WO2011093098A1 - 新規インドシアニン化合物、その合成法及びその精製法、そのインドシアニン化合物を用いた診断用組成物、その診断用組成物を使用する生体内動態測定装置、並びに循環可視化装置 - Google Patents
新規インドシアニン化合物、その合成法及びその精製法、そのインドシアニン化合物を用いた診断用組成物、その診断用組成物を使用する生体内動態測定装置、並びに循環可視化装置 Download PDFInfo
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- WO2011093098A1 WO2011093098A1 PCT/JP2011/000489 JP2011000489W WO2011093098A1 WO 2011093098 A1 WO2011093098 A1 WO 2011093098A1 JP 2011000489 W JP2011000489 W JP 2011000489W WO 2011093098 A1 WO2011093098 A1 WO 2011093098A1
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- cyclodextrin
- indocyanine compound
- bound indocyanine
- compound
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B68/00—Organic pigments surface-modified by grafting, e.g. by establishing covalent or complex bonds, in order to improve the pigment properties, e.g. dispersibility or rheology
- C09B68/40—Organic pigments surface-modified by grafting, e.g. by establishing covalent or complex bonds, in order to improve the pigment properties, e.g. dispersibility or rheology characterised by the chemical nature of the attached groups
- C09B68/41—Polymers attached to the pigment surface
Definitions
- the present invention is a green pigment useful for medical diagnosis technology, medical surgery technology, scientific measurement analysis technology, printing technology, writing technology, painting technology, dye technology, and dyeing technology, and has a property of emitting near-infrared fluorescence.
- the present invention relates to a novel indocyanine compound, a synthesis method thereof, a purification method thereof, and a diagnostic composition.
- a cyclic sugar chain cyclodextrin-linked indocyanine compound having a green pigment and a property of emitting near-infrared fluorescence a synthesis method and purification method thereof, a diagnostic composition using the indocyanine compound, and diagnosis thereof
- the present invention relates to an in vivo kinetic measurement apparatus using a composition for blood circulation and a circulation visualization apparatus.
- indocyanine compounds that have been green pigments and emit near-infrared fluorescence have been synthesized so far.
- they are dyes used for vitreous surgery of eyes, pigments used for liver function test drugs, and circulation.
- dyes for functional test agents dyes used in surgical operations, near-infrared fluorescent compounds used in surgery, dyeing and fluorescent compounds such as proteins and sugars in the scientific field, and dyes in printing technology.
- ICG indocyanine green
- ICG is used as a trial, but using the nature of ICG having high light permeability from living tissue, the body, for example, blood vessels, lymph vessels, brain, ICG is locally administered to the eye, stomach, milk, esophagus, skin, or other sites, and medical surgery and medical diagnosis are performed by observing near-infrared fluorescence of ICG (Non-patent Document 1). ).
- ICG's green chromophore (chemical structure necessary to exhibit green color) and near-infrared fluorophore (chemical structure necessary to emit near-infrared fluorescence) are hydrophobic, A sulfonyl group is bonded to the end of the side chain. For this reason, the conventional ICG has many problems as follows.
- Non-patent Document 2 In general medical use of ICG preparation, about 5 mL to 10 mL of distilled water is added to 25 mg of ICG and dissolved by vibration stirring. When ICG is not completely dissolved, nausea, nausea, fever, and shock-like symptoms may appear (Non-patent Document 2). Moreover, since it is insolubilized, it cannot be initially dissolved in other aqueous solutions such as physiological saline (Non-patent Document 2).
- ICG is soluble in water because the sulfonyl group is bonded as described above, but has a property of causing adsorption to lipids because of its many hydrophobic hydrocarbon groups in chemical structure and surface activity. Therefore, when it is injected into a living tissue such as a blood vessel or an organ, it may adhere to the injection site, or may accidentally leak or adhere to an undesired living tissue by flowing backward. ICG adhering to a living tissue cannot be easily removed from the living tissue by a wiping operation or a suction operation, which may hinder a surgical operation or medical diagnosis.
- ICG has the property of molecular association in an aqueous solution.
- One of the factors is that the fluorescence intensity in the aqueous solution is low (Non-patent Documents 3 and 4).
- ICG is insolubilized with time after being dissolved in water, and it is difficult to store it as an aqueous solution for a long time, and cryopreservation at a low temperature promotes insolubilization.
- the ICG preparation contains 5% or less of NaI and has a problem that it may cause iodine hypersensitivity (Non-patent Document 2).
- Non-patent Document 2 iodine hypersensitivity
- ICG intravenously injected, it quickly accumulates in the liver and is excreted by the liver, so that it is difficult to perform fluorescence imaging of other organs such as the kidney, ureter, bladder, urethra, heart, and lung.
- ICG migrates with blood when injected intravenously, it is difficult to see the transition to the interstitium because there is little migration to peripheral tissues.
- the present invention aims to solve the problems of the conventional ICG as described above. That is, it is highly soluble in water or physiological saline, can be easily removed from living tissues, has low molecular association in aqueous solution, has high near-infrared fluorescence intensity in aqueous solution, and organs other than liver
- An object of the present invention is to provide a novel indocyanine compound that emits near-infrared fluorescence with a green dye characterized by fluorescent imaging of, for example, the kidney, ureter, bladder, urethra, heart, and lung.
- the present invention also provides a chemical synthesis method of a novel indocyanine compound having this characteristic and a purification method thereof.
- Another object to be solved is to provide a diagnostic composition containing the novel indocyanine compound. Furthermore, by using these diagnostic compositions, in vivo kinetics measuring devices that can evaluate the pharmacokinetics of novel indocyanine compounds related to water balance in vivo, blood, lymph, urine and others in the body Another object of the present invention is to provide a method and apparatus for visualizing the water circulation.
- the present inventor emits near-infrared fluorescence that can be used in surgery and medical diagnosis utilizing the property of emitting near-infrared fluorescence.
- the above-mentioned problems of ICG were solved.
- a novel indocyanine compound characterized by emitting external fluorescence has been found, and the present invention has been completed. Furthermore, the inventors have found a chemical synthesis method and a purification method for the novel indocyanine compound, and have completed the present invention. Furthermore, it came to provide the diagnostic composition containing the said novel indocyanine compound. Furthermore, the use of these diagnostic compositions has led to the provision of a method for fluorescence imaging of organs other than the liver both in intravenous administration.
- the first novel indocyanine compound of the present invention is cyclic to ICG's green chromophore (chemical structure necessary for exhibiting green color) and near-infrared fluorophore (chemical structure necessary to emit near-infrared fluorescence).
- the second novel indocyanine compound of the present invention includes a naphthyl site that is a hydrophilic glucose group and a hydrophobic site by including a naphthyl site that is a hydrophobic site of an indocyanine structure in a cavity of cyclodextrin.
- ICG is a novel indocyanine compound characterized in that many regions of the indocyanine molecular structure are made hydrophilic three-dimensionally. Therefore, ICG is characterized by a surfactant-like property having both a hydrophobic site and the hydrophilicity of a sulfonyl group, whereas the compound of the present invention coats the hydrophobic site in the molecule with cyclodextrin. It is characterized by not having surface-like properties. More particularly, the present invention provides:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 are a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxyl group, amino group, carboxyl group, formyl group, sulfonyl group , Sulfonic acid group, phosphoric acid group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyl group, arylcarbonyl group or heterocyclic ring, and these substituents (carboxylic acid, sulfonic acid, phosphoric acid) Yes, when a hydrogen ion dissociates in the substituent, a metal ion such as sodium ion, potassium
- Level 4 is also selected An alkyl group as substituent to.).
- R 8 and R 9 CH 2, CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 CH 2 cyclic structures
- alkyl groups instead of hydrogen atoms, alkyl groups, aryl groups, halogen atoms, alkoxy groups, amino groups, carboxyl groups, formyl groups, sulfonyl groups, sulfonic acid groups, phosphoric acid groups
- a functional group substituted by an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group or a heterocyclic ring is also selected.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 are a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxyl group, amino group, carboxyl group, formyl group, sulfonyl group , Sulfonic acid group, phosphoric acid group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyl group, arylcarbonyl group or heterocyclic ring, and these substituents (carboxylic acid, sulfonic acid, phosphoric acid)
- a hydrogen ion dissociates in the substituent, a metal ion such as a sodium ion,
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 are a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxyl group, amino group, carboxyl group, formyl group, sulfonyl group , Sulfonic acid group, phosphoric acid group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyl group, arylcarbonyl group or heterocyclic ring, and these substituents (carboxylic acid, sulfonic acid, phosphoric acid)
- a hydrogen ion dissociates in the substituent, a metal ion such as a sodium ion,
- R 8 and R 9 cyclic structure CH 2, CH 2 CH 2, CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 is also selected.
- alkyl groups instead of hydrogen atoms, alkyl groups, aryl groups, halogen atoms, alkoxy groups, amino groups, carboxyl groups, formyl groups, sulfonyl groups, sulfonic acid groups, phosphoric acid groups, alkyloxycarbonyl groups, A functional group substituted with an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group or a heterocyclic ring is also selected.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 are a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxyl group, amino group, carboxyl group, formyl group, sulfonyl group , Sulfonic acid group, phosphoric acid group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyl group, arylcarbonyl group or heterocyclic ring, and these substituents (carboxylic acid, sulfonic acid, phosphoric acid)
- a hydrogen ion dissociates in the substituent, a metal ion such as a sodium ion,
- R 8 and R 9 cyclic structure CH 2, CH 2 CH 2, CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 is also selected.
- alkyl groups instead of hydrogen atoms, alkyl groups, aryl groups, halogen atoms, alkoxy groups, amino groups, carboxyl groups, formyl groups, sulfonyl groups, sulfonic acid groups, phosphoric acid groups, alkyloxycarbonyl groups, A functional group substituted with an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group or a heterocyclic ring is also selected.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 3 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 5.
- m, n, p and q are integers of 2 or more and 6 or less.
- R is an integer of 5 or more and 7 or less.
- S is an integer of 0 or more and 4 or less.
- R is a hydrogen atom or an alkyl group.
- ⁇ 6> The cyclodextrin-bound indocyanine compound according to Chemical Formula 4, which is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 6.
- m, n, p and q are integers of 2 or more and 6 or less.
- R is an integer of 5 or more and 7 or less.
- S is an integer of 0 or more and 4 or less.
- R is a hydrogen atom or an alkyl group. , Aryl group, halogen atom, alkoxy group, amino group, carboxyl group, formyl group, sulfonyl group, sulfonic acid group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyl group, arylcarbonyl group or heterocyclic ring.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 3 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 7.
- R is a hydrogen atom, an alkyl group, an aryl group, A halogen atom, an alkoxy group, an amino group, a carboxyl group, a formyl group, a sulfonyl group, a sulfonic acid group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group, or a heterocyclic ring.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 4 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 8.
- R is a hydrogen atom, an alkyl group, an aryl group, A halogen atom, an alkoxy group, an amino group, a carboxyl group, a formyl group, a sulfonyl group, a sulfonic acid group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group, or a heterocyclic ring.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 3 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 9.
- R is a hydrogen atom, an alkyl group, an aryl group, A halogen atom, an alkoxy group, an amino group, a carboxyl group, a formyl group, a sulfonyl group, a sulfonic acid group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group, or a heterocyclic ring.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 4 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 10.
- R is a hydrogen atom, an alkyl group, an aryl group, A halogen atom, an alkoxy group, an amino group, a carboxyl group, a formyl group, a sulfonyl group, a sulfonic acid group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group, or a heterocyclic ring.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 3 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 11.
- R is a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxy group, amino group, carboxyl group, formyl group, sulfonyl group, sulfonic acid group, alkyloxycarbonyl group, An aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group or a heterocyclic ring.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 4 is a cyclodextrin-bound indocyanine compound represented by Chemical Formula 12.
- R is a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxy group, amino group, carboxyl group, formyl group, sulfonyl group, sulfonic acid group, alkyloxycarbonyl group, An aryloxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group or a heterocyclic ring.
