, lipid, etc., which has been a drawback of the resonance imaging method, can be removed, and only a probe composed of a compound having a 1 H- 13 C- 15 N bond is highly selective. It can be seen that can be imaged.
実験例３
　１３Ｃ／１５Ｎ－ＰＭＰＣ水溶液（１３Ｃ／１５Ｎ－ＰＭＰＣの分子量４４０００、溶液中における１３Ｃ／１５Ｎ－ＰＭＰＣの濃度：８ｍｇ／ｍＬ）０．５ｍＬ、１３Ｃ－ＰＭＰＣ水溶液（１３Ｃ－ＰＭＰＣの分子量３５０００、溶液中における１３Ｃ－ＰＭＰＣの濃度：８ｍｇ／ｍＬ）０．５ｍＬ、オレイン酸（１．１体積％１３Ｃ－オレイン酸を含有する）０．５ｍＬおよび水０．５ｍＬそれぞれを試料として用いた。各試料を円筒型コイル上に並べて配置した。 Experimental example 3
13 C / 15 N-PMPC aqueous solution ( 13 C / 15 N-PMPC molecular weight 44000, 13 C / 15 N-PMPC concentration in solution: 8 mg / mL) 0.5 mL, 13 C-PMPC aqueous solution ( 13 C- PMPC molecular weight 35000, 13 C-PMPC concentration in solution: 8 mg / mL 0.5 mL, oleic acid (containing 1.1 vol% 13 C-oleic acid) 0.5 mL and water 0.5 mL each Used as a sample. Each sample was placed side by side on a cylindrical coil.
　つぎに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－磁気共鳴画像化方法により、前記試料の１Ｈ－磁気共鳴画像を撮像した。１Ｈ－磁気共鳴画像化方法では、高速スピンエコー法を用い、積算回数１回、撮像時間１６秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Next, a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) using Ltd.] by 1 H- magnetic resonance imaging method, we were imaged 1 H- magnetic resonance image of said sample. In the 1 H-magnetic resonance imaging method, a high-speed spin echo method is used, the number of times of integration is 1, the imaging time is 16 seconds, the repetition time (TR) is 1000 ms, the echo train number (ETL) is 8 and the imaging range (FOV) is 5 × 5 cm. Two conditions were used.
　また、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像化方法により、前記試料の１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ｝二重磁気共鳴画像化方法では、高速スピンエコー法を１Ｈ－｛１３Ｃ｝二重共鳴に拡張した撮像法を用い、積算回数１６回、撮像時間１６秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）３２および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Further, 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd. The 1 H- { 13 C} double magnetic resonance image of the sample was imaged by the 1 H- { 13 C} double magnetic resonance imaging method. In the 1 H- { 13 C} double magnetic resonance imaging method, an imaging method in which the fast spin echo method is extended to 1 H- { 13 C} double resonance is used, and the number of integrations is 16 times, and the imaging time is 16 seconds. Conditions of time (TR) 1000 ms, echo train number (ETL) 32, and imaging range (FOV) 5 × 5 cm 2 were used.
　さらに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法により、前記試料の１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法では、図１に示されるパルス系列を用い、積算回数１０２４回、撮像時間１０２４秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）３２および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Furthermore, an MRI apparatus for 7T animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T ( 1 H / 13 C / 15 N) cylindrical coil for 7T MRI (manufactured by Doty Scientific) The 1 H- { 13 C- 15 N} triple magnetic resonance image of the sample was imaged by the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method. In the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method, the pulse sequence shown in FIG. 1 is used, the number of times of integration is 1024 times, the imaging time is 1024 seconds, the repetition time (TR) is 1000 ms, the number of echo trains (ETL ) 32 and an imaging range (FOV) of 5 × 5 cm 2 were used.
　実験例３において、１Ｈ－磁気共鳴画像を撮像した結果を図４（ａ）、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像を撮像した結果を図４（ｂ）、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を図４（ｃ）、（ａ）～（ｃ）の各画像における各試料の配置図を図４（ｄ）に示す。図４（ｄ）中、（ａ）は水、（ｂ）は１３Ｃ／１５Ｎ－ＰＭＰＣ水溶液、（ｃ）は１３Ｃ－ＰＭＰＣ水溶液、（ｄ）はオレイン酸を示す。 In Experimental Example 3, the result of imaging a 1 H-magnetic resonance image is shown in FIG. 4A, the result of imaging a 1 H- { 13 C} double magnetic resonance image is shown in FIG. 4B, and 1 H- { 13 Figure 4 (c) the results of the captured c-15 N} triple magnetic resonance image, shown in (a) ~ FIG. 4 the layout of each sample in each image of (c) (d). In FIG. 4D, (a) shows water, (b) shows 13 C / 15 N-PMPC aqueous solution, (c) shows 13 C-PMPC aqueous solution, and (d) shows oleic acid.
　図４（ａ）に示された結果から、１Ｈ－磁気共鳴画像化方法を行なった場合、すべての試料中の１Ｈに起因するシグナルが検出されることがわかる。また、図４（ｂ）に示された結果から、１Ｈ－｛１３Ｃ｝二重磁気共鳴画像法を行なった場合、１３Ｃ／１５Ｎ－ＰＭＰＣ、１３Ｃ－ＰＭＰＣおよびオレイン酸それぞれの１Ｈ－｛１３Ｃ｝に起因するシグナルが検出されることがわかる。 From the results shown in FIG. 4 (a), it can be seen that when the 1 H-magnetic resonance imaging method is performed, signals due to 1 H in all samples are detected. Further, from the results shown in FIG. 4B, when 1 H- { 13 C} double magnetic resonance imaging is performed, each of 13 C / 15 N-PMPC, 13 C-PMPC and oleic acid is 1 It can be seen that a signal due to H- { 13 C} is detected.
　これに対して、図４（ｃ）に示された結果から、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なった場合、１３Ｃ／１５Ｎ－ラベル化ＰＭＰＣの１Ｈ－｛１３Ｃ－１５Ｎ｝に起因するシグナルのみが特異的に検出されることがわかる。 In contrast, from the results shown in FIG. 4 (c), when the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method is performed, the 1 H of 13 C / 15 N-labeled PMPC It can be seen that only the signal due to-{ 13 C- 15 N} is specifically detected.
　これらの結果から、１Ｈ－１３Ｃ－１５Ｎ結合を有する化合物からなるプローブを用いて１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なうことにより、従来の１Ｈ－磁気共鳴画像化方法の欠点であった内在性の水、脂質などに起因する内在性ノイズシグナルを除去することができ、１Ｈ－１３Ｃ－１５Ｎ結合を有する化合物からなるプローブのみを高い選択性で画像化できることがわかる。 From these results, by performing a 1 H- { 13 C- 15 N} triple magnetic resonance imaging method using a probe made of a compound having a 1 H- 13 C- 15 N bond, the conventional 1 H-magnetic The intrinsic noise signal caused by endogenous water, lipid, etc., which has been a drawback of the resonance imaging method, can be removed, and only a probe composed of a compound having a 1 H- 13 C- 15 N bond is highly selective. It can be seen that can be imaged.
実施例１
　Ｂａｌｂ／ｃ　ｎｕ－ｎｕ雌マウス（６週齢）の右腹部に、マウス大腸癌細胞ｃｏｌｏｎ２６懸濁液（１．９×１０６細胞／５０μＬ５０体積％ゲルマトリックス（インビトロジェン社製、商品名：Ｇｅｌｔｒｅｘ）含有生理食塩水溶液）５０μＬを皮下注射するとともに、当該マウスの左腹部に、マウス大腸癌細胞ｃｏｌｏｎ２６懸濁液（０．８×１０６細胞／５０μＬ５０体積％ゲルマトリックス（インビトロジェン社製、商品名：Ｇｅｌｔｒｅｘ）含有生理食塩水溶液）５０μＬを皮下注射した。 Example 1
In the right abdomen of a Balb / c nu-nu female mouse (6 weeks old), a mouse colon cancer cell colon 26 suspension (1.9 × 10 6 cells / 50 μL 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 μL of a physiological saline solution (containing saline) was injected subcutaneously, and a mouse colon cancer cell colon 26 suspension (0.8 × 10 6 cells / 50 μL 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) was injected into the left abdomen of the mouse. ) Containing saline solution) 50 μL was injected subcutaneously.
　皮下注射終了後１１日目のマウスの尾静脈に、１３Ｃ／１５Ｎ－ＰＭＰＣ生理食塩水溶液（２５０ｍｇ／ｍＬ生理食塩水溶液）２００μＬを投与した。投与終了から４日間経過後、マウスの癌組織を摘出した。 On the 11th day after the completion of the subcutaneous injection, 200 μL of 13 C / 15 N-PMPC physiological saline solution (250 mg / mL physiological saline solution) was administered to the tail vein of the mouse. After 4 days from the end of administration, the mouse cancer tissue was removed.