- a diagnostic composition that is used by being injected into the body which is an aqueous solution containing the cyclodextrin-bound indocyanine compound according to any one of Chemical Formulas 1 to 12.
- Excitation light irradiation means for irradiating the cyclodextrin-bound indocyanine compound with excitation light for a part of the living body administered with the diagnostic composition of ⁇ 16> or ⁇ 17>
- Fluorescence intensity measuring means for measuring the intensity of fluorescence emitted from the cyclodextrin-bound indocyanine compound excited by the excitation light irradiation means;
- the cyclodextrin-bound indocyanine compound is transferred into the interstitial fluid in a part of the living body by obtaining a temporal change in the temporal change rate of the fluorescence intensity from the fluorescence intensity acquired over time from the fluorescence intensity measuring means.
- In vivo kinetics calculating means for calculating the speed and / or the speed of moving out of the interstitium, It is an in-vivo dynamics measuring apparatus of the said cyclodextrin coupling
- Excitation light irradiation means for irradiating the cyclodextrin-bound indocyanine compound with excitation light for a part of the living body administered with the diagnostic composition of ⁇ 16> or ⁇ 17>
- a fluorescence imaging means for obtaining in vivo distribution state data of the cyclodextrin-bound indocyanine compound by two-dimensionally acquiring the intensity of fluorescence emitted by the cyclodextrin-bound indocyanine compound excited by the excitation light irradiation means;
- Morphological imaging means for two-dimensionally acquiring the intensity of light of a wavelength other than the fluorescence wavelength emitted by the cyclodextrin-bound indocyanine compound to obtain morphological data about a part of the living body;
- Display means for displaying the distribution state of the cyclodextrin-bound indocyanine compound in a part of the living body by superimposing the distribution state data obtained by the fluorescence imaging means on
- ⁇ 20> The circulation visualization device according to ⁇ 19> 9, wherein the display unit displays a part of the living body where a distribution amount of the cyclodextrin-bound indocyanine compound is lower than a predetermined reference as a necrotic part.
- the in vivo kinetics according to ⁇ 18> further comprising a swelling progress prediction means for predicting a degree of swelling that proceeds later in a part of the living body from a speed at which the part of the living body moves into and out of interstitial fluid. It is a measuring device.
- the swelling progress predicting means is the interstitial fluid after a lapse of a predetermined time which is a time from when the diagnostic composition is administered to when the cyclodextrin-bound indocyanine compound is dispersed in the whole body blood.
- Excitation light irradiation means for irradiating the cyclodextrin-bound indocyanine compound with excitation light for a part of a living body administered with the diagnostic composition according to ⁇ 16> or ⁇ 17> and a control site; Fluorescence intensity measuring means for measuring the intensity of fluorescence emitted from the cyclodextrin-bound indocyanine compound excited by the excitation light irradiation means; The rate at which the cyclodextrin-bound indocyanine compound migrates into the interstitial fluid in a part of the living body by determining the change over time of the fluorescence intensity from the fluorescence intensity acquired over time from the fluorescence intensity measuring means and / or In vivo dynamics calculating means for calculating the speed of transition to the outside of the interstitium, A swelling progression predicting means for predicting the degree of swelling that proceeds later in the part of the living body from the speed of moving into and out of the interstitial fluid in the part of the living
- Excitation light irradiation means for irradiating the cyclodextrin-bound indocyanine compound with excitation light for a living organ administered with the diagnostic composition according to ⁇ 16> or ⁇ 17>, Fluorescence intensity measuring means for measuring the intensity of fluorescence emitted from the cyclodextrin-bound indocyanine compound excited by the excitation light irradiation means;
- In vivo kinetics measuring device comprising: in vivo kinetics calculating means for evaluating in vivo kinetics of the cyclodextrin-bound indocyanine compound in the organ from the fluorescence intensity acquired over time from the fluorescence intensity measuring means It is.
- ⁇ 25> The in vivo kinetic measurement device according to ⁇ 24>, wherein the organ is any one of a kidney, a ureter, a bladder, and a urethra.
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 1 or Chemical Formula 2 of the present invention it is more soluble in water or physiological saline than ICG, and can be easily removed from biological tissues. Fluorescence imaging of organs other than the liver with low molecular association, high near-infrared fluorescence intensity in aqueous solution, and emission of near-infrared fluorescence with a green dye characterized by not containing iodine A compound can be provided.
- a useful synthesis of a cyclodextrin-bound indocyanine compound can be provided according to the method for synthesizing a cyclodextrin-bound indocyanine compound of the present invention.
- a cyclodextrin-bound indocyanine compound of the present invention useful purification of the cyclodextrin-bound indocyanine compound can be provided.
- the cyclodextrin-bound indocyanine compound of the present invention exhibits sufficient solubility without containing iodine, it is also possible to provide a diagnostic composition that does not contain iodine, which causes iodine hypersensitivity. Since this diagnostic composition exhibits a different in vivo behavior from that of a diagnostic composition containing only conventional ICG, various useful devices can be provided by utilizing its properties.
- FIG. 15 It is a figure which shows the mode of the fluorescence in the abdominal cavity at the time of administering the isomerization equilibrium compound (TK1) shown by ICG, Chemical formula 19 and 20, and the isomerization equilibrium compound (TK2) shown by Chemical formula 15 and 16 to a rat. .
- the vertical axis is the volume (mL).
- Von Frey test on the left foot of rats measured immediately after administration (post injection) and after 1 week (1w after) for the group that received carrageenan (edema) and the group that did not (normal) It is a graph which shows the result.
- the vertical axis represents the load (g) at which reaction occurred.
- the vertical axis represents luminance (arbitrary unit), and the horizontal axis represents time (seconds). It is the graph which showed the mode of the change of the brightness
- the vertical axis represents luminance (arbitrary unit), and the horizontal axis represents time (seconds).
- the vertical axis is the volume (mL).
- Von Frey test on the left foot of rats measured immediately after administration (post injection) and after one week (1w after) for the group that received carrageenin (edema) and the group that did not (normal) It is a graph which shows the result.
- the vertical axis represents the load (g) at which reaction occurred.
- the vertical axis represents luminance (arbitrary unit), and the horizontal axis represents time (seconds). It is the graph which showed the mode of change of the brightness
- the vertical axis represents luminance (arbitrary unit), and the horizontal axis represents time (seconds).
- the diagnostic composition of the present invention can be used for diagnosis without containing iodine by employing the cyclodextrin-bound indocyanine compound of the present invention described later as a pigment.
- This diagnostic composition can replace the conventionally used diagnostic composition containing indocyanine green.
- liver function test drugs and circulatory function test drugs.
- observe near-infrared fluorescence generated by administration to the body such as blood vessels, lymph vessels, brain, eyes, stomach, milk, esophagus, skin, kidney, ureter, bladder, urethra, lung, heart, or other parts. It can be applied to medical surgery and medical diagnosis.
- the dye contained in the diagnostic composition of the present invention has a low binding property to a living body and can label a necessary site for a long time.
- the diagnostic composition may contain a salt as an isotonic agent and other additives as necessary.
- a salt as an isotonic agent
- other additives as necessary.
- This diagnostic composition can be administered by injection, infusion, application, oral administration and the like.
- This diagnostic composition can be suitably used for visualizing the circulation of blood, lymph, interstitial water, and aqueous solutions such as urine.
- visualizing the circulation of blood or the like for example, it can be used for judgment of necrosis by evaluating peripheral circulation, evaluation of tissue survival after revascularization or transplantation, diagnosis of poor circulation, and the like.
- fundus angiography cerebral circulation evaluation
- intraoperative imaging in brain surgery identification of sentinel lymph nodes in cancer (breast cancer, esophageal cancer, stomach cancer, colon cancer, prostate cancer, skin cancer, etc.), lymphedema
- cancer breast cancer, esophageal cancer, stomach cancer, colon cancer, prostate cancer, skin cancer, etc.
- lymphedema It can also be applied to evaluation, intraoperative cholangiography, tumor marking, coronary angiography, abdominal angiography (hepatic artery, abdominal aorta, gastrointestinal blood flow, etc.). It also enables fluorescent imaging of renal excretion systems such as kidney, ureter, bladder, and urethra.
- Non-inclusion cyclodextrin-bound indocyanine compound and synthesis thereof examples include Chemical Formula 1, Chemical Formula 3, Chemical Formula 5, Chemical Formula 7, Chemical Formula 9, and Chemical Formula 11, and the synthesis method thereof includes indocyanine compound and cyclodextrin. This is accomplished by reacting the compound in solution.
- R 1 to R 4 and R 13 to R 16 are preferably not bulky so as not to inhibit inclusion by cyclodextrin. .
- hydrogen, a methyl group, and a methoxy group are desirable, and hydrogen is more desirable.
- R 5 , R 6 , R 11, and R 12 are also preferably not bulky for inclusion by cyclodextrin, although not as much as R 1 to R 4 and R 13 to R 16 .
- R 1 to R 6 and R 11 to R 16 are sites to be included by cyclodextrin, so that even when a hydrophilic functional group is introduced, it is desirable to make them hydrophobic as a whole.
- R 17 , R 18 , R 22 and R 23 are not particularly limited as long as they are the above-mentioned substituents because they do not significantly affect the inclusion of cyclodextrin.
- R 7 , R 10 , R 19 and R 21 are preferably hydrogen from the viewpoint of ease of synthesis.
- R 8 , R 9 and R 20 are not particularly limited as long as they are the above-described substituents.
- the non-inclusion cyclodextrin-bound indocyanine compound is formed by covalently bonding an indocyanine compound and a cyclodextrin compound by an amide bond
- the non-inclusion cyclodextrin-linked indocyanine compound synthesis method is indocyanine This can be achieved by dehydrating condensation reaction of a carboxylic acid compound and an aminocyclodextrin compound in a solution.
- the cyclodextrin-bound indocyanine compound of the present invention is a cyclodextrin-bound indocyanine compound formed by covalently bonding an indocyanine represented by Chemical Formula 2 and a cyclic sugar chain cyclodextrin, wherein at least a part of the naphthyl group of indocyanine is It is a compound characterized in that it is enclosed in a cyclodextrin cavity.
- the indocyanine group may have a substituent as long as the naphthyl group of indocyanine is included in the cyclodextrin cavity and emits near-infrared fluorescence.
- Various types of cyclodextrins are known, but it is a necessary condition that the naphthyl group of indocyanine is included in the cavity of cyclodextrin.
- ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin are exemplified.
- Preferred is ⁇ -cyclodextrin.
- the cyclodextrin may have a substituent.
- R 1 to R 4 and R 13 to R 16 are desirably not bulky so as not to inhibit inclusion by cyclodextrin.
- hydrogen, a methyl group, and a methoxy group are desirable, and hydrogen is more desirable.
- R 5 , R 6 , R 11, and R 12 are also preferably not bulky for inclusion by cyclodextrin, although not as much as R 1 to R 4 and R 13 to R 16 .
- R 1 to R 6 and R 11 to R 16 are sites to be included by cyclodextrin, so that even when a hydrophilic functional group is introduced, it is desirable to make them hydrophobic as a whole.
- R 17 , R 18 , R 22 and R 23 are not particularly limited as long as they are the above-mentioned substituents because they do not significantly affect the inclusion of cyclodextrin.
- R 7 , R 10 , R 19 and R 21 are preferably hydrogen from the viewpoint of ease of synthesis.
- R 8 , R 9 and R 20 are not particularly limited as long as they are the above-described substituents.
- the bond between the indocyanine group and the cyclodextrin is not particularly limited as long as it is a covalent bond, and examples thereof include an alkyl bond, an amino bond, an amide bond, a double bond, a triple bond, an ester bond, and an ether bond. It can be illustrated. However, amide bonds are preferred if importance is placed on efficiency in chemical synthesis.