　つぎに、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法により、前記癌組織の１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法では、図１に示されるパルス系列を用い、積算回数１０２４回、撮像時間１０６５秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）３２および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Next, a 7T MRI apparatus for animals (Bruker BioSpin) and 7T MRI 3 nuclei ( 1 H / 13 C / 15 N) cylindrical coil (Doty Scientific) 1 H- { 13 C- 15 N} triple magnetic resonance image of the cancer tissue was imaged by the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method. In the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method, the pulse sequence shown in FIG. 1 is used, the number of times of integration is 1024, the imaging time is 1065 seconds, the repetition time (TR) is 1000 ms, the number of echo trains (ETL) ) 32 and an imaging range (FOV) of 5 × 5 cm 2 were used.
　なお、参照として、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－磁気共鳴画像化方法により、前記癌組織の１Ｈ－磁気共鳴画像を撮像した。１Ｈ－磁気共鳴画像化方法では、高速スピンエコー法を用い、積算回数１回、撮像時間８０秒間、繰り返し時間（ＴＲ）２５００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Incidentally, as reference, MRI apparatus for 7T Animals [Bruker BioSpin (Bruker BioSpin Corp.)] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific ) using a manufactured] by 1 H- magnetic resonance imaging method, were imaged 1 H- magnetic resonance image of the cancerous tissue. In the 1 H-magnetic resonance imaging method, a high-speed spin echo method is used, the number of times of integration is 1, the imaging time is 80 seconds, the repetition time (TR) is 2500 ms, the number of echo trains (ETL) is 8 and the imaging range (FOV) is 5 × 5 cm. Two conditions were used.
　実施例１において、１Ｈ－磁気共鳴画像を撮像した結果を図５（ａ）、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を図５（ｂ）、１Ｈ－磁気共鳴画像と１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像とを重ね合わせた結果を図５（ｃ）に示す。 In Example 1, the result of imaging a 1 H-magnetic resonance image is shown in FIG. 5A, the result of imaging a 1 H- { 13 C- 15 N} triple magnetic resonance image is shown in FIG. 5B, and 1 H- The result of superimposing the magnetic resonance image and the 1 H- { 13 C- 15 N} triple magnetic resonance image is shown in FIG.
　また、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用いた１３Ｃ－磁気共鳴スペクトロスコピーにより、前記癌組織の１３Ｃ－磁気共鳴スペクトルを測定した。 Further, 7T animal MRI system [(manufactured by Bruker BioSpin Co.) Bruker BioSpin] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific) Ltd. ] the 13 C- magnetic resonance spectroscopy was used to measure the 13 C- magnetic resonance spectrum of the cancerous tissue.
　実施例１において、癌組織の１３Ｃ－磁気共鳴スペクトルを調べた結果を図６に示す。 The results of examining the 13 C-magnetic resonance spectrum of the cancer tissue in Example 1 are shown in FIG.
　図５（ａ）～（ｃ）に示された結果から、癌組織において、シグナルが検出されていることがわかる。また、図６に示された結果から、１３Ｃ／１５Ｎ－ＰＭＰＣのメチル基の１３Ｃのシグナルが観測されたことから、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法によって検出されたシグナルが１３Ｃ／１５Ｎ－ＰＭＰＣの１Ｈ－｛１３Ｃ－１５Ｎ｝に起因するシグナルであることがわかる。これらの結果から、１３Ｃ／１５Ｎ－ＰＭＰＣがＥＰＲ効果によって癌組織に集積していることがわかる。 From the results shown in FIGS. 5A to 5C, it can be seen that a signal is detected in the cancer tissue. Further, from the results shown in FIG. 6, since the signal of 13 C / 15 13 C methyl group N-PMPC were observed by 1 H- {13 C- 15 N} triple magnetic resonance imaging method It can be seen that the detected signal is a signal resulting from 1 H- { 13 C- 15 N} of 13 C / 15 N-PMPC. From these results, it can be seen that 13 C / 15 N-PMPC is accumulated in the cancer tissue by the EPR effect.
実施例２
　Ｂａｌｂ／ｃ　ｎｕ－ｎｕ雌マウス（６週齢）の右腹部に、マウス大腸癌細胞ｃｏｌｏｎ２６懸濁液（１．９×１０６細胞／５０μＬ５０体積％ゲルマトリックス（インビトロジェン社製、商品名：Ｇｅｌｔｒｅｘ）含有生理食塩水溶液）５０μＬを皮下注射するとともに、当該マウスの左腹部に、マウス大腸癌細胞ｃｏｌｏｎ２６懸濁液（０．８×１０６細胞／５０μＬ５０体積％ゲルマトリックス（インビトロジェン社製、商品名：Ｇｅｌｔｒｅｘ）含有生理食塩水溶液）５０μＬを皮下注射した。 Example 2
In the right abdomen of a Balb / c nu-nu female mouse (6 weeks old), a mouse colon cancer cell colon 26 suspension (1.9 × 10 6 cells / 50 μL 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 μL of a physiological saline solution (containing saline) was injected subcutaneously, and a mouse colon cancer cell colon 26 suspension (0.8 × 10 6 cells / 50 μL 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) was injected into the left abdomen of the mouse. ) Containing saline solution) 50 μL was injected subcutaneously.
　皮下注射終了後１１日目のマウスの尾静脈に、１３Ｃ／１５Ｎ－ＰＭＰＣ生理食塩水溶液（７２．５ｍｇ／ｍＬ生理食塩水溶液）２００μＬを皮下注射した。 On the 11th day after the completion of the subcutaneous injection, 200 μL of 13 C / 15 N-PMPC physiological saline solution (72.5 mg / mL physiological saline solution) was subcutaneously injected into the tail vein of the mouse.
　皮下注射終了から１日間経過後、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法により、前記マウスの１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した。１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法では、図１に示されるパルス系列を用い、積算回数１０２４回、撮像時間１０２４秒間、繰り返し時間（ＴＲ）１０００ｍｓ、エコートレイン数（ＥＴＬ）３２および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 One day after the completion of subcutaneous injection, 7T MRI device for animals (Bruker BioSpin (manufactured by Bruker BioSpin)) and 3T for 7T MRI ( 1 H / 13 C / 15 N) cylindrical coil [Dorty Scientific using Fick (Doty Scientific) Ltd.] by 1 H- {13 C- 15 N} triple magnetic resonance imaging method, were imaged 1 H- {13 C- 15 N} triple magnetic resonance imaging of the mouse. In the 1 H- { 13 C- 15 N} triple magnetic resonance imaging method, the pulse sequence shown in FIG. 1 is used, the number of times of integration is 1024 times, the imaging time is 1024 seconds, the repetition time (TR) is 1000 ms, the number of echo trains (ETL ) 32 and an imaging range (FOV) of 5 × 5 cm 2 were used.
　なお、参照として、７Ｔ動物用ＭＲＩ装置〔ブルカー・バイオスピン（Ｂｒｕｋｅｒ　ＢｉｏＳｐｉｎ社製）〕および７Ｔ　ＭＲＩ用３核（１Ｈ／１３Ｃ／１５Ｎ）円筒型コイル〔ドーティー・サイエンティフィック（Ｄｏｔｙ　Ｓｃｉｅｎｔｉｆｉｃ）社製〕を用い、１Ｈ－磁気共鳴画像化方法により、前記マウスの１Ｈ－磁気共鳴画像を撮像した。１Ｈ－磁気共鳴画像化方法では、高速スピンエコー法を用い、積算回数１回、撮像時間８０秒間、繰り返し時間（ＴＲ）２５００ｍｓ、エコートレイン数（ＥＴＬ）８および撮像範囲（ＦＯＶ）５×５ｃｍ２の条件を用いた。 Incidentally, as reference, MRI apparatus for 7T Animals [Bruker BioSpin (Bruker BioSpin Corp.)] and 7T MRI for 3 nuclei (1 H / 13 C / 15 N) cylindrical coil [Doti Scientific (Doty Scientific The 1 H-magnetic resonance image of the mouse was imaged by the 1 H-magnetic resonance imaging method. In the 1 H-magnetic resonance imaging method, a high-speed spin echo method is used, the number of times of integration is 1, the imaging time is 80 seconds, the repetition time (TR) is 2500 ms, the number of echo trains (ETL) is 8 and the imaging range (FOV) is 5 × 5 cm. Two conditions were used.