- a spacer is used and the indocyanine and the cyclic sugar chain cyclodextrin are covalently bonded via the spacer. At this time, it is possible to control the degree of inclusion of the naphthyl group of indocyanine into the cyclodextrin cavity by adjusting the length of the spacer in Chemical Formula 2.
- a cyclodextrin-bound indocyanine compound in which indocyanine and cyclic sugar chain cyclodextrin are covalently bonded via a spacer, characterized in that the naphthyl group of indocyanine is included in the cyclodextrin cavity.
- Preferred examples of the compound to be used are those represented by Chemical Formula 4.
- the thing of Chemical formula 6, Chemical formula 8, Chemical formula 10 is illustrated preferably.
- the thing of Chemical formula 12 is illustrated more preferable.
- m, n, p, and q in Chemical Formula 6 it is desirable that m + p and n + q are 5 or more and 7 or less, respectively.
- cyclodextrin in any chemical formula (chemical formulas 1 to 10), in the structure (spacer) between the nitrogen atom in the structure corresponding to indocyanine and the oxygen atom in the structure corresponding to cyclodextrin
- the number of atoms is preferably 7 or more and 9 or less.
- the inclusion type cyclodextrin-bound indocyanine compound in the present invention is as described above, and the synthesis method thereof is to use the non-inclusion type cyclodextrin-linked indocyanine compound synthesized above as a synthesis precursor, This is accomplished by dissolving in an aqueous solution.
- the aqueous solution may contain any substance as long as it does not prevent inclusion, and the water content is not particularly limited.
- the temperature suitable for inclusion is -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
- the time required for inclusion is about one month immediately after the addition to the aqueous solution.
- the inclusion reaction takes various forms depending on the properties of the non-inclusion cyclodextrin-bound indocyanine compound, the temperature of the inclusion reaction, the composition of the aqueous solution, the concentration, and the like.
- the non-inclusion cyclodextrin-bound indocyanine compound in the present invention can be converted to an inclusion-type cyclodextrin-bound indocyanine compound by dissolving in a solvent containing water.
- the content ratio of water in the solvent is not particularly limited. However, the larger the content, the easier the clathrate proceeds, and it is desirable that the content is 50% by mass or more. Further, if there is a compound that forms an inclusion type cyclodextrin-bound indocyanine compound in a solvent other than an aqueous solution, it is not particularly necessary to perform inclusion in an aqueous solution.
- the inclusion type cyclodextrin-linked indocyanine compound is formed at the stage of synthesis of the non-inclusion type cyclodextrin-linked indocyanine compound. In this case, it is not necessary to perform the inclusion reaction again.
- the indocyanine compound represented by Chemical Formula 11 includes, for example, the compound described in Chemical Formula 13 synthesized by the method described in Non-Patent Document 5, the Chemical Formula 14 synthesized by the method described in Non-Patent Document 6, and the dehydrating condensing agent as, for example, Water-soluble carbodiimide (WSC: for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) and dicyclohexylcarboic imide (DCC) and pyridine or N, N-dimethylformamide as a solvent or It can be obtained by adding an aqueous solution and reacting at ⁇ 20 ° C.
- WSC Water-soluble carbodiimide
- DCC dicyclohexylcarboic imide
- 1-hydroxybenzotriazole HOBt
- the amount of the dehydrating condensing agent is two times or more that of the compound represented by Chemical Formula 13, and the solvent used is not limited as long as the reactant is dissolved and does not interfere with the dehydrating condensation reaction.
- the activator is not limited as long as it activates the dehydration condensation reaction, and the amount to be added is not limited as long as the dehydration condensation reaction proceeds as expected.
- the acid is not limited as long as the non-inclusion cyclodextrin-bound indocyanine compound is not decomposed and the elution is efficient and the treatment after the elution is easy.
- hydrochloric acid, trifluoroacetic acid, acetic acid, sulfuric acid examples include nitric acid and formic acid.
- Preferred are hydrochloric acid, trifluoroacetic acid, acetic acid, and more preferred are hydrochloric acid.
- the concentration of the acid is not limited as long as the non-inclusion cyclodextrin-bound indocyanine compound is not decomposed and elution is efficient, and treatment after elution is easy, but is preferably 0.01 mM to 10 mM, 0.1 mM to 1 mM is more preferable. By setting the concentration within this range, the target compound is not decomposed and can be eluted quickly.
- the eluted non-inclusion cyclodextrin-bound indocyanine compound can be obtained as a solid by removing the solvent. As a method for removing the solvent, lyophilization can also be performed.
- the inclusion compound is in an aqueous solution, it exists as an inclusion compound and can be used as an inclusion compound. Further, the clathrate compound in the aqueous solution can be made into a solid by removing water from the aqueous solution, and the clathrate compound can be made into a solid.
- the rate of metabolism of the compound of the present invention into the interstitium is relatively larger than that of ICG because the metabolic rate of the compound of the present invention and the transfer rate from the circulatory system such as blood and lymph to the interstitium are different from those of ICG. Therefore, by analyzing the dynamics of the compound of the present invention in vivo, the mechanism of fluid movement (in vivo dynamics) in the living body can be accurately evaluated. In addition, this apparatus can measure an in-vivo dynamic more correctly by making measurement conditions (activity state of a biological body, atmospheric temperature, etc.) into a steady state as much as possible.
- body fluid (water) movement in the living body is largely considered to flow from the artery to the stroma and from the stroma to the vein.
- the water movement from the artery to the vein is based on the difference between the water movement (A) flowing out of the circulatory system based on the difference between the arterial pressure and the interstitial pressure, and the difference between the vein pressure and the interstitial pressure.
- the in vivo kinetic measurement apparatus of the present invention has excitation light irradiation means, fluorescence intensity measurement means, in vivo kinetic calculation means, and other means. Other means are selected as necessary, for example, in-vivo concentration calculating means for calculating the concentration of the cyclodextrin-bound indocyanine compound from the fluorescence intensity measured by the fluorescence intensity measuring means.
- This apparatus is an apparatus for measuring at least a part of a living body to which the above-described diagnostic composition of the present invention is administered.
- the dose of the diagnostic composition is such that fluorescence can be observed when the excitation light is irradiated at the site to be measured. Accordingly, the appropriate amount varies depending on the measurement site.
- the type of the compound of the present invention contained in the diagnostic composition is not particularly limited.
- the compounds of the present invention can be used singly or in combination of two or more.
- a diagnostic composition having the same or different composition can be additionally administered during the measurement.
- the excitation light irradiation means is means for irradiating excitation light having a wavelength capable of generating fluorescence in the compound of the present invention contained in the administered diagnostic composition.
- the wavelength of the excitation light to be irradiated can be limited to an appropriate range. By limiting the wavelength to the narrowest possible range, fluorescence and excitation light can be reliably separated.
- the wavelength can be limited by selecting a light source that emits light having an appropriate wavelength, or by limiting the wavelength with a filter.
- the mode of irradiation with excitation light is not particularly limited as long as the generated fluorescence can be measured by a fluorescence intensity measuring means described later.
- the excitation light includes a continuous light, a pulsed light, and a light whose intensity changes.
- the intensity of the excitation light can be modulated by irradiating a pulse of the excitation light at a predetermined interval.
- the modulation of the excitation light it is desirable to employ pulse amplitude modulation to modulate the intensity of the excitation light.
- Excitation light is irradiated to a portion to be irradiated by an appropriate optical system.
- the site to be irradiated is a site that wants to measure in vivo kinetics. For example, when it is desired to evaluate a site where edema has occurred, it is desirable to directly irradiate the site where edema has occurred with excitation light.
- the range for irradiating the excitation light is not particularly limited. Determine the irradiation range as required. By irradiating a narrow area, it is possible to accurately measure the in vivo dynamics subdivided in the irradiated narrow portion. When irradiated over a wide range, the relative intensity of the compound of the present invention that emits fluorescence when irradiated with excitation light increases, so that the fluorescence intensity can be measured more precisely.
- the excitation light irradiation by the excitation light irradiation means is preferably performed in a state in which the influence of ambient light is suppressed.
- the fluorescence intensity measuring means is means for measuring the intensity of the fluorescence emitted from the site irradiated with the excitation light by the excitation light irradiating means.
- the fluorescence intensity is preferably measured through a filter that can selectively transmit emitted fluorescence to exclude light other than fluorescence (such as ambient light and excitation light).
- a component showing a change corresponding to the modulation can be separated from the measured intensity of light to obtain fluorescence intensity.
- the fluorescence intensity can be separated by demodulating the light component that changes according to the intensity of the modulated pulse and measuring the intensity. it can. Therefore, the influence which environmental light has on the measurement result of fluorescence intensity can be reduced.
- the in vivo concentration calculating means is a means for calculating the in vivo concentration of the compound of the present invention based on the fluorescence intensity measured by the fluorescence intensity measuring means.
- the relationship between the fluorescence intensity and the in vivo concentration of the compound of the present invention can be calculated by an appropriate method. For example, a calibration curve can be prepared in advance, and the in vivo concentration of the compound of the present invention can be calculated based on the calibration curve. Further, the absolute value of the fluorescence intensity can be used as it is as a value related to the in vivo concentration of the compound of the present invention.
- the in vivo concentration calculating means calculates the in vivo concentration of the compound of the present invention over time.
- the in vivo kinetic calculation means is means for obtaining a change over time of the time change rate of the in vivo concentration from the in vivo concentration data of the compound of the present invention acquired over time by the in vivo concentration calculation means.
- the in vivo kinetic calculation means calculates the speed at which the compound of the present invention moves from the circulatory system into the interstitium and the speed from the interstitium into the circulatory system in a part of the living body from the time change rate of the in vivo concentration.
- the transition speed directly into and out of the interstitium may be calculated from the change in fluorescence intensity obtained over time from the fluorescence intensity measuring means.
- the measurement of the pharmacokinetics of the compound of the present invention at the measurement site The state of moisture movement can be evaluated. Furthermore, it is considered that when the abnormality of the blood vessel wall occurs and the permeability of the substance is not normal, the kinetics of the compound of the present invention in vivo is changed. Permeability can be evaluated.
- the temporal change rate of the fluorescence intensity (or in vivo concentration) is obtained by differentiating the change over time in the fluorescence intensity (or in vivo concentration) with time, or by calculating the fluorescence intensity (or in vivo concentration) per predetermined time. It can be obtained as a difference from the fluorescence intensity (or in vivo concentration) before time (after a predetermined time).
- the rate at which the compound of the present invention is taken into and discharged from interstitial fluid in a part of the living body is calculated from the time change rate of the obtained fluorescence intensity (or biological concentration).
- the speed at which it is taken into and discharged from the interstitial fluid can be determined as a relative value from the fluorescence intensity, and when it is determined more precisely, the concentration of the compound of the present invention in the interstitium And can be calculated based on the amount of interstitial fluid. In addition, it can be calculated more precisely by considering the concentration and amount of the compound of the present invention in blood or lymph.
- the concentration of the compound of the present invention in blood or the like can be accurately measured by actually collecting blood.
- the following method can be exemplified as a method for calculating the concentration in the interstitial fluid.
- a first method there is a method of approximating that the calculated in vivo concentration of the compound of the present invention is the concentration in the interstitial fluid in a part of the living body as it is.
- the concentration in the interstitial fluid can be calculated in consideration of the amount of the interstitial fluid.
- a second method a substance that is present in a blood vessel by a technique such as using another standard substance (ICG or the like) that does not transfer to the interstitium after measuring the concentration of the compound of the present invention actually present in blood. It is also conceivable to calculate the concentration in the interstitial fluid by calculating the ratio that contributes to the measured value measured by the fluorescence intensity measuring means and excluding the effect of the actually measured concentration of the compound of the present invention in the blood.
- the rate of change over time of the concentration of the compound of the present invention in the interstitial fluid can be calculated by subtracting the rate of transition from the interstitium into the outside of the interstitium.