　実施例２において、１Ｈ－磁気共鳴画像を撮像した結果を図７（ａ）、１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像した結果を図７（ｂ）、１Ｈ－磁気共鳴画像と１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像とを重ね合わせた結果を図７（ｃ）に示す。 In Example 2, the result of imaging a 1 H-magnetic resonance image is shown in FIG. 7A, the result of imaging a 1 H- { 13 C- 15 N} triple magnetic resonance image is shown in FIG. 7B, and 1 H- FIG. 7C shows the result of superimposing the magnetic resonance image and the 1 H- { 13 C- 15 N} triple magnetic resonance image.
　図７（ａ）～（ｃ）に示された結果から、マウスの癌部位において、１３Ｃ／１５Ｎ－ＰＭＰＣの１Ｈ－｛１３Ｃ－１５Ｎ｝に起因するシグナルが検出されていることがわかる。これらの結果から、１Ｈ－１３Ｃ－１５Ｎ結合を有する化合物からなるプローブを用いて１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なうことにより、マウス個体の１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像を撮像することができることがわかる。 From the results shown in FIGS. 7 (a) to (c), a signal derived from 1 H- { 13 C- 15 N} of 13 C / 15 N-PMPC was detected in the cancer site of the mouse. I understand. From these results, by performing a 1 H- { 13 C- 15 N} triple magnetic resonance imaging method using a probe comprising a compound having a 1 H- 13 C- 15 N bond, 1 H- It can be seen that a { 13 C- 15 N} triple magnetic resonance image can be taken.
実施例３
　Ｂａｌｂ／ｃ　ｎｕ－ｎｕ雌マウス（６週齢）の右腹部に、マウス大腸癌細胞ｃｏｌｏｎ２６懸濁液（１．９×１０６細胞／５０μＬ５０体積％ゲルマトリックス（インビトロジェン社製、商品名：Ｇｅｌｔｒｅｘ）含有生理食塩水溶液）５０μＬを皮下注射するとともに、当該マウスの左腹部に、マウス大腸癌細胞ｃｏｌｏｎ２６懸濁液（０．８×１０６細胞／５０μＬ５０体積％ゲルマトリックス（インビトロジェン社製、商品名：Ｇｅｌｔｒｅｘ）含有生理食塩水溶液）５０μＬを皮下注射した。 Example 3
In the right abdomen of a Balb / c nu-nu female mouse (6 weeks old), a mouse colon cancer cell colon 26 suspension (1.9 × 10 6 cells / 50 μL 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) 50 μL of a physiological saline solution (containing saline) was injected subcutaneously, and a mouse colon cancer cell colon 26 suspension (0.8 × 10 6 cells / 50 μL 50% by volume gel matrix (manufactured by Invitrogen, trade name: Geltrex) was injected into the left abdomen of the mouse. ) Containing saline solution) 50 μL was injected subcutaneously.
　皮下注射終了後１１日目のマウスの尾静脈に、１３Ｃ／１５Ｎ－ＰＭＰＣ生理食塩水溶液（２５０ｍｇ／ｍＬ生理食塩水溶液）２００μＬを投与した。投与終了から４日間経過後、マウスの右腹部および左腹部の癌組織、肝臓、腎臓および心臓の各組織〔癌組織０．５９～１．５ｇ（平均１．０ｇ）、肝臓組織０．８８～１．１ｇ（平均１．０ｇ）、腎臓組織０．１９～０．３１ｇ（平均０．２７ｇ）、心臓組織０．１３～０．１９ｇ（平均０．１６ｇ）〕を得た。得られた組織を、１０体積％トリクロロ酢酸水溶液に入れて可溶化させた。得られた可溶化物を１４０００×ｇで３０分間の遠心分離に供し、上清を得た。得られた上清を凍結乾燥させた後、組織重量の４倍量の重水に再溶解させて試料を得た。 On the 11th day after the completion of the subcutaneous injection, 200 μL of 13 C / 15 N-PMPC physiological saline solution (250 mg / mL physiological saline solution) was administered to the tail vein of the mouse. Four days after the end of administration, the right and left abdominal cancer tissues, liver, kidney and heart tissues of mice [cancer tissue 0.59 to 1.5 g (average 1.0 g), liver tissue 0.88 to 1.1 g (average 1.0 g), kidney tissue 0.19 to 0.31 g (average 0.27 g), and heart tissue 0.13 to 0.19 g (average 0.16 g)]. The obtained tissue was solubilized in 10 volume% trichloroacetic acid aqueous solution. The obtained lysate was subjected to centrifugation at 14000 × g for 30 minutes to obtain a supernatant. The obtained supernatant was freeze-dried and then redissolved in 4 times the amount of tissue water to obtain a sample.
　つぎに、クライオプローブを装備した６００ＭＨｚのＮＭＲ装置（Ｂｒｕｋｅｒ社製）を用い、前記試料の１Ｈ－｛１３Ｃ－１５Ｎ｝－ＮＭＲスペクトルを測定した（積算回数１６回）。また、得られた１Ｈ－｛１３Ｃ－１５Ｎ｝－ＮＭＲスペクトルより１Ｈ－｛１３Ｃ－１５Ｎ｝三重共鳴ＮＭＲシグナルのＳ／Ｎ比を求め、各組織における１３Ｃ／１５Ｎ－ＰＭＰＣの蓄積量を算出した。 Next, a 1 H- { 13 C- 15 N} -NMR spectrum of the sample was measured using a 600 MHz NMR apparatus (manufactured by Bruker) equipped with a cryoprobe (16 times of integration). Further, the S / N ratio of the 1 H- { 13 C- 15 N} triple resonance NMR signal was determined from the obtained 1 H- { 13 C- 15 N} -NMR spectrum, and 13 C / 15 N— in each tissue was obtained. The amount of accumulated PMPC was calculated.
　実施例３で得られた各組織の１Ｈ－｛１３Ｃ－１５Ｎ｝－ＮＭＲスペクトルを図８に示す。また、実施例３において、各組織における１３Ｃ／１５Ｎ－ＰＭＰＣの蓄積量を調べた結果を図９に示す。図８および図９中、「肝臓」、「腎臓」および「心臓」は、それぞれ「肝臓組織」、「腎臓組織」および「心臓組織」を意味する。 The 1 H- { 13 C- 15 N} -NMR spectrum of each structure obtained in Example 3 is shown in FIG. In addition, FIG. 9 shows the results of examining the amount of 13 C / 15 N-PMPC accumulated in each tissue in Example 3. 8 and 9, “liver”, “kidney” and “heart” mean “liver tissue”, “kidney tissue” and “heart tissue”, respectively.
　図８に示された結果から、左腹部および右腹部の癌組織でのみ、１３Ｃ／１５Ｎ－ＰＭＰＣの１Ｈ－１３Ｃ－１５Ｎの１Ｈに帰属される１Ｈ－｛１３Ｃ－１５Ｎ｝三重共鳴ＮＭＲシグナルのピークが検出されることがわかる。これに対し、肝臓組織、腎臓組織および心臓組織からはシグナルが検出されないことがわかる。また、図９に示された結果から、右腹部癌には１０．８Ｉ．Ｄ．％／ｇ組織質量（５．４ｍｇ／ｇ組織質量）、左腹部癌には１０．４Ｉ．Ｄ．％／ｇ組織質量（５．０ｍｇ／ｇ組織質量）の１３Ｃ／１５Ｎ－ＰＭＰＣが蓄積していることから、１３Ｃ／１５Ｎ－ＰＭＰＣは、皮下注射終了から４日日経過後には、癌組織に蓄積しているが、癌組織が存在しない臓器から完全にクリアランスされていることがわかる。これらの結果から、癌組織に特異的に蓄積する１３Ｃ／１５Ｎ－ＰＭＰＣのように、生体に対して作用する機能を有するプローブを用いて、本発明の多核多重磁気共鳴画像化方法を行なった場合には、生体内におけるプローブの動態を調べることができることが示唆される。 From the results shown in FIG. 8, it was found that 1 H- { 13 C- attributed to 1 H of 13 C / 15 N-PMPC 1 H- 13 C- 15 N only in left and right abdominal cancer tissues. It can be seen that the peak of the 15 N} triple resonance NMR signal is detected. On the other hand, it can be seen that no signal is detected from liver tissue, kidney tissue and heart tissue. In addition, from the results shown in FIG. D. % / G tissue mass (5.4 mg / g tissue mass), 10.4 I. D. Since 13 C / 15 N-PMPC of% / g tissue mass (5.0 mg / g tissue mass) is accumulated, 13 C / 15 N-PMPC is obtained after 4 days from the end of subcutaneous injection. Although it accumulates in the cancer tissue, it can be seen that the cancer tissue is completely cleared from the organ. From these results, the multinuclear multiple magnetic resonance imaging method of the present invention was performed using a probe having a function of acting on a living body, such as 13 C / 15 N-PMPC that specifically accumulates in cancer tissue. This suggests that the dynamics of the probe in vivo can be examined.
　以上の結果から、１Ｈ－１３Ｃ－１５Ｎ結合を有する化合物からなるプローブを用いて１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像化方法を行なうことにより、生体の１Ｈ－｛１３Ｃ－１５Ｎ｝三重磁気共鳴画像が得られ、しかも生体におけるプローブの動態を直接観察することができることから、１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブを用いる本発明の多核多重磁気共鳴画像化方法によれば、生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを正確で、かつ生体に対して低負荷で可視化することができると考えられる。 From the above results, by performing a 1 H- { 13 C- 15 N} triple magnetic resonance imaging method using a probe made of a compound having a 1 H- 13 C- 15 N bond, 1 H- { 13 C- 15 N} triple magnetic resonance images can be obtained, and the dynamics of the probe in the living body can be directly observed. Therefore, at least two types of nuclear magnetism selected from the group consisting of 1 H, 13 C, and 15 N are used. According to the multinuclear multiple magnetic resonance imaging method of the present invention using a probe comprising a compound having a resonance active nucleus and a bond comprising at least three nuclear magnetic resonance active nuclei having different resonance frequencies. It is considered that the function of this probe, the metabolic reaction via the probe in vivo, and the like can be accurately visualized with a low load on the living body.