- the transfer of the compound of the present invention into the interstitium (outside) proceeds at a rate that correlates with the moisture transfer rate in the body fluid, and that it can be assumed that the moisture transfer has reached equilibrium. Since the rate of transition into and out of the interstitium can be regarded as a constant, changes in the concentration of the compound of the present invention in the blood (changes due to metabolism, excretion, transition to tissues, etc.) and interstitial fluid
- the transition speed can be calculated from the transition of the rate of change in concentration over time.
- the transition speeds can be calculated by creating and applying a model corresponding to the change.
- the calculated transition speed is out of the range of values indicated by the normal blood vessel wall, it can be estimated that an abnormality has occurred in the blood vessel wall.
- the permeability of the compound of the present invention may be improved or decreased.
- tissue is swollen acutely due to various tissue disorders such as acute inflammation, ischemia, and trauma, and is an extremely important tissue reaction in the medical field regardless of the field.
- tissue disorders such as acute inflammation, ischemia, and trauma
- sutures such as the intestinal tract during surgery
- degree of inflammation such as pneumonia
- suitability for organ transplantation functions in the brain, kidney, etc.
- the progress of swelling can be predicted by calculating the water transfer rate inside and outside the interstitium by using the in vivo kinetic measuring apparatus of the present invention.
- ICG does not enter the interstitium as the swelling progresses.
- the cyclodextrin-bound indocyanine compound of the present invention can move into and out of the interstitium, and it is known that the transition into the interstitium is further promoted with the movement of moisture during the progression of swelling. . Therefore, the progression of swelling can be predicted by evaluating the transition of the cyclodextrin-bound indocyanine compound of the present invention into the stroma.
- the migration rate can be calculated by calculating the concentration of the cyclodextrin-bound indocyanine compound, or can be calculated using the fluorescence intensity as it is.
- the transition speed to and from the interstitium can be calculated as an absolute value, as well as a relative value (for example, the change rate of the fluorescence intensity may be adopted as a value related to the transition speed as it is). And the progression of swelling according to the value can be predicted.
- the progression of swelling based on the rate of transition into the interstitium during normal periods when swelling is not progressing.
- the transition speed into the stroma during normal times may not be known, in that case, a site where swelling has not progressed is selected as a control site, and substitution can be performed by obtaining the transition rate at that site.
- the degree of blood circulation and the degree of metabolism may be evaluated using ICG that does not migrate into the interstitium, and the degree of migration into the interstitium of the cyclodextrin-bound indocyanine compound of the present invention may be evaluated. .
- the degree to which the cyclodextrin-bound indocyanine compound of the present invention migrates into the interstitium is measured after a lapse of a predetermined time from administration of the diagnostic composition of the present invention in vivo.
- the predetermined time is the time required for the diagnostic composition of the present invention to be distributed in the blood.
- the reason for performing the evaluation using data after the lapse of a predetermined time is that, after administration of the diagnostic composition, it is hardly affected by the degree of progression until it is distributed in the blood over a predetermined time. This is because the blood concentration rapidly rises, so that there is almost no difference in the change in fluorescence intensity regardless of whether or not the swelling has progressed.
- the rate of migration into the interstitium changes depending on whether or not the progression of swelling, so that the fluorescence intensity is selectively improved at the site where migration proceeds (ie, the site where swelling progresses). Will be.
- the blood volume is estimated from the body weight and the like, and the peak size of fluorescence intensity and the time to reach the peak are calculated from the estimated blood volume.
- Circulation visualization device This device is the degree to which the cyclodextrin-bound indocyanine compound of the present invention (hereinafter sometimes referred to as “the present compound”) adopted in the diagnostic composition of the present invention moves into the interstitium. It was completed based on the fact that its pharmacokinetics differ from ICG.
- the circulation visualization apparatus of the present invention includes excitation light irradiation means, fluorescence imaging means, morphology imaging means, and display means.
- This apparatus is an apparatus for measuring at least a part of a living body to which the above-described diagnostic composition of the present invention is administered.
- the dose of the diagnostic composition is such that fluorescence can be observed when the excitation light is irradiated at the site to be measured. Accordingly, the appropriate amount varies depending on the measurement site.
- the type of the compound of the present invention contained in the diagnostic composition is not particularly limited.
- the compounds of the present invention can be used singly or in combination of two or more.
- a diagnostic composition having the same or different composition can be additionally administered during the measurement.
- the excitation light irradiation means is means for irradiating excitation light having a wavelength capable of generating fluorescence in the compound of the present invention contained in the administered diagnostic composition.
- the wavelength of the excitation light to be irradiated can be limited to an appropriate range. By limiting the wavelength to the narrowest possible range, fluorescence and excitation light can be reliably separated.
- the wavelength can be limited by selecting a light source that emits light having an appropriate wavelength, or by limiting the wavelength with a filter.
- the mode of irradiation with excitation light is not particularly limited as long as the generated fluorescence can be measured by a fluorescence imaging means described later.
- the excitation light includes a continuous light, a pulsed light, and a light whose intensity changes.
- the intensity of the excitation light can be modulated by irradiating a pulse of the excitation light at a predetermined interval.
- the modulation of the excitation light it is desirable to employ pulse amplitude modulation to modulate the intensity of the excitation light.
- Excitation light is irradiated to a portion to be irradiated by an appropriate optical system.
- the site to be irradiated is a site that wants to visualize the state of circulation in the living body, and is, for example, a site where tissue necrosis due to burns, frostbite, inflammation, wound, infarction, etc. is progressing and its surroundings. Since blood is not circulated in the necrotic part of the tissue and it is almost never advantageous to leave it as it is, it can be considered to be removed. In that case, it is ideal to completely remove only the necrotic portion of the necrotic portion and the normal portion.
- the necrotic portion has been identified by angiography performed by administering a contrast medium or a method for detecting a decrease in body temperature associated with the blood circulation price, but angiography is performed by a device such as an X-ray irradiation apparatus.
- angiography is performed by a device such as an X-ray irradiation apparatus.
- the device of the present invention can be used for the purpose of evaluating a necrotic part and a normal part by the presence or absence of circulation of a body fluid (blood). If a portion without circulation can be visualized, it is easy to remove that portion. In addition to visualizing the necrotic part, blood circulation can be directly observed, so that it is possible to easily determine the occurrence of an abnormality occurring in the circulatory function. For example, although necrosis has not occurred, a portion where infarction or the like has occurred and the circulatory function is reduced can be visualized.
- the range for irradiating the excitation light is determined as necessary so as to include a portion that wants to visualize the circulation. Furthermore, the excitation light irradiation by the excitation light irradiation means is preferably performed in a state in which the influence of ambient light is suppressed. For example, it is preferable to irradiate excitation light in a dark place, or to irradiate excitation light in a state where a portion irradiated with excitation light is covered from outside light.
- the fluorescence imaging means is a means for obtaining in vivo distribution state data of the compound of the present invention by two-dimensionally acquiring the intensity of the fluorescence emitted by the compound of the present invention excited by the excitation light irradiation means. That is, this means is a means for obtaining distribution state data representing the distribution state of the compound of the present invention as two-dimensional image data for a part of a living body. For example, it can be configured by a combination of an appropriate optical system and an image sensor such as a CCD. The resolution of data acquired two-dimensionally is set to a required value according to the purpose.
- the fluorescence intensity is preferably measured through a filter that can selectively transmit emitted fluorescence to exclude light other than fluorescence (such as ambient light and excitation light).
- the excitation light irradiating means When a means for irradiating excitation light with modulated intensity is adopted as the excitation light irradiating means, a component showing a change corresponding to the modulation can be separated from the measured intensity of the light to obtain the fluorescence intensity.
- the fluorescence intensity can be separated by demodulating the light component that changes according to the intensity of the modulated pulse and measuring the intensity. it can. Therefore, the influence which environmental light has on the measurement result of fluorescence intensity can be reduced.
- the morphological imaging means is a means for obtaining morphological data of a part of a living body by two-dimensionally acquiring the intensity of light having a wavelength other than the fluorescence wavelength emitted by the compound of the present invention. That is, this means is a means for acquiring a form of a part of the living body as form data representing the form as two-dimensional image data.
- the form imaging means can be constituted by an appropriate optical system and an image sensor such as a CCD.
- the resolution of data acquired two-dimensionally is set to a required value according to the purpose. In that case, the fluorescence emitted by the excitation light is not detected (or the detection sensitivity is lowered).
- the form imaging means shares most of the optical system with the above-described fluorescence imaging means, and finally guides light having a wavelength corresponding to fluorescence to the fluorescence imaging means by a spectroscopic prism or the like in the optical path before being finally introduced into the imaging device, A configuration that guides light of other wavelengths to the morphological imaging means can be employed.
- the spectral prism can appropriately control the wavelength of light to be separated by appropriately forming a dichroic film or the like.
- the fluorescence imaging means and the morphological imaging means can be shared by a single imaging device. That is, the fluorescence and other light may be separated mathematically after being converted into two-dimensional image data.
- the distribution state data can be obtained as a plurality of image data from the surface of a part of the living body toward the depth direction.
- a plurality of two-dimensional image data in the depth direction can be obtained by moving the focal point in the optical system employed in the fluorescence imaging means in the depth direction.
- an excitation light irradiation means that can change the focal length in the optical system is adopted, the focal point is moved inside the depth direction instead of the surface of a part of the living body, or the excitation light is narrowed down to a part of the living body.
- the display means is means for displaying the distribution state of the compound of the present invention in a part of the living body by superimposing and displaying the distribution state data obtained by the fluorescence imaging means on the shape data obtained by the shape imaging means.
- the fluorescence wavelength is not in the visible light range
- the fluorescence wavelength is converted into visible light having an appropriate wavelength for display.
- a portion where the distribution amount (that is, fluorescence intensity) of the compound of the present invention is low is determined according to the purpose of visualizing the circulation. For example, for the purpose of visualizing the necrotic portion, the portion that is not circulated.
- a portion where fluorescence is not recognized is displayed so as to be distinguishable from other portions.
- the portion can be displayed in a different color from other portions, or can be blinked.
- the superposition of the distribution state data and the form data can be realized by a logic on a computer.
- the display of two-dimensional data can be realized by a general display device. By installing this display device between a living body and a measurer, it is also possible to perform treatment on the living body while viewing the display device.
- alkyl group means a linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent, for example, methyl, ethyl, propyl, butyl , Pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosanyl, or a group bonded in a branched manner.
- the “alkoxyl group” means, for example, a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, ethoxypropoxy, methoxyethoxyethoxy group or the like having 1 to 20 carbon atoms.
- a number of alkoxyl groups are bonded on a straight chain or branched.
- examples of the “aryl group” include aromatic hydrocarbons having 6 to 20 carbon atoms such as phenyl and naphthyl.
- ⁇ Test 1 Synthesis and purification of compounds represented by Chemical Formula 15 and Chemical Formula 16>
- a mixture of 0.20 g of the compound represented by chemical formula 13, 0.94 g of the compound represented by chemical formula 14, 0.18 g of WSC, 0.12 g of HOBt, 4.0 mL of pyridine, and 2.0 mL of N, N-dimethylformamide was placed at 0 ° C. in the dark. For 6 hours. Thereafter, 50 mL of acetone was added, the precipitate was filtered under reduced pressure, the precipitate was dissolved in a 0.1% aqueous trifluoroacetic acid solution, and subjected to ODS column chromatography.
- a mixture of water and methanol containing 1 mM hydrochloric acid was used as an eluent to elute the compound represented by Chemical Formula 15.
- the eluate was concentrated under reduced pressure to obtain 0.65 g of an inclusion compound represented by the chemical formula 16 as a green solid (in the concentration of eluate under reduced pressure, the content of water is high at the end of concentration, so that it naturally becomes an inclusion type. ).
- ⁇ Test 2 Synthesis and purification of compounds represented by Chemical Formula 19 and Chemical Formula 20> A mixture of 0.17 g of the compound represented by Chemical Formula 17, 5 mL of methanol and 0.30 g of t-BuOK was stirred at room temperature for 12 hours. Thereafter, 3 mL of 1M hydrochloric acid was added, and 50 mL of water was further added. The precipitate was filtered, and the precipitate was washed with water and dried under reduced pressure to obtain 0.17 g of a compound represented by Chemical Formula 18.
- the eluate was concentrated under reduced pressure to obtain 0.045 g of an inclusion compound represented by the chemical formula 20 as a green solid. (When the eluate is concentrated under reduced pressure, the water content is high at the end of concentration, so it is naturally an inclusion type.)
- ⁇ Test 3 Synthesis and purification of compound represented by Chemical Formula 21> 0.04 g of the compound represented by Chemical Formula 13, 0.18 g of mono-6-amino-6-deoxy- ⁇ -cyclodextrin, 0.05 g of WSC, 0.025 g of HOBt, 0.8 mL of pyridine, 0.4 mL of N, N-dimethylformamide The mixture was stirred at 0 ° C. in the dark for 3 hours. Thereafter, 10 mL of acetone was added, the precipitate was filtered under reduced pressure, the precipitate was dissolved in a 0.1% aqueous trifluoroacetic acid solution, and subjected to ODS column chromatography.
- a mixture of water and methanol containing 1 mM hydrochloric acid was used as an eluent to elute the compound represented by Chemical Formula 21.
- the eluate was concentrated under reduced pressure to obtain 0.11 g of a compound represented by Chemical Formula 21 as a green solid.
- ⁇ Test 4 Synthesis and purification of compound represented by Chemical Formula 23> A mixture of 0.02 g of the compound represented by Chemical Formula 22, 0.096 g of mono-6-amino-6-deoxy- ⁇ -cyclodextrin, 0.032 g of WSC, 0.5 mL of pyridine, and 0.05 mL of 0.1 M phosphate buffer Stir at room temperature in the dark for 24 hours. Thereafter, 10 mL of acetone was added, the precipitate was filtered under reduced pressure, the precipitate was dissolved in a 0.1% aqueous trifluoroacetic acid solution, and subjected to ODS column chromatography.
- ⁇ Test 5 Synthesis and purification of compound represented by chemical formula 24> A mixture of 0.20 g of the compound represented by Chemical Formula 22, 0.02 g of 3-amino-3-deoxy- ⁇ -cyclodextrin, 0.096 g of WSC, 0.013 g of HOBt, 0.4 mL of pyridine, and 0.2 mL of N, N-dimethylformamide was stirred at room temperature in the dark for 1 hour. Thereafter, 10 mL of acetone was added, the precipitate was filtered under reduced pressure, the precipitate was dissolved in a 0.1% aqueous trifluoroacetic acid solution, and subjected to ODS column chromatography. A mixture of water and methanol was used as the eluent, and the compound represented by Chemical Formula 24 was eluted. The eluate was concentrated under reduced pressure to obtain 0.013 g of a compound represented by Chemical Formula 24 as a green solid.
- ⁇ Test 6 Synthesis and purification of compound represented by Chemical Formula 25>
- a mixture of 0.02 g of the compound represented by the chemical formula 22, 0.1 g of the compound represented by the chemical formula 14, 0.032 g of WSC, 0.5 mL of pyridine, and 0.05 mL of 0.1 M phosphate buffer was stirred at room temperature in the dark for 24 hours. did. Thereafter, 10 mL of acetone was added, the precipitate was filtered under reduced pressure, the precipitate was dissolved in a 0.1% aqueous trifluoroacetic acid solution, and subjected to ODS column chromatography. A mixture of water and methanol was used as the eluent, and the compound represented by Chemical Formula 25 was eluted. The eluate was concentrated under reduced pressure to obtain 0.021 g of a compound represented by Chemical Formula 25 as a green solid.
- ⁇ Test 7 Solubility of cyclodextrin-bound indocyanine compound of the present invention> The solubility test of ICG and the cyclodextrin-bound indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) in water and physiological saline was performed. In order to dissolve the powdered ICG of Molecular Probe using water and physiological saline, vigorous vibrational stirring for about 1 minute is required. However, the cyclodextrin-conjugated indocyanine compound of the present invention, particularly represented by Chemical Formula 16 and Chemical Formula 20, The compounds shown did not require vibrational stirring and dissolved quickly.
- ⁇ Test 8 Adsorption of cyclodextrin-bound indocyanine compound of the present invention to human skin>
- Each 1 mM aqueous solution (0.03 mL) of ICG and the cyclodextrin-linked indocyanine compound of the present invention (Chemical Formula 16, 20, 21, 23 to 25) was placed on the arm, washed with water after 5 minutes, and further rubbed and washed with water.
- ICG could not be washed completely with water, but the cyclodextrin-bound indocyanine compound of the present invention, particularly the compounds represented by Chemical Formula 16 and Chemical Formula 20, can be easily washed with water.
- the adsorptivity to human skin was shown to be much lower than ICG (FIG. 1).
- ⁇ Test 9 Adsorbability of the cyclodextrin-bound indocyanine compound of the present invention to cellulose fibers>
- ⁇ Test 10 Adsorbability of the cyclodextrin-bound indocyanine compound of the present invention to a biological meat model>
- the adsorptivity test of ICG and the cyclodextrin-bound indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) to a living meat model was conducted.
- a commercially available pork loin meat is used as a biological meat model, and a concave of 5 mm in diameter is formed in the pork loin meat.
- Each of the ICG and the cyclodextrin-bound indocyanine compounds (chemical formulas 16, 20, 21, 23 to 25) of the present invention is used.
- ⁇ Test 11 Adsorbability of the cyclodextrin-bound indocyanine compound of the present invention to a protein model in the living body>
- the adsorptivity test of the ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) to a biological protein model was performed.
- a commercially available chicken breast meat is used as a protein model of a living body, a 5 mm diameter recess is made in the chicken breast meat, and each 1 mM aqueous solution of ICG and the cyclodextrin-bound indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25).
- ⁇ Test 12 Adsorption of cyclodextrin-bound indocyanine compound of the present invention onto hydrophobic chemical fiber> The adsorptivity test of ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) to hydrophobic chemical fibers was performed.
- each 1 mM aqueous solution of ICG and cyclodextrin-bound indocyanine compound (chemical formulas 16, 20, 21, 23 to 25) of the present invention 0.05 mL
- the sample was allowed to stand for 20 minutes (the sample did not adhere to the mask if it had moisture, and was left for 20 minutes to remove moisture), and then washed with running water (tap water, 1 L / min) for 1 second.
- ICG could not be washed completely with water, but the cyclodextrin-bound indocyanine compound of the present invention, particularly the compounds represented by Chemical Formula 16 and Chemical Formula 20, can be easily washed with water.
- the adsorptivity to hydrophobic chemical fibers was shown to be much lower than ICG (FIG. 5).
- ⁇ Test 13 Molecular association in aqueous solution of cyclodextrin-bound indocyanine compound of the present invention> The molecular association properties of ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) in an aqueous solution were examined. Quartz with an optical path length of 1 mm prepared by adjusting 0.01 g, 0.025 mM, 0.05 mM, and 0.1 mM aqueous solutions of ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25), respectively.
- the sample was put in a cell, and a light absorption spectrum from 600 nm to 1000 nm was measured at 25 ° C.
- ICG caused molecular association called H-aggregation within this concentration range (FIG. 6, left figure).
- the cyclodextrin-bound indocyanine compound of the present invention particularly the compounds represented by Chemical Formula 16 and Chemical Formula 20, It was shown that molecular association called H-aggregation does not occur in the concentration range (the right figure in FIG. 6).
- ⁇ Test 14 Fluorescence in aqueous solution of cyclodextrin-bound indocyanine compound of the present invention> The fluorescence properties of ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) in aqueous solutions were examined. Each 0.1 ⁇ M aqueous solution of ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) is placed in a 1 cm square quartz cell at 25 ° C., and excitation light of 720 nm (band pass: 10 nm) ) And a fluorescence spectrum (band pass: 10 nm) was measured.
- the fluorescence efficiency is the same as that of ICG. DMSO, 25 ° C.).
- the fluorescence quantum efficiency of ICG is 0.021
- the fluorescence quantum efficiency of the cyclodextrin-bound indocyanine compound of the present invention, particularly the compounds represented by Chemical Formula 16 and Chemical Formula 20 is 0.054 and 0.042
- the fluorescence quantum efficiency was 2.6 times and 2 times that of ICG.
- ⁇ Test 15 Fluorescence in Blood of Cyclodextrin-Binding Indocyanine Compound of the Present Invention> The fluorescence in the blood of ICG and the cyclodextrin-linked indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) was examined. Each of ICG and the cyclodextrin-bound indocyanine compound of the present invention (chemical formulas 16, 20, 21, 23 to 25) was dissolved in blood (human) to a concentration of 100 ⁇ M. The blood was placed in a triangular quartz cell at 25 ° C., excited with 760 nm excitation light (bandpass: 10 nm), and the surface fluorescence spectrum (bandpass: 10 nm) was measured.
- the fluorescence intensity at the maximum fluorescence wavelength was 58 (arbitrary unit) for ICG.
- the fluorescence intensity of the cyclodextrin-linked indocyanine compound of the present invention, particularly the compounds represented by Chemical Formula 16 and Chemical Formula 20, is 270 (arbitrary units) and 190 (arbitrary units), 4.7 times and 3.3 times that of ICG. there were. This was thought to be because the cyclodextrin-bound indocyanine compound of the present invention was not inhibited in light emission in vivo.
- TK1 isomerized equilibrium compound represented by chemical formulas 19 and 20
- TK2 isomerized equilibrium compound represented by chemical formulas 15 and 16 in human blood and rat body as biological objects are shown. evaluated.
- ICG, TK1, and TK2 were evaluated for concentration dependency of surface fluorescence intensity in human venous blood in triangular cells. Specifically, 1.0 mL of human venous blood was placed in a triangular quartz cell, and ICG, TK1, and TK2 were added at predetermined concentrations. Excitation light of 760 nm (band pass: 10 nm) was irradiated at 25 ° C., and surface fluorescence (band pass: 10 nm) was measured. The results are shown in FIG.
- both TK1 and TK2 emit fluorescence when irradiated with excitation light in human venous blood.
- aqueous solution with a concentration of 1 mM was prepared for each of ICG, TK1, and TK2, and 0.1 mL of each was injected while exposing the femoral vein of the opened rat. Then, the presence or absence of fluorescence was evaluated by irradiating the laparotomy part with excitation light of 760 nm.
- the rat's tail root was driven with a rubber band, the tail vein was secured with a 24G surfro needle, and a peripheral line was secured by attaching a 3-way stopcock and an extension tube. Rats were fixed in a supine position on a flat table (FIG. 8).
- a PDE camera unit made by Hamamatsu Photonics was accurately placed at a position 16 cm from the body of the rat. However, when photographing the whole body over a wide area, it was set to 20 cm. The observation range was the range indicated by the black circles in FIG. Thereafter, ICG, TK1, and TK2 were administered at a concentration of 1 mM from the reserved peripheral line. The dose was 0.1 mL.
- FIG. 9 shows the state of fluorescence in the abdominal cavity when the abdomen was opened 20 minutes after administration
- FIG. 12 shows the state of fluorescence on the back of the foot (image at the time of maximum luminance).
- FIG. 9 shows that ICG is mainly accumulated in the liver (FIG. 9 (a)), TK1 is mainly accumulated in the kidney (FIG. 9 (b)), and TK2 is also mainly accumulated in the kidney (FIG. 9 (c)). ing.
- the kidney, ureter, and bladder could be clearly imaged (FIG. 10).
- the ureter can be imaged with a near-infrared endoscope (FIG. 11).
- fluorescence was emitted in the back of the foot according to the flow of blood flow.
- FIG. 13 and FIG. 14 show the temporal change of the fluorescence intensity in the foot back part.
- Table 1 shows the time to reach the maximum fluorescence intensity value (Imax), the Imax value, and the time (t1 / 2) that is half of the Imax value.