実施例４
　式（ｐ２）のｎが６０である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量１８０００）の重水溶液（溶液における１３Ｃ／１５Ｎ－ＰＭＰＣの濃度：０．７μＭ、０．１μＭ、０．０７μＭ、または０．０３μＭ）０．５ｍＬを、クライオプローブを装備した７００ＭＨｚのＮＭＲ装置（Ｂｒｕｋｅｒ社製）に付して、それぞれの各１３Ｃ／１５Ｎ－ＰＭＰＣの重水溶液の１Ｈ－｛１３Ｃ－１５Ｎ｝－ＮＭＲスペクトルを測定した（積算回数２５６回）。つぎに、得られた１Ｈ－｛１３Ｃ－１５Ｎ｝－ＮＭＲスペクトルから信号対雑音比（Ｓ／Ｎ）を算出した。 Example 4
Heavy water solution (in 13 C / 15 N-PMPC in solution concentration of n in the formula (p2) is 60 13 C / 15 N-PMPC ( molecular weight 18000): 0.7μM, 0.1μM, 0.07μM or, 0.03 μM) 0.5 mL was attached to a 700 MHz NMR apparatus (manufactured by Bruker) equipped with a cryoprobe, and 1 H- { 13 C- 15 of each 13 C / 15 N-PMPC heavy aqueous solution. N} -NMR spectrum was measured (256 integrations). Next, the signal-to-noise ratio (S / N) was calculated from the obtained 1 H- { 13 C- 15 N} -NMR spectrum.
　また、前記において、式（ｐ２）のｎが６０である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量：１８０００）の重水溶液（溶液における１３Ｃ／１５Ｎ－ＰＭＰＣの濃度：０．７μＭ、０．１μＭ、０．０７μＭ、または０．０３μＭ）を用いる代わりに、式（ｐ２）のｎが４０である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量１２０００）の重水溶液（溶液における１３Ｃ／１５Ｎ－ＰＭＰＣの濃度：０．６μＭ、０．１μＭ、０．０６μＭ、または０．０３μＭ）、式（ｐ２）のｎが３３である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量１００００）の重水溶液（溶液における１３Ｃ／１５Ｎ－ＰＭＰＣの濃度：０．５μＭ、０．１μＭ、０．０５μＭ、または０．０２５μＭ）または式（ｐ２）のｎが１である場合と等価である式（ｊ１）（式中、ａ＝２、ｂ＝２）で表される化合物（１３Ｃ／１５Ｎ－ＭＰＣ）の重水溶液（溶液における１３Ｃ／１５Ｎ－ＭＰＣの濃度：１μＭ）を用いたことを除き、前記と同様の操作を行ない、信号対雑音比（Ｓ／Ｎ）を算出した。 Further, in the above, n is 60 and is 13 C / 15 N-PMPC (molecular weight: 18000) of the formula (p2) heavy water solution (in 13 C / 15 N-PMPC in solution concentration of: 0.7 [mu] M, 0.1 [mu] M , 0.07 μM, or 0.03 μM), a heavy aqueous solution of 13 C / 15 N-PMPC (molecular weight 12000) in which n in the formula (p2) is 40 ( 13 C / 15 N-PMPC in solution) Concentration: 0.6 μM, 0.1 μM, 0.06 μM, or 0.03 μM), 13 C / 15 N-PMPC (molecular weight 10,000) of heavy aqueous solution ( 13 C / in solution) where n in formula (p2) is 33 15 concentration of n-PMPC: 0.5μM, 0.1μM, 0.05μM or 0.025 uM) or formula (j1) (wherein n is equivalent to the case 1 of the formula (p2), a, 2, b = 2) heavy water solution of the compound represented by (13 C / 15 N-MPC ) ( of 13 C / 15 N-MPC in solution concentration: except using 1 [mu] M), by the same operation The signal-to-noise ratio (S / N) was calculated.
　１３Ｃ／１５Ｎ－ＰＭＰＣの濃度と信号対雑音比との関係を図１０に示す。図中、黒矩形は式（ｐ２）のｎが６０である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量１８０００）、黒四角は式（ｐ２）のｎが４０である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量１２０００）、黒三角は式（ｐ２）のｎが３３である１３Ｃ／１５Ｎ－ＰＭＰＣ（分子量：１００００）、黒丸は式（ｐ２）のｎが１である場合と等価である式（ｊ１）（式中、ａ＝２、ｂ＝２）で表される化合物を示す。 FIG. 10 shows the relationship between the concentration of 13 C / 15 N-PMPC and the signal-to-noise ratio. In the figure, the black rectangle is 13 C / 15 N-PMPC (molecular weight 18000) where n in the formula (p2) is 60, and the black square is 13 C / 15 N-PMPC (molecular weight where n is 40 in the formula (p2)) 12000), the black triangle is 13 C / 15 N-PMPC (molecular weight: 10000) where n in the formula (p2) is 33, and the black circle is the formula (j1) equivalent to the case where n is 1 in the formula (p2) The compound represented by (In formula, a = 2, b = 2) is shown.
　図１０に示された結果から、式（ｐ２）のｎが１である場合と等価である式（ｊ１）（式中、ａ＝２、ｂ＝２）で表される化合物（１３Ｃ／１５Ｎ－ＭＰＣ）の信号対雑音比と比べ、重合度が高くなるほど、１３Ｃ／１５Ｎ－ＰＭＰＣの信号対雑音比が高くなる傾向にあることがわかる。これらの結果から、主鎖の重合度が１であるモノマーからなるプローブよりも、主鎖の重合度が２以上の重合体からなるであるプローブのほうが好ましいことが示唆される。 From the results shown in FIG. 10, the compound ( 13 C / 15 ) represented by the formula (j1) (wherein a = 2, b = 2) is equivalent to the case where n in the formula (p2) is 1. It can be seen that the signal-to-noise ratio of 13 C / 15 N-PMPC tends to be higher as the degree of polymerization is higher than the signal-to-noise ratio of N-MPC). From these results, it is suggested that a probe made of a polymer having a main chain polymerization degree of 2 or more is preferable to a probe made of a monomer having a main chain polymerization degree of 1.
　１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブは、放射線を発生しない天然に存在する原子核から構成され、しかも生体における存在率が低い配列を有する結合を有しているので、かかるプローブを用いる本発明の多核多重磁気共鳴画像化方法は、多重磁気共鳴画像化装置という１つのモダリティのみで、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができ、正確で、かつ検体への負荷が少ない画像診断に使用されることが期待されるものである。また、本発明の多核多重磁気共鳴画像化装置は、検体の形態情報のみならず当該検体中におけるプローブの位置情報を得るとともに生体内でのプローブの機能、生体内でのプローブを介した代謝反応などを可視化することができることから、正確で、かつ検体への負荷が少ない画像診断に使用されることが期待されるものである。 A compound having at least two nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and having a bond consisting of at least three nuclear magnetic resonance active nuclei having different resonance frequencies The probe is composed of naturally occurring nuclei that do not generate radiation, and has a bond having a sequence with a low abundance in living bodies. Therefore, the multinuclear multiple magnetic resonance imaging method of the present invention using such a probe is In addition, with only one modality of multiple magnetic resonance imaging apparatus, not only the morphology information of the specimen but also the position information of the probe in the specimen is obtained, and the function of the probe in the living body, the metabolic reaction via the probe in the living body Can be visualized, and is expected to be used for diagnostic imaging that is accurate and has a low load on the specimen. In addition, the multinuclear multiple magnetic resonance imaging apparatus of the present invention obtains not only the morphology information of the specimen but also the positional information of the probe in the specimen, and the function of the probe in the living body, the metabolic reaction via the probe in the living body. Therefore, it is expected to be used for diagnostic imaging that is accurate and has a low load on the specimen.
　１　多核多重磁気共鳴画像化装置
　１０　ガントリー部
　１１　静磁場磁石
　１２　シムコイル
　１３　勾配磁場コイル
　１４　ＲＦコイル
　２０　パルス印加部
　２１　第１パルス印加部
　２２　第２パルス印加部
　２３　第３パルス印加部
　３０　電源部
　３１　シムコイル電源
　３２　勾配磁場コイル電源
　４０　パルス系列制御部
　５０ａ　検出部
　５０ｂ　検出部
　５１　第１受信部
　５２　第２受信部
　５３　第３受信部
　５４　受信部
　６０　データ収集部
　７０　コンピュータ
　７１　演算装置
　７２　入力装置
　７３　出力装置
　７４　記憶部 DESCRIPTION OF SYMBOLS 1 Multinuclear multiple magnetic resonance imaging apparatus 10 Gantry part 11 Static magnetic field magnet 12 Shim coil 13 Gradient magnetic field coil 14 RF coil 20 Pulse application part 21 1st pulse application part 22 2nd pulse application part 23 3rd pulse application part 30 Power supply part 31 Shim coil power supply 32 Gradient magnetic field coil power supply 40 Pulse sequence control unit 50a detection unit 50b detection unit 51 first reception unit 52 second reception unit 53 third reception unit 54 reception unit 60 data collection unit 70 computer 71 arithmetic device 72 input device 73 output Device 74 Memory