- TK1 and TK2 were found to be longer than ICG in terms of time to reach the maximum fluorescence intensity value and time to halve. That is, it was found that fluorescence can be emitted in the body for a long time. For example, in ICG, the fluorescence intensity decreased to the initial value in less than 10 minutes after administration, whereas TK1 and TK2 showed high fluorescence intensity even after 1 hour after administration. It was. ⁇ Observation at the blood vessel level
- ICG and TK1 were administered with the method disclosed in Non-Patent Documents 7 and 8 (FIG. 15) in a state where the rat blood vessels were directly exposed and observed.
- the state of the levator ani muscle flap after exposure is shown in FIG. Observation was performed by administering ICG and TK1 with the blood vessels exposed.
- ICG appeared to be unevenly distributed in the blood vessel as compared with TK1. That is, it was found that TK1 was transferred from the blood vessel into the interstitial fluid.
- FIG. 17 ICG
- FIG. 18 TK1
- the part (ROI) to be measured with the PDE camera was set at the center of the back of the foot and turned off. After starting the measurement, 0.1 mL of 1 mmol TK1 aqueous solution was injected from the tail vein and flushed with 1 mL of physiological saline over 5 seconds. The first 5 minutes after the injection were taken continuously to measure the brightness at the ROI. Thereafter, the luminance was measured for 1 minute at intervals of 5 minutes and continued until 120 minutes after injection. After completion of the measurement, isoflurane was turned off and awakened and returned to the cage (acute inflammation experiment).
- rat Von Frey Immediately after the test, general anesthesia was introduced into the rat with isoflurane, and the left foot volume of the rat was measured with a rat footpad volume meter. After securing the rat tail vein with a 24G surflo needle, the rat was placed in a supine position and fixed on a horizontal platform. A PDE camera manufactured by Hamamatsu Photonics was installed and fixed at a height of 16 cm from the back of the rat's foot, and the ROI was set at the center of the back of the foot. 0.1 mL of 1 mmol TK1 aqueous solution was injected from the tail vein and flushed with 1 mL of physiological saline over 5 seconds.
- the first 5 minutes after the injection were taken continuously to measure the brightness at the ROI. Thereafter, the luminance was measured for 1 minute at intervals of 5 minutes and continued until 120 minutes after injection. After completion of the measurement, isoflurane was turned off and awakened to return to the cage. A similar test was conducted for the group not injected with ⁇ carrageenan. The above process was also performed in ICG.
- the rat left paw volume measured for the group administered with TK1 is shown in FIG. 19 (vertical axis is larger as it goes up), and the result of Von Frey test is shown in FIG. 20 (vertical axis as it goes down).
- FIG. 21 shows the state of the luminance change immediately after that (the vertical axis is brighter as it goes upward)
- FIG. 23 shows the state of the luminance change after one week after the carrageenin injection (the vertical axis is higher as it goes upward). Shown in The rat left paw volume measured for the ICG-administered group is injected in FIG. 23 (vertical axis is larger as it goes upward), and the result of Von Frey test is shown in FIG.
- FIG. 25 shows the state of the luminance change immediately after that (the vertical axis is brighter as it goes upward), and FIG. 26 shows the state of the luminance change one week after the carrageenin injection (the vertical axis is brighter as it goes upward). Shown in The values on the vertical axis of all graphs are arbitrary units.
- vascular phase a portion reflecting the initial rapid passage in blood vessels
- interval a phase in which TK1 gradually leaking into the interstitium thereafter emits fluorescence
- the rat foot volume increased markedly after ⁇ carrageenin injection, but normalized to the same level as the tendon side after 1 week (FIGS. 19 and 23).
- the Von Frey test showed marked hyperalgesia after ⁇ carrageenin injection, and was normalized to the same level as the tendon one week later (FIGS. 20 and 24).
- the TK1 group showed no difference in the luminance change in the vascular phase from the control group, but the stromal phase showed a faster increase in luminance in the ⁇ carranigen administration group, and the evaluation time It was accepted to keep high value through (FIG. 21).
- the cyclodextrin-bound indocyanine compound represented by Chemical Formula 1 or Chemical Formula 2 of the present invention it is more soluble in water or physiological saline than ICG, and can be easily removed from biological tissues. It is possible to provide a compound that emits near-infrared fluorescence with a green pigment characterized by low molecular association at, high near-infrared fluorescence intensity in an aqueous solution, and no iodine.
- a useful synthesis of a cyclodextrin-bound indocyanine compound can be provided.
- a cyclodextrin-bound indocyanine compound of the present invention useful purification of the cyclodextrin-bound indocyanine compound can be provided.
- the cyclodextrin-bound indocyanine compound of the present invention exhibits sufficient solubility without containing iodine, it is also possible to provide a diagnostic composition that does not contain iodine, which causes iodine hypersensitivity. Since this diagnostic composition exhibits a behavior in the body that is different from that of a diagnostic composition containing only conventional ICG, various useful diagnostic methods and diagnostic devices can be provided by utilizing its properties.
Abstract
Description
又、ICGは、水に溶解後時間とともに不溶化し、水溶液として長期保存することは困難であり、また低温による凍結保存は、不溶化を助長する。
又、ICGは、静脈注射した際、速やかに肝臓に集積し肝排泄されるため他の器官、例えば腎臓、尿管、膀胱、尿道、心臓、肺などの器官の蛍光撮像が困難である。
又、ICGは、静脈注射した際、血液とともに移行することから、末梢組織への移行が少ないため、間質への移行を観ることは困難である。
<2>インドシアニンのナフチル基の少なくとも一部がシクロデキストリンの空洞に包接されることを特徴とする、化学式2で示されるシクロデキストリン結合インドシアニン化合物である。
<3>インドシアニン類と環状糖鎖シクロデキストリンがアミド結合を介して共有結合してなること特徴とする化学式1に記載のシクロデキストリン結合インドシアニン化合物であって、化学式3で示されるシクロデキストリン結合インドシアニン化合物である。
<6>化学式4に記載のシクロデキストリン結合インドシアニン化合物において、化学式6で示されるシクロデキストリン結合インドシアニン化合物である。
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を測定する蛍光強度測定手段と、
前記蛍光強度測定手段から経時的に取得した前記蛍光強度からその蛍光強度の時間変化率の経時変化を求めることにより前記シクロデキストリン結合インドシアニン化合物が前記生体の一部において間質液中に移行する速度及び/又は前記間質外に移行する速度を算出する生体内動態算出手段と、
を有する前記シクロデキストリン結合インドシアニン化合物の生体内動態測定装置である。
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を二次元的に取得して前記シクロデキストリン結合インドシアニン化合物の生体内における分布状態データを得る蛍光イメージング手段と、
前記シクロデキストリン結合インドシアニン化合物が発する前記蛍光波長以外の波長の光の強度を二次元的に取得して前記生体の一部についての形態データを得る形態イメージング手段と、
前記形態イメージング手段により得られた前記形態データに前記蛍光イメージング手段により得られた前記分布状態データを重ね合わせて前記生体の一部における前記シクロデキストリン結合インドシアニン化合物の分布状態を表示する表示手段と、
を有する循環可視化装置である。
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を測定する蛍光強度測定手段と、
前記蛍光強度測定手段から経時的に取得した前記蛍光強度からその蛍光強度の経時変化を求めることにより前記シクロデキストリン結合インドシアニン化合物が前記生体の一部において間質液中に移行する速度及び/又は前記間質外に移行する速度を算出する生体内動態算出手段と、
前記生体の一部において間質液内外に移行する速度から前記生体の一部において以後に進行する腫脹の程度を予測する腫脹進行予測手段とを有し、
前記腫脹進行予測手段は、