Claims (14)

  1. 　検体中のプローブに起因する多重共鳴シグナルを検出して画像化する多核多重磁気共鳴画像化方法であって、
    （Ａ）１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブを検体に付与するステップ、および
    （Ｂ）　前記ステップ（Ａ）でプローブが付与された前記検体に電磁波を照射して前記プローブの前記結合中の各核の間での磁化移動を行ない、当該磁化移動を利用して前記プローブに起因する多重共鳴シグナルを検出するステップ
    を含むことを特徴とする多核多重磁気共鳴画像化方法。     A multinuclear multiple magnetic resonance imaging method for detecting and imaging multiple resonance signals due to probes in a specimen,
    (A) a bond comprising at least two nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C and 15 N, and comprising at least three nuclear magnetic resonance active nuclei having different resonance frequencies; And (B) magnetizing transfer between the nuclei during the binding of the probe by irradiating the specimen to which the probe has been applied in step (A) with an electromagnetic wave. And a step of detecting a multiple resonance signal caused by the probe using the magnetization movement, and a multinuclear multiple magnetic resonance imaging method.
  2. 　前記プローブとして、１Ｈ－１３Ｃ－１５Ｎ結合、１Ｈ－１５Ｎ－１３Ｃ結合または１Ｈ－１３Ｃ－１３Ｃ結合を有する化合物からなるプローブと、前記結合に基づく三重核磁気共鳴法および磁気共鳴撮像法の各パルス系列とを用いて前記プローブに起因する多重共鳴シグナルを検出する請求項１に記載の多核多重磁気共鳴画像化方法。 As the probe, a probe comprising a compound having 1 H- 13 C- 15 N bond, 1 H- 15 N- 13 C bond or 1 H- 13 C- 13 C bond, and a triple nuclear magnetic resonance method based on the bond The multinuclear multiple magnetic resonance imaging method according to claim 1, wherein a multiple resonance signal caused by the probe is detected using a pulse sequence of the magnetic resonance imaging method.
  3. 　前記プローブが、
    　式（ｘ１）～（ｘ３）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、Ｒ１～Ｒ４はそれぞれ独立して水素原子または置換基を有していてもよい炭素数１～９の炭化水素基、Ｒ５は置換基を有していてもよい炭素数１～４の炭化水素基、＊は側鎖に直接またはリンカーを介して結合する。ただし、Ｒ5が炭素数２～４の炭化水素基である場合、当該炭化水素基中の少なくとも１つの炭素原子が前記側鎖に直接またはリンカーを介して結合する）
    で表わされる繰返し単位からなる群より選ばれた少なくとも１種の繰返し単位を含む重合度が１～５０００の主鎖を有し、かつ前記側鎖として式（ｙ１）～（ｙ３）：
    Figure JPOXMLDOC01-appb-C000002
    〔式中、Ｒ６は直接結合または置換基を有していてもよい炭素数１～４の炭化水素基、Ｚは１価の官能基を示し、＊は前記式（ｘ１）～（ｘ３）における＊に直接またはリンカーを介して結合する〕
    で表わされる官能基からなる群より選ばれた少なくとも１種の官能基を有する化合物である請求項１または２に記載の多核多重磁気共鳴画像化方法。     The probe is
    Formulas (x1) to (x3):
    Figure JPOXMLDOC01-appb-C000001
    (Wherein R 1 to R 4 are each independently a hydrogen atom or a hydrocarbon group having 1 to 9 carbon atoms which may have a substituent, and R 5 is a carbon number optionally having a substituent) 1 to 4 hydrocarbon group, * is bonded to the side chain directly or via a linker, provided that when R 5 is a hydrocarbon group having 2 to 4 carbon atoms, at least one carbon in the hydrocarbon group Atoms are attached to the side chain directly or via a linker)
    Having a main chain having a degree of polymerization of 1 to 5000 containing at least one repeating unit selected from the group consisting of repeating units represented by formulas (y1) to (y3):
    Figure JPOXMLDOC01-appb-C000002
    [Wherein R 6 is a hydrocarbon group having 1 to 4 carbon atoms which may have a direct bond or a substituent, Z represents a monovalent functional group, and * represents the above formulas (x1) to (x3) (Directly or via a linker)
    The multinuclear multiple magnetic resonance imaging method according to claim 1, wherein the compound has at least one functional group selected from the group consisting of functional groups represented by the formula:
  4. 　前記側鎖が、式（ｙ１）または（ｙ２）で表わされる官能基であり、前記式（ｙ１）または（ｙ２）におけるＺが式（ｚ１）：
    ＊－１５ＮＨ２　　（ｚ１）
    〔式中、＊は前記式（ｙ１）または（ｙ２）で表わされる官能基に結合する結合手を示す〕
    で表わされる官能基である請求項３に記載の多核多重磁気共鳴画像化方法。     The side chain is a functional group represented by the formula (y1) or (y2), and Z in the formula (y1) or (y2) is the formula (z1):
    * - 15 NH 2 (z1)
    [Wherein, * represents a bond bonded to the functional group represented by the formula (y1) or (y2)]
    The multinuclear multiple magnetic resonance imaging method according to claim 3, wherein the functional group is represented by:
  5. 　前記式（ｙ１）～（ｙ３）におけるＺが式（ｚ２）～（ｚ４）：
    ＊－１３ＣＨ３　　（ｚ２）
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    〔式中、＊は前記式（ｙ１）～（ｙ３）で表わされる官能基に結合する結合手、ｄは１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい〕
    で表される請求項３に記載の多核多重磁気共鳴画像化方法。     In the formulas (y1) to (y3), Z represents formulas (z2) to (z4):
    * - 13 CH 3 (z2)
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    [In the formula, * represents a bond bonded to the functional group represented by the formulas (y1) to (y3), d represents an integer of 1 to 4, and the hydrogen atom of the methylene group is substituted with another atom. (May be)
    The multinuclear multiple magnetic resonance imaging method of Claim 3 represented by these.
  6. 　前記リンカーが、置換基を有していてもよい炭素数１～４の炭化水素基および式（ｌ１）～（ｌ３）：
    Figure JPOXMLDOC01-appb-C000005
    Figure JPOXMLDOC01-appb-C000006
    Figure JPOXMLDOC01-appb-C000007
    〔式中、Ｌ’は置換基を有していてもよい炭素数１～４の炭化水素基または式（ｌ’）：
    Figure JPOXMLDOC01-appb-C000008
    （式中、ａおよびｂはそれぞれ独立して１～４の整数を示し、メチレン基の水素原子は他の原子で置換されていてもよい）
    で表わされる官能基を示し、＊は前記式（ｘ１）～（ｘ３）における＊または前記式（ｙ１）～（ｙ３）における＊に結合する〕
    で表わされる官能基からなる群より選ばれた少なくとも１種の官能基である請求項３～５のいずれかに記載の多核多重磁気共鳴画像化方法。     The linker may have a substituent and may have a hydrocarbon group having 1 to 4 carbon atoms and formulas (l1) to (l3):
    Figure JPOXMLDOC01-appb-C000005
    Figure JPOXMLDOC01-appb-C000006
    Figure JPOXMLDOC01-appb-C000007
    [In the formula, L ′ represents an optionally substituted hydrocarbon group having 1 to 4 carbon atoms or a formula (l ′):
    Figure JPOXMLDOC01-appb-C000008
    (Wherein, a and b each independently represent an integer of 1 to 4, and the hydrogen atom of the methylene group may be substituted with another atom)
    Wherein * is bonded to * in the above formulas (x1) to (x3) or * in the above formulas (y1) to (y3).
    The multinuclear multiple magnetic resonance imaging method according to any one of claims 3 to 5, which is at least one functional group selected from the group consisting of functional groups represented by:
  7. 　前記主鎖と側鎖とがリンカーを介して結合しており、前記リンカーと前記側鎖とからなる構造が、式（ｙ５）～（ｙ７）：
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
    Figure JPOXMLDOC01-appb-C000011
    〔式中、＊は前記式（ｘ１）～（ｘ３）における＊に結合する結合手、ａおよびｂはそれぞれ独立して１～４の整数を示し、式（ｙ５）～（ｙ７）中のメチレン基の水素原子は他の原子で置換されていてもよい〕
    で表わされる構造からなる群より選ばれた構造である請求項３に記載の多核多重磁気共鳴画像化方法。     The main chain and the side chain are bonded via a linker, and the structure composed of the linker and the side chain has the formulas (y5) to (y7):
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
    Figure JPOXMLDOC01-appb-C000011
    [In the formula, * represents a bond bonded to * in the formulas (x1) to (x3), a and b each independently represents an integer of 1 to 4, and methylene in the formulas (y5) to (y7) The hydrogen atom of the group may be substituted with another atom)
    The multinuclear multiple magnetic resonance imaging method according to claim 3, wherein the structure is selected from the group consisting of the structures represented by:
  8. 　前記主鎖が、（メタ）アクリレートモノマーに由来する繰返し単位、（メタ）アクリルアミドモノマーに由来する繰り返し単位、アミノ酸モノマーに由来する繰返し単位およびヒドロキシ酸モノマーに由来する繰返し単位からなる群より選ばれた繰返し単位をさらに有する請求項３～７のいずれかに記載の多核多重磁気共鳴画像化方法。 The main chain was selected from the group consisting of repeating units derived from (meth) acrylate monomers, repeating units derived from (meth) acrylamide monomers, repeating units derived from amino acid monomers, and repeating units derived from hydroxy acid monomers. The multinuclear multiple magnetic resonance imaging method according to any one of claims 3 to 7, further comprising a repeating unit.
  9. 　前記主鎖が、式（ａ１）～（ａ３）：
    Figure JPOXMLDOC01-appb-C000012
    Figure JPOXMLDOC01-appb-C000013
    Figure JPOXMLDOC01-appb-C000014
    （式中、Ｒ1～Ｒ５は前記と同じ。Ｒ７は水素原子または置換基を有していてもよい炭素数１～６の炭化水素基を示す）
    で表わされる繰返し単位からなる群より選ばれた繰返し単位をさらに有する請求項３～７のいずれかに記載の多核多重磁気共鳴画像化方法。     The main chain has the formulas (a1) to (a3):
    Figure JPOXMLDOC01-appb-C000012
    Figure JPOXMLDOC01-appb-C000013
    Figure JPOXMLDOC01-appb-C000014
    (In the formula, R 1 to R 5 are the same as above. R 7 represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may have a substituent.)
    The multinuclear multiple magnetic resonance imaging method according to any one of claims 3 to 7, further comprising a repeating unit selected from the group consisting of repeating units represented by:
  10. 　前記繰り返し単位の末端に、炭素数１～１２のアルキル基、炭素数２～１２のアルケニル基、炭素数２～４のアルキニル基、水酸基、チオール基、アミノ基、アジド基、マレイミド基、Ｎ－ヒドロキシスクシンイミド基およびトリクロロシリル基のいずれかの官能基を有する請求項３～９のいずれかに記載の多核多重磁気共鳴画像化方法。 At the terminal of the repeating unit, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a hydroxyl group, a thiol group, an amino group, an azide group, a maleimide group, N— The multinuclear multiple magnetic resonance imaging method according to any one of claims 3 to 9, which has a functional group selected from a hydroxysuccinimide group and a trichlorosilyl group.
  11. 　前記重合体の繰り返し単位の末端に有する官能基に、標的部位に特異的に結合する捕捉分子が結合されてなる請求項１０に記載の多核多重磁気共鳴画像化方法。 The multinuclear multiple magnetic resonance imaging method according to claim 10, wherein a capture molecule that specifically binds to a target site is bound to a functional group at the end of a repeating unit of the polymer.
  12. 　検体中のプローブに起因する多重共鳴シグナルを検出して画像化するための多核多重磁気共鳴画像化装置であって、
    　前記プローブが、１Ｈ、１３Ｃおよび１５Ｎからなる群より選ばれた少なくとも２種類の核磁気共鳴活性核を有し、かつ異なる共鳴周波数を有する少なくとも３個の核磁気共鳴活性核からなる結合を有する化合物からなるプローブであり、
    　前記結合に含まれる少なくとも３個の核磁気共鳴活性核それぞれの共鳴周波数に相当するＲＦパルスを印加するパルス印加部と、
    　前記プローブに勾配磁場を印加する勾配磁場印加部と、
    　前記結合に含まれる核磁気共鳴活性核それぞれの磁気共鳴信号を検出する検出部と、
    　所定のパルス系列が生成されるように前記パルス印加部と前記勾配磁場印加部とを制御する制御部と
    を備えており、
    　前記所定のパルス系列が、
    　前記結合に含まれる各核磁気共鳴活性核間の磁化移動を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、
    　前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列と
    を含むことを特徴とする多核多重磁気共鳴画像化装置。     A multinuclear multiple magnetic resonance imaging apparatus for detecting and imaging multiple resonance signals caused by probes in a specimen,
    The probe has at least two types of nuclear magnetic resonance active nuclei selected from the group consisting of 1 H, 13 C, and 15 N, and is composed of at least three nuclear magnetic resonance active nuclei having different resonance frequencies. A probe comprising a compound having
    A pulse applying unit for applying an RF pulse corresponding to a resonance frequency of each of at least three nuclear magnetic resonance active nuclei included in the coupling;
    A gradient magnetic field application unit for applying a gradient magnetic field to the probe;
    A detection unit for detecting a magnetic resonance signal of each of the nuclear magnetic resonance active nuclei included in the binding;
    A control unit that controls the pulse application unit and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
    The predetermined pulse sequence is
    A magnetization transfer pulse sequence for applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization transfer between each nuclear magnetic resonance active nucleus included in the coupling; and
    A multinuclear multiple magnetic resonance imaging apparatus comprising: a signal acquisition pulse sequence for adding position information to the magnetic resonance signal and acquiring the magnetic resonance signal.
  13. 　前記プローブが、第１核磁気共鳴活性核と当該第１核磁気共鳴活性核に磁気的に結合した第２核磁気共鳴活性核と当該第２核磁気共鳴活性核に磁気的に結合した第３核磁気共鳴活性核とからなる結合を有する化合物からなるプローブであり、
    　前記第１核磁気共鳴活性核に当該第１核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第１パルス印加部と、
    　前記第２核磁気共鳴活性核に当該第２核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第２パルス印加部と、
    　前記第３核磁気共鳴活性核に当該第３核磁気共鳴活性核の共鳴周波数に相当するＲＦパルスを印加する第３パルス印加部と、
    　前記プローブに勾配磁場を印加する勾配磁場印加部と、
    　前記第１核磁気共鳴活性核、前記第２核磁気共鳴活性核および前記第３核磁気共鳴活性核からなる群より選ばれた少なくとも１つの核磁気共鳴活性核の磁気共鳴信号を検出する検出部と、
    　所定のパルス系列が生成されるように前記第１パルス印加と前記第２パルス印加部と前記第３パルス印加部と前記勾配磁場印加部とを制御する制御部と
    を備えており、
    　前記所定のパルス系列が、
    　前記第１核磁気共鳴活性核から第２核磁気共鳴活性核への磁化移動を行なった後、前記第２核磁気共鳴活性核から第３核磁気共鳴活性核への磁化移動を行ない、さらに前記第３核磁気共鳴活性核から前記第２核磁気共鳴活性核を経て前記第１核磁気共鳴活性核への磁化を行なうようにＲＦパルスおよび勾配磁場を前記プローブに印加して磁化移動を行なうための磁化移動パルス系列と、
    　前記磁気共鳴信号に位置情報を付加し、当該磁気共鳴信号を収集するための信号収集パルス系列と
    を含む、請求項１２に記載の多核多重磁気共鳴画像化装置。     The probe is magnetically coupled to a first nuclear magnetic resonance active nucleus, a second nuclear magnetic resonance active nucleus that is magnetically coupled to the first nuclear magnetic resonance active nucleus, and a third magnetically coupled to the second nuclear magnetic resonance active nucleus. A probe comprising a compound having a bond comprising a nuclear magnetic resonance active nucleus,
    A first pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the first nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus;
    A second pulse applying unit that applies an RF pulse corresponding to a resonance frequency of the second nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus;
    A third pulse applying unit for applying an RF pulse corresponding to the resonance frequency of the third nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus;
    A gradient magnetic field application unit for applying a gradient magnetic field to the probe;
    A detector for detecting a magnetic resonance signal of at least one nuclear magnetic resonance active nucleus selected from the group consisting of the first nuclear magnetic resonance active nucleus, the second nuclear magnetic resonance active nucleus, and the third nuclear magnetic resonance active nucleus When,
    A control unit that controls the first pulse application, the second pulse application unit, the third pulse application unit, and the gradient magnetic field application unit so that a predetermined pulse sequence is generated;
    The predetermined pulse sequence is
    After performing the magnetization transfer from the first nuclear magnetic resonance active nucleus to the second nuclear magnetic resonance active nucleus, performing the magnetization transfer from the second nuclear magnetic resonance active nucleus to the third nuclear magnetic resonance active nucleus, In order to perform magnetization transfer by applying an RF pulse and a gradient magnetic field to the probe so as to perform magnetization from the third nuclear magnetic resonance active nucleus to the first nuclear magnetic resonance active nucleus through the second nuclear magnetic resonance active nucleus. A magnetization transfer pulse sequence of