前記診断用組成物を投与してから前記シクロデキストリン結合インドシアニン化合物が全身の血液中に分散するまでの時間である所定時間に至るまでの、前記生体の一部における蛍光強度の変化と前記対照部位における蛍光強度の変化とから、対照部位に流れる血流量と前記生体の一部における血流量との関係を求め、
前記所定時間経過以降における、前記対照部位における蛍光強度の変化を対照とした前記生体の一部における蛍光強度の変化の程度をその関係を用いて算出し、
算出した前記変化の程度の大きさに応じた腫脹の進行を予測する手段であることを特徴とする生体内動態測定装置である。
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を測定する蛍光強度測定手段と、
前記蛍光強度測定手段から経時的に取得した前記蛍光強度から前記器官における前記シクロデキストリン結合インドシアニン化合物の生体内動態を評価する生体内動態算出手段とを有することを特徴とする生体内動態測定装置である。
本発明における非包接型シクロデキストリン結合インドシアニン化合物としては、化学式1、化学式3、化学式5、化学式7、化学式9、化学式11を挙げることができ、その合成法は、インドシアニン化合物とシクロデキストリン化合物を溶液中において反応させることにより成し遂げられる。
本発明のシクロデキストリン結合インドシアニン化合物は、化学式2で示されるインドシアニン類と環状糖鎖シクロデキストリンが共有結合してなるシクロデキストリン結合インドシアニン化合物であり、インドシアニンのナフチル基の少なくとも一部がシクロデキストリンの空洞に包接されていることを特徴とする化合物である。又、インドシアニンのナフチル基がシクロデキストリンの空洞に包接され、近赤外蛍光を発するのであれば、インドシアニン基に置換基を有していても良い。又、シクロデキストリンには、さまざまな種類が知られているが、インドシアニンのナフチル基がシクロデキストリンの空洞に包接されるものであることが必要条件となる。例えば、α-シクロデキストリン、β-シクロデキストリン、γ-シクロデキストリンが例示される。好ましくは、β-シクロデキストリンがあげられる。又、シクロデキストリンに置換基が付いていても良い。
本発明における包接型シクロデキストリン結合インドシアニン化合物は、以上の通りのものであり、その合成法は、上記で合成した非包接型シクロデキストリン結合インドシアニン化合物を合成前駆体とし、該化合物を水溶液中に溶解することにより成し遂げられる。水溶液には、包接化を妨げなければ、如何なる物質を含んでいても良く、水含量は、特に限定されることはない。又、包接化に適した温度は、-20℃から100℃であり、好ましくは0℃から50℃である。又、包接化に要する時間は、水溶液に添加した直後から1ヶ月程度である。包接化反応は、以上のごとく非包接型シクロデキストリン結合インドシアニン化合物の性質、包接化反応の温度、水溶液の組成、濃度などによりさまざまな形態をとることは明白である。
化学式11に示される化合物の合成を一例として挙げる。化学式11で示されるインドシアニン化合物は、例えば非特許文献5に記載の方法により合成する化学式13に記載の化合物と、非特許文献6に記載の方法により合成する化学式14と、脱水縮合剤として例えば水溶性カルボジイミド(WSC:例えば、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩が挙げられる)やジシクロヘキシルカルボ汁イミド(DCC)と、溶媒としてのピリジンやN,N-ジメチルホルムアミドあるいは水溶液と、を加え-20℃から60℃で10分から100時間反応することにより得ることができる。又、反応を活性化させるために活性化剤として例えば1-ヒドロキシベンゾトリアゾール(HOBt)を添加することもできる。脱水縮合剤の量は、化学式13に記載の化合物と2倍モルあるいはそれ以上であり、使用する溶媒は、反応物が溶解し、脱水縮合反応を妨げなければ制限されない。活性化剤は、脱水縮合反応を活性化するものであれば制限されず、添加する量は脱水縮合反応が期待どおりに進行する量であれば制限されない。
上記の方法で合成した非包接型シクロデキストリン結合インドシアニン化合物を含む混合物を酸性水溶液に溶解し、逆相カラムクロマトグラフィーに供し、溶出液として例えば酸を含む水とメタノール混合液、あるいは酸を含む水とアセトニトリル混合液、あるいは酸を含む水とエタノール混合液、あるいは酸を含む水とアセトン混合液のうちのいずれかを用いることにより溶出させ、高純度の非包接型シクロデキストリン結合インドシアニン化合物を単離・精製することができる。酸としては、非包接型シクロデキストリン結合インドシアニン化合物が分解せず、溶出が効率的であり、溶出後の処理が容易であれば制限されないが、例えば塩酸、トリフルオロ酢酸、酢酸、硫酸、硝酸、蟻酸などをあげることができる。好ましくは塩酸、トリフルオロ酢酸、酢酸、更に好ましくは塩酸をあげることができる。酸の濃度は、非包接型シクロデキストリン結合インドシアニン化合物が分解せず、溶出が効率的であり、溶出後の処理が容易であれば制限されないが、0.01mMから10mMが好ましく、さらには、0.1mMから1mMがより好ましい。濃度をこの範囲内にすることにより目的の化合物が分解されず且つ速やかに溶出させることができる。溶出された非包接型シクロデキストリン結合インドシアニン化合物は、溶媒を除去することにより固体として得ることができる。溶媒の除去方法としては凍結乾燥することもできる。
上記の方法で合成及び精製した化学式11で記載される非包接型シクロデキストリン結合インドシアニン化合物は、例えばDMSO中では非包接型であるが、水に溶解するとすぐに、包接型である化学式12で記載の化合物となる。この現象は、1H
NMRで確認することができる。
・生体内動態測定装置
本装置は本発明の診断用組成物に採用した本発明のシクロデキストリン結合インドシアニン化合物(以下、適宜「本発明化合物」と称することがある)が間質内に移行する程度などの体内動態がICGと異なることに基づき完成したものである。
この動脈から静脈に向けての水分移動は、動脈の圧力と間質圧との差に基づき循環系外に向けて流れる水分移動(A)と、静脈の圧力と間質圧との差に基づき循環系内に向けて流れる水分移動(B)と、間質液の浸透圧と動脈血の浸透圧との差に基づき間質から動脈内に向けて流れる水分移動(C)と、間質液の浸透圧と静脈血の浸透圧との差に基づき間質から静脈内に向けて流れる水分移動(D)とから(A)-(B)-(C)+(D)として算出できると考えることができる。
本装置は上述した本発明の診断用組成物を投与した生体の少なくとも一部について測定を行う装置である。診断用組成物の投与量としては測定する部位において励起光を照射した際に蛍光が観測可能な量とする。従って、測定部位に応じて適正量は変化する。診断用組成物に含まれる本発明化合物の種類としては特に限定しない。本発明化合物は1種類で用いることもできるし、2種類以上混合して用いることもできる。また、測定の途中に同一又は異なる組成をもつ診断用組成物を追加して投与することもできる。
励起光を照射する範囲としては特に限定しない。必要に応じて照射する範囲を決定する。狭い範囲に照射すると、照射された狭い部分において細分化された生体内動態を精密に測定できる。広い範囲に照射すると、励起光を照射されて蛍光を発することとなる本発明化合物の相対的な量が増えるため蛍光強度を更に精密に測定することができる。
蛍光強度測定手段は励起光照射手段によって励起光を照射する部位から発せられる蛍光の強度を測定する手段である。蛍光強度の測定は、発せられる蛍光を選択的に透過できるフィルタを介して行うことで蛍光以外の光(環境光、励起光など)を除外して測定することが好ましい。
算出された移行速度が正常な血管壁が示す値の範囲より外れている場合には血管壁に異常が生じていることが推測できる。なお、血管壁に異常が生じた結果、本発明化合物の透過性は向上する場合も低下する場合も両方ありうる。
例えば、純粋に腫脹の発生自体が問題になる場合の他、手術時などにおいて腸管などの縫合の評価、肺炎等の炎症の程度の評価、臓器移植における適合性の評価、脳,腎臓などにおける機能不全の評価など、全臓器に関連する事項である。
早期に高い精度を持って腫脹の可能性を予測できれば、腫脹を軽減する処置を早期に施すことで影響を最小限に抑えられることになる。たとえば脳出血直後にその後発生する脳浮腫の程度を正確に予測ができれば早期に減圧処置や血管透過性を低める対策をとることでその影響を最小限にとどめることができる。同様に虚血ストレスによる影響を事前に予測できれば心筋梗塞や四肢外傷などによる2次性の障害を最小限にとどめることも可能となる。このように腫脹の高精度定量的予測という技術は医療全般に対して少なからぬインパクトを与える可能性を秘めている。
このような問題に対して、本発明の生体内動態測定装置を用いることにより、間質内外の水分移行速度を算出することで腫脹の進行を予測することができる。実施例にて詳述するようにICGは腫脹の進行時には間質への移行はしないことが分かっている。それに対して本発明のシクロデキストリン結合インドシアニン化合物は間質内外の移行が可能であり、間質内への移行は、腫脹の進行時には水分の移行に伴い、更に促進されることが分かっている。そのため、本発明のシクロデキストリン結合インドシアニン化合物の間質内への移行を評価することで腫脹の進行を予測することができる。
本装置は本発明の診断用組成物に採用した本発明のシクロデキストリン結合インドシアニン化合物(以下、適宜「本発明化合物」と称することがある)が間質内に移行する程度などの体内動態がICGと異なることに基づき完成したものである。
本発明の循環可視化装置は励起光照射手段と蛍光イメージング手段と形態イメージング手段と表示手段とを有する。本装置は上述した本発明の診断用組成物を投与した生体の少なくとも一部について測定を行う装置である。診断用組成物の投与量としては測定する部位において励起光を照射した際に蛍光が観測可能な量とする。従って、測定部位に応じて適正量は変化する。診断用組成物に含まれる本発明化合物の種類としては特に限定しない。本発明化合物は1種類で用いることもできるし、2種類以上混合して用いることもできる。また、測定の途中に同一又は異なる組成をもつ診断用組成物を追加して投与することもできる。
従来、壊死部分の特定は、造影剤を投与して行う血管造影法や血液循環定価に伴う体温低下を検知する方法などにより行われていたが、血管造影法はX線照射装置などの装置の取り扱いが容易でなかったり、体温により判断する方法は正確な判断を行うことは容易でなかったりする問題があった。
更に、励起光照射手段による励起光の照射は環境光の影響を抑制した状態で行うことが好ましい。例えば、暗所にて励起光を照射したり、励起光を照射する部分を外光から覆った状態で励起光を照射したりすることが好ましい。
例えば、適正な光学系と、CCDなどの撮像素子との組み合わせにより構成できる。二次元的に取得するデータの解像度としては目的に応じて必要な値に設定される。蛍光強度の測定は、発せられる蛍光を選択的に透過できるフィルタを介して行うことで蛍光以外の光(環境光、励起光など)を除外して測定することが好ましい。
形態イメージング手段は本発明化合物が発する蛍光波長以外の波長の光の強度を二次元的に取得して生体の一部についての形態データを得る手段である。つまり、本手段は生体の一部についてその形態を二次元の画像データとして表している形態データとして取得するための手段である。
本発明において、「アルキル基」とは、置換基を有していてもよい炭素数1個~20個の直鎖状又は分岐鎖状のアルキル基をいい、例えば、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル、ヘキサデシル、ヘプタデシル、オクタデシル、ノナデシル、イコサニルなどの直鎖の基、又は分岐状に結合した基をいう。
本発明において、「アリール基」とは、フェニル、ナフチルなどの炭素数6~20個の芳香族炭化水素を挙げることができる。
化学式13で示される化合物0.20g、化学式14で示される化合物0.94g、WSC0.18g、HOBt0.12g、ピリジン4.0mL、N,N-ジメチルホルムアミド2.0mLの混合物を0℃、暗所において6時間撹拌した。その後、アセトン50mLを加え、析出物を減圧濾過し、析出物を0.1%トリフルオロ酢酸水溶液に溶解し、ODSカラムクロマトグラフィーに供した。溶出液に1mM塩酸を含む水及びメタノールの混合液を使用し、化学式15で示される化合物を溶出した。溶出液を減圧濃縮し緑色固体の化学式16で示される包接型化合物0.65gを得た(溶出液の減圧濃縮では、濃縮の最後は水の含有量が高いので自然と包接型となる)。
J = 9.2 Hz), 3.2-4.1 (m), 4.19 (2H, t, J = 9.8 Hz), 4.26 (2H, t, J = 9.8 Hz), 4.33 (2H, m), 4.43 (2H, m), 4.71 (2H, d, J = 2.4 Hz), 4.81 (4H, d, J = 3.7 Hz), 4.91 (2H, d, J = 3.7 Hz), 4.99 (2H, d, J = 3.7 Hz), 5.08 (2H, d, J = 3.7 Hz), 5.13 (2H, d, J = 3.1 Hz), 6.15 (2H, d, J = 13 Hz), 6.52 (2H, t, J = 12 Hz), 7.43 (4H, m), 7.57 (1H, d, J = 12 Hz), 7.57 (2H, d, J = 9.2 Hz), 7.78 (2H, m), 8.06 (3H, m), 8.15 (2H, d, J = 8.5 Hz).ESI-MS m/z calcd for C131H191N4O722972,
found 2973 [M]+.
化学式17で示される化合物0.17g、メタノール5mL、t-BuOK0.30gの混合物を室温で12時間撹拌した。その後、1M塩酸3mLを加え、さらに水50mLを加えた。析出物をろ過し、析出体を水で洗浄した後、減圧乾燥し化学式18で示される化合物0.17gを得た。
Hz), 3.17 (2H, dd, J = 3.7, 9.8 Hz), 3.26 (2H, t, J = 9.8 Hz), 3.35-4.30 (m), 4.35 (2H, t, J = 9.2 Hz), 4.50 (2H, t, J =9.2 H), 4.52 (2H, m), 4.63 (2H, m), 4.87 (2H, d,
J = 3.7 Hz), 4.95 (d, J = 3.1 Hz), 4.97 (2H, d, J = 3.7 Hz), 5.08 (2H, d, J = 3.7 Hz), 5.15 (2H, d, J = 4.3 Hz), 5.25 (2H, d, J = 3.7 Hz), 5.29 (2H, d, J = 3.7 Hz), 6.30 (2H, d, J = 14.6 Hz), 7.58 (4H, m), 7.73 (2H, d, J = 8.5 Hz), 7.95 (2H, m), 8.25 (2H, m), 8.32 (2H, d, J = 14.6 Hz), 8.35 (2H, d, J = 8.5 Hz).ESI-MS m/z calcd for C135H197N4O733042,
found 3042 [M]+.
化学式13で示される化合物0.04g、モノ-6-アミノ-6-デオキシ-β-シクロデキストリン0.18g、WSC0.05g、HOBt0.025g、ピリジン0.8mL、N,N-ジメチルホルムアミド0.4mLの混合物を0℃、暗所において3時間撹拌した。その後、アセトン10mLを加え、析出物を減圧濾過し、析出物を0.1%トリフルオロ酢酸水溶液に溶解し、ODSカラムクロマトグラフィーに供した。溶出液に1mM塩酸を含む水及びメタノールの混合液を使用し、化学式21で示される化合物を溶出した。溶出液を減圧濃縮し緑色固体の化学式21で示される化合物0.11gを得た。
29 ℃,
Acetone: 2.10 ppm) 1.79 (12H, br.), 2.68 (4H, br.), 3.0-4.5 (98H), 4.4 (4H, br.), 4.5-5.3 (14H, br.), 6.18 (2H, br.), 6.46 (2H, br.), 7.3-8.2 (15H).ESI-MS m/z calcd for C125H179N4O702856,
found 2856 [M]+.