    The multinuclear multiple magnetic resonance imaging apparatus according to claim 12, further comprising: a signal collection pulse sequence for adding position information to the magnetic resonance signal and collecting the magnetic resonance signal.
  14. 　前記磁化移動パルス系列は、前記制御部によって下記（ａ１）～（ａ１６）：
    　（ａ１）前記第１核磁気共鳴活性核に９０度の第１ＲＦパルスを印加した後、当該第１核磁気共鳴活性核に１８０度の第２ＲＦパルスをさらに印加するステップ、
    　（ａ２）前記第２ＲＦパルスを印加すると同時または印加した後、前記第２核磁気共鳴活性核に１８０度の第３ＲＦパルスを印加するステップ、
    　（ａ３）前記第１核磁気共鳴活性核に９０度の第４ＲＦパルスを印加した後、前記第２核磁気共鳴活性核に９０度の第５ＲＦパルスを印加するステップ、
    　（ａ４）前記第２核磁気共鳴活性核に１８０度の第６ＲＦパルスを印加するステップ、
    　（ａ５）前記第６ＲＦパルスを印加すると同時または印加した後、前記第３核磁気共鳴活性核に１８０度の第７ＲＦパルスを印加するステップ、
    　（ａ６）前記第２核磁気共鳴活性核に９０度の第８ＲＦパルスを印加した後、前記第３核磁気共鳴活性核に９０度の第９ＲＦパルスを印加するステップ、
    　（ａ７）前記第２核磁気共鳴活性核に１８０度の第１０ＲＦパルスを印加するステップ、
    　（ａ８）前記第１核磁気共鳴活性核に１８０度の第１１ＲＦパルスと前記第３核磁気共鳴活性核に１８０度の第１２ＲＦパルスとを同時に印加するステップ、
    　（ａ９）前記第２核磁気共鳴活性核に１８０度の第１３ＲＦパルスを印加するステップ、
    　（ａ１０）前記第３核磁気共鳴活性核に９０度の第１４ＲＦパルスを印加するステップ、
    　（ａ１１）前記第２核磁気共鳴活性核に９０度の第１５ＲＦパルスを印加するステップ、
    　（ａ１２）前記第２核磁気共鳴活性核に１８０度の第１６ＲＦパルスを印加するステップ、
    　（ａ１３）前記第１６ＲＦパルスと同時または印加後に、前記第３核磁気共鳴活性核に１８０度の第１７ＲＦパルスを印加するステップ、
    　（ａ１４）前記第２核磁気共鳴活性核に９０度の第１８ＲＦパルスを印加した後、前記第１核磁気共鳴活性核に９０度の第１９ＲＦパルスを印加するステップ、および
    　（ａ１５）前記第１核磁気共鳴活性核に１８０度の第２０ＲＦパルスを印加するステップ、
    　（ａ１６）前記第２０ＲＦパルスを印加すると同時または印加後に、前記第２核磁気共鳴活性核に１８０度の第２１ＲＦパルスを印加するステップ
    の各ステップがこの順に実行されることによって生成されるＲＦパルス印加系列と、前記制御部によって下記（ｂ１）～（ｂ１２）：
    　（ｂ１）前記第１ＲＦパルスと前記第２ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ２）前記第３ＲＦパルスと前記第４ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ３）前記第４ＲＦパルスと前記第５ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ４）前記第８ＲＦパルスと前記第９ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ５）前記第９ＲＦパルスと前記第１０ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ６）前記第１０ＲＦパルスと前記第１１ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ７）前記第１２ＲＦパルスと前記第１３ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ８）前記第１３ＲＦパルスと前記第１４ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ９）前記第１４ＲＦパルスと前記第１５ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ１０）前記第１８ＲＦパルスと前記第１９ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、
    　（ｂ１１）前記第１９ＲＦパルスと前記第２０ＲＦパルスとのインターバルにおいて、前記プローブに勾配磁場を印加するステップ、および
    　（ｂ１２）前記第２１ＲＦパルスの印加後において、前記プローブに勾配磁場を印加するステップ
    がこの順に実行されることによって生成される勾配磁場印加系列と
    を含む、請求項１３に記載の多核多重磁気共鳴画像化装置。     The magnetization transfer pulse sequence is the following (a1) to (a16):
    (A1) applying a first RF pulse of 90 degrees to the first nuclear magnetic resonance active nucleus, and further applying a second RF pulse of 180 degrees to the first nuclear magnetic resonance active nucleus;
    (A2) applying a third RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus simultaneously with or after applying the second RF pulse;
    (A3) applying a 90 degree fourth RF pulse to the first nuclear magnetic resonance active nucleus and then applying a 90 degree fifth RF pulse to the second nuclear magnetic resonance active nucleus;
    (A4) applying a 180 ° sixth RF pulse to the second nuclear magnetic resonance active nucleus;
    (A5) applying a seventh RF pulse of 180 degrees to the third nuclear magnetic resonance active nucleus simultaneously with or after applying the sixth RF pulse;
    (A6) applying a 90-degree ninth RF pulse to the third nuclear magnetic resonance active nucleus after applying a 90-degree eighth RF pulse to the second nuclear magnetic resonance active nucleus;
    (A7) applying a 180 degree tenth RF pulse to the second nuclear magnetic resonance active nucleus;
    (A8) applying a 180 degree eleventh RF pulse to the first nuclear magnetic resonance active nucleus and a 180 degree twelfth RF pulse simultaneously to the third nuclear magnetic resonance active nucleus;
    (A9) applying a 13th RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus;
    (A10) applying a 14th RF pulse of 90 degrees to the third nuclear magnetic resonance active nucleus;
    (A11) applying a 90 degree 15th RF pulse to the second nuclear magnetic resonance active nucleus;
    (A12) applying a 180 degree sixteenth RF pulse to the second nuclear magnetic resonance active nucleus;
    (A13) applying a 180 degree 17th RF pulse to the third nuclear magnetic resonance active nucleus simultaneously with or after the application of the 16th RF pulse;
    (A14) applying a 90 degree 18th RF pulse to the second nuclear magnetic resonance active nucleus and then applying a 90 degree 19th RF pulse to the first nuclear magnetic resonance active nucleus; and (a15) the first nuclear magnetic resonance active nucleus Applying a 180 degree 20th RF pulse to the nuclear magnetic resonance active nucleus;
    (A16) RF pulse generated by performing each step of applying the 21st RF pulse of 180 degrees to the second nuclear magnetic resonance active nucleus in this order at the same time or after the application of the 20th RF pulse The following (b1) to (b12) by the application sequence and the control unit:
    (B1) applying a gradient magnetic field to the probe in the interval between the first RF pulse and the second RF pulse;
    (B2) applying a gradient magnetic field to the probe in the interval between the third RF pulse and the fourth RF pulse;
    (B3) applying a gradient magnetic field to the probe in an interval between the fourth RF pulse and the fifth RF pulse;
    (B4) applying a gradient magnetic field to the probe in the interval between the eighth RF pulse and the ninth RF pulse;
    (B5) applying a gradient magnetic field to the probe in the interval between the ninth RF pulse and the tenth RF pulse;
    (B6) applying a gradient magnetic field to the probe in the interval between the tenth RF pulse and the eleventh RF pulse;
    (B7) applying a gradient magnetic field to the probe in the interval between the twelfth RF pulse and the thirteenth RF pulse;
    (B8) applying a gradient magnetic field to the probe in an interval between the thirteenth RF pulse and the fourteenth RF pulse;
    (B9) applying a gradient magnetic field to the probe in an interval between the 14th RF pulse and the 15th RF pulse;
    (B10) applying a gradient magnetic field to the probe in the interval between the 18th RF pulse and the 19th RF pulse;
    (B11) applying a gradient magnetic field to the probe in the interval between the 19th RF pulse and the 20th RF pulse; and (b12) applying a gradient magnetic field to the probe after applying the 21st RF pulse. The multinuclear multiple magnetic resonance imaging apparatus according to claim 13, further comprising a gradient magnetic field application sequence generated by being executed in this order.
PCT/JP2014/055848 2013-03-07 2014-03-06 Polynuclear and multiple magnetic resonance imaging method and imaging device WO2014136905A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2015504398A JP6233815B2 (en) 2013-03-07 2014-03-06 Multinuclear multiple magnetic resonance imaging method and imaging apparatus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2013-045724 2013-03-07
JP2013045724 2013-03-07

Publications (1)

Publication Number Publication Date
WO2014136905A1 true WO2014136905A1 (en) 2014-09-12

Family

ID=51491412

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2014/055848 WO2014136905A1 (en) 2013-03-07 2014-03-06 Polynuclear and multiple magnetic resonance imaging method and imaging device

Country Status (2)

Country Link
JP (1) JP6233815B2 (en)
WO (1) WO2014136905A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017200559A (en) * 2016-05-02 2017-11-09 キル メディカル センター Magnetic resonance video system

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009079046A (en) * 2007-09-07 2009-04-16 Kyoto Univ Compound, diagnostic agent, method of nuclear magnetic resonance analysis, method of nuclear magnetic resonance-imaging, method of mass analysis and method of mass analysis-imaging
JP2009078141A (en) * 2007-09-07 2009-04-16 Kyoto Univ Nuclear magnetic resonance measuring method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009079046A (en) * 2007-09-07 2009-04-16 Kyoto Univ Compound, diagnostic agent, method of nuclear magnetic resonance analysis, method of nuclear magnetic resonance-imaging, method of mass analysis and method of mass analysis-imaging
JP2009078141A (en) * 2007-09-07 2009-04-16 Kyoto Univ Nuclear magnetic resonance measuring method

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017200559A (en) * 2016-05-02 2017-11-09 キル メディカル センター Magnetic resonance video system

Also Published As

Publication number Publication date
JP6233815B2 (en) 2017-11-29
JPWO2014136905A1 (en) 2017-02-16

Similar Documents

Publication Publication Date Title
Vinogradov et al. CEST: from basic principles to applications, challenges and opportunities
Van Zijl et al. Chemical exchange saturation transfer (CEST): what is in a name and what isn't?
JP5328269B2 (en) Nuclear magnetic resonance measurement
Schmidt et al. In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding
US8463358B2 (en) Elimination of contrast agent concentration dependency in MRI
Epel et al. In vivo pO2 imaging of tumors: oxymetry with very low-frequency electron paramagnetic resonance
US9131870B2 (en) Blood signal suppressed contrast enhanced magnetic resonance imaging
US6685915B2 (en) Extended-linear polymeric contrast agents, and synthesizing methods, for medical imaging
EP2130058A1 (en) Magnetic resonance device and method
CA2717906A1 (en) System and method for magnetic resonance imaging
US10048340B2 (en) System and method for superfast chemical exchange saturation transfer spectral imaging
US20150338483A1 (en) System and Method for Sensitivity-Enhanced Multi-Echo Chemical Exchange Saturation Transfer (MECEST) Magentic Resonance Imaging
Perman et al. Fast volumetric spatial-spectral MR imaging of hyperpolarized 13C-labeled compounds using multiple echo 3D bSSFP
Bakermans et al. Small animal cardiovascular MR imaging and spectroscopy
JP5160008B2 (en) MR method for in vivo measurement of temperature or pH value using hyperpolarized contrast agent
US9149203B2 (en) Blood signal suppressed enhanced magnetic resonance imaging
WO2003049604A2 (en) Method for mr/nmr imaging
JP6233815B2 (en) Multinuclear multiple magnetic resonance imaging method and imaging apparatus
Elas et al. Electron paramagnetic resonance imaging-solo and orchestra
US11835610B2 (en) Systems and methods for susceptibility contrast imaging of nanoparticles at low magnetic fields
Artemov MR Imaging
TW200812624A (en) Magnetic resonance contrast medium using polyethylene glycol and magnetic resonance image pick-up method
Elas Martyna Elas, Martyna Krzykawska-Serda, Michał Gonet, Anna Kozińska, and Przemysław M. Płonka
Hager et al. The Variable Echo Time (vTE) Sequence
Wade HyperCEST MR studies of Xenon-129 (129Xe) biosensors and MRI detection of 129Xe in the brain

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14759672

Country of ref document: EP

Kind code of ref document: A1

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: 2015504398

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14759672

Country of ref document: EP

Kind code of ref document: A1