化学式22で示される化合物0.02g、モノ-6-アミノ-6-デオキシ-β-シクロデキストリン0.096g、WSC0.032g、ピリジン0.5mL、0.1Mリン酸緩衝液0.05mLの混合物を室温、暗所において24時間撹拌した。その後、アセトン10mLを加え、析出物を減圧濾過し、析出物を0.1%トリフルオロ酢酸水溶液に溶解し、ODSカラムクロマトグラフィーに供した。溶出液に水及びアセトニトリルの混合液を使用し、化学式23で示される化合物を溶出した。溶出液を減圧濃縮し緑色固体の化学式23で示される化合物0.014gを得た。
26 ℃,
Acetone: 2.15 ppm) 1.26 (4H, m), 1.5-2.25 (24H, br), 2.7-4.2 (88H), 4.82 (2H, br), 4.90 (8H, br), 4.97 (2H, br), 5.03 (2H, br), 6.11 (2H, br), 6.36 (2H, br), 7.3-8.01 (15H, br).ESI-MS m/z calcd for C131H191N4O702940,
found 2940 [M]+.
化学式22で示される化合物0.20g、3-アミノ-3-デオキシ-β-シクロデキストリン0.02g、WSC0.096g、HOBt0.013g、ピリジン0.4mL、N,N-ジメチルホルムアミド0.2mLの混合物を室温、暗所において1時間撹拌した。その後、アセトン10mLを加え、析出物を減圧濾過し、析出物を0.1%トリフルオロ酢酸水溶液に溶解し、ODSカラムクロマトグラフィーに供した。溶出液に水及びメタノールの混合液を使用し、化学式24で示される化合物を溶出した。溶出液を減圧濃縮し緑色固体の化学式24で示される化合物0.013gを得た。
29 ℃,
Acetone: 2.10 ppm) 1.1-2.5 (28H), 3.0-4.25 (88H), 4.5-5.2 (14H), 7.3-8.02(15H).ESI-MS m/z calcd for C131H191N4O702940,
found 2940 [M]+.
化学式22で示される化合物0.02g、化学式14で示される化合物0.1g、WSC0.032g、ピリジン0.5mL、0.1Mリン酸緩衝液0.05mLの混合物を室温、暗所において24時間撹拌した。その後、アセトン10mLを加え、析出物を減圧濾過し、析出物を0.1%トリフルオロ酢酸水溶液に溶解し、ODSカラムクロマトグラフィーに供した。溶出液に水及びメタノールの混合液を使用し、化学式25で示される化合物を溶出した。溶出液を減圧濃縮し緑色固体の化学式25で示される化合物0.021gを得た。
25 ℃,
Acetone: 2.10 ppm) 1.0-2.5 (32H), 3.0-4.5 (96H), 4.8-5.2 (14H), 6.09 (2H,br), 6.37 (2H, br), 7.3-8.02 (15H, br).ESI-MS m/z calcd for C137H203N4O723056,
found 3056 [M]+.
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の水及び生理食塩水への溶解性試験を行った。水及び生理食塩水を用いたMolecular Probe社の粉末状のICGの溶解には1分間ほどの激しい振動撹拌が必要であるが、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物では振動撹拌は不要であり速やかに溶解した。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のヒトの皮膚への吸着性試験を行った。ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれの1mM水溶液(0.03mL)を腕にのせ、5分後に水洗し、さらに擦って水洗した。その結果、ICGは水洗では完全に洗えなかったが、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物は容易に水洗でき、本発明のシクロデキストリン結合インドシアニン化合物のヒトの皮膚への吸着性は、ICGよりはるかに低いことが示された(図1)。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のセルロース繊維への吸着性試験を行った。セルロース繊維のモデルとして綿棒(株式会社三洋)を用い、ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれの1mM水溶液0.05mLを塗布し、3分後に流水(水道水、1L/min)で5秒間水洗した。その結果、ICGは水洗では完全に洗えなかったが、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物は容易に水洗でき、本発明のシクロデキストリン結合インドシアニン化合物で示される化合物のセルロース繊維への吸着性は、ICGよりはるかに低いことが示された(図2)。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の生体の肉モデルへの吸着性試験を行った。生体の肉モデルとして市販の豚ロース肉を用い、豚ロース肉に直径5mmの凹を作り、ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれの1mM水溶液0.05mLを塗布し、3分後に流水(水道水、1L/min)で10秒間水洗した。その結果、ICGは水洗では完全に洗えなかったが、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物は容易に水洗でき、本発明のシクロデキストリン結合インドシアニン化合物の生体の肉モデルへの吸着性は、ICGよりはるかに低いことが示された(図3)。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の生体のタンパク質モデルへの吸着性試験を行った。生体のタンパク質モデルとして市販の鶏ささみ肉を用い、鶏ささみ肉に直径5mmの凹を作り、ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれの1mM水溶液0.05mLを塗布し、3分後に流水(水道水、1L/min)で10秒間水洗した。その結果、ICGは水洗では完全に洗えなかったが、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物は容易に水洗でき、本発明のシクロデキストリン結合インドシアニン化合物の生体のタンパク質モデルへの吸着性は、ICGよりはるかに低いことが示された(図4)。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の疎水性化学繊維への吸着性試験を行った。疎水性化学繊維のモデルとしてポリプロピレンマスク(玉川衛材株式会社)を用い、ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれの1mM水溶液0.05mLを塗布し、20分放置後(サンプルの水分が有るとマスクに付着しないため、水分を除去するために20分放置)に流水(水道水、1L/min)で1秒間水洗した。その結果、ICGは水洗では完全に洗えなかったが、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物は容易に水洗でき、本発明のシクロデキストリン結合インドシアニン化合物の疎水性化学繊維への吸着性は、ICGよりはるかに低いことが示された(図5)。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の水溶液中での分子会合性について検討した。ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の0.01mM、0.025mM、0.05mM、0.1mM水溶液をそれぞれ調整し、光路長1mmの石英セルに入れ、25℃で600nmから1000nmの光吸収スペクトルを測定した。その結果、ICGはこの濃度範囲においてH-aggregationとよばれる分子会合が生じたが(図6左図)、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物はこの濃度範囲においてH-aggregationとよばれる分子会合は生じないことが示された(図6右図)。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の水溶液中での蛍光性について検討した。ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれの0.1μM水溶液を25℃で1cm角石英セルに入れ、720nmの励起光(バンドパス:10nm)で励起し、蛍光スペクトル(バンドパス:10nm)を測定した。蛍光効率は、ICGの蛍光効率0.13(in
DMSO、25℃)をもとに算出した。その結果、ICGの蛍光量子効率は0.021であり、本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物の蛍光量子効率は0.054及び0.042であり、蛍光量子効率はICGの2.6倍と2倍であった。
ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)の血液中での蛍光性について検討した。ICG及び本発明のシクロデキストリン結合インドシアニン化合物(化学式16,20,21,23乃至25)のそれぞれを100μMになるように血液(人)中に溶解させた。それらの血液を25℃で三角石英セルに入れ、760nmの励起光(バンドパス:10nm)で励起し、表面蛍光スペクトル(バンドパス:10nm)を測定した。極大蛍光波長における蛍光強度は、ICGは58(任意単位)であった。本発明のシクロデキストリン結合インドシアニン化合物、特に化学式16及び化学式20で示される化合物の蛍光強度は270(任意単位)及び190(任意単位)であり、ICGの4.7倍と3.3倍であった。これは本発明のシクロデキストリン結合インドシアニン化合物が生体内において、発光を阻害されないためであると考えられた。
代表例として、化学式19および20で示される異性化平衡化合物(TK1)と化学式15および16で示される異性化平衡化合物(TK2)とについて、生体対象物としてのヒト血液およびラット体内での挙動を評価した。
ICG,TK1、及びTK2について、三角セル中におけるヒト静脈血中における表面蛍光強度の濃度依存性について評価を行った。具体的には、三角石英セルにヒト静脈血液1.0 mLをいれ、ICG,TK1、及びTK2を所定の濃度加えた。25℃で760 nm(バンドパス:10 nm)の励起光を照射し、表面蛍光(バンドパス:10 nm)を測定した。結果を図7に示す。
・ラット体内への投与可能性の検討
ICG,TK1,及びTK2のそれぞれについて濃度1mMの水溶液を調製し、それぞれについて0.1mLずつ、開腹したラットの大腿静脈を露出して注射した。その後、760nmの励起光を開腹部に照射して蛍光の有無を評価した。
・ラット体内での分布の観察
Wistar雄ラット(9週齢、体重は350g)をエーテル麻酔後、ネンブタール0.1mL26G針で腹腔内投与にて麻酔した。ラットの尾付け根をゴム帯で駆血し、24Gサーフロ針で尾静脈を確保して、3方活栓と延長チューブを装着して末梢ラインを確保した。ラットを平面な台上に仰臥位に固定した(図8)。浜松ホトニクス製のPDEカメラユニットをラットの体から16cmの位置に正確に設置した。ただし全身を広範囲に撮影する場合は20cmとした。観察範囲は図8における黒丸で示した程度の範囲となった。その後、確保しておいた末梢ラインより、濃度1mMで、ICG並びにTK1、及びTK2を投与した。投与量は0.1mLとした。投与20分後に開腹した際の腹腔内における蛍光の様子を図9に、足背部における蛍光の様子(最高輝度になった時点での画像)を図12に示す。
撮像図12より明らかなように、足背部においては血流の流れに応じて蛍光を発する様子が明らかになった。なお、図には示さないが、ラットの右大腿動脈結紮による下肢虚血モデルついて、ICG、TK1、及びTK2を同様に投与して蛍光を観察したところ、虚血部分においては蛍光が認められず、蛍光の有無を頼りに血流の程度を評価することができることが分かった。
・血管レベルでの観察
(評価方法)
ラット(雄、Wister rat)10週齢約350gを試験動物として選択した(n=4)。ラットにイソフルレンで全身麻酔を導入し、左後足蹠に0.5%λカラゲニン0.1mLを26G針で注射する。結果、速やかに足浮腫が出現した。15分後ラット足蹠容積測定器(室町機械株式会社製:MK-101CMP PLETHYSMOMETER)にてラットの左足容積を測定した。
testを行った後速やかにラットにイソフルランで全身麻酔を導入しラット足蹠容積測定器にてラットの左足容積を測定した。ラット尾静脈を24Gサーフロ針で確保した後、仰臥位とし水平な台の上に固定した。浜松ホトニクス社製PDEカメラを設置し、ラットの足背から16cm高さに合わせ固定し、ROIを足背中央部に設定、消灯の後計測をスタートした。1mmolTK1水溶液0.1mLを尾静脈より注入し、1mLの生理食塩水にて5秒かけてフラッシュした。注入より最初の5分間は連続で撮影しROIにおける輝度を計測した。以後は5分間隔で1分間輝度を計測し注入後120分に至るまで継続した。計測終了後、イソフルレンをoffとし覚醒させケージに戻した。λカラゲニンを注射しない群についても同様に試験を行った。
以上の過程をICGでも同様に行った。
結果を図19~26に示す。TK1を投与した群について測定したラットの左足容積を図19(縦軸は上方に行くほど体積大)に、Von Frey testの結果を図20(縦軸は下方に行くほど痛覚過敏)に、注射直後の輝度の変化の様子を図21(縦軸は上方に行くほど輝度大)に、カラゲニン注射後1週間経過後の輝度の変化の様子を図23(縦軸は上方に行くほど輝度大)に示す。ICGを投与した群について測定したラットの左足容積を図23(縦軸は上方に行くほど体積大)に、Von Frey testの結果を図24(縦軸は下方に行くほど痛覚過敏)に、注射直後の輝度の変化の様子を図25(縦軸は上方に行くほど輝度大)に、カラゲニン注射後1週間経過後の輝度の変化の様子を図26(縦軸は上方に行くほど輝度大)に示す。全てのグラフの縦軸の値は任意単位である。
足背の輝度において、TK1群は血管相での輝度変化の状況はコントロール群との間で差を認めなかったが、間質相ではλカラニゲン投与群でより早い輝度の増加を認め、評価時間を通じて高い値を保つことが認められた
(図21)。λカラニゲン投与による炎症が消腿した投与1週間後においてはカラゲニン投与側と健側の間に間質相の輝度変化には差を認めなかった(図22)。図21のグラフに明瞭に示されているように間質相における輝度の推移はなめらかな曲線を描いて推移し、その山の高さは間質相の立ち上がりの変化率に依存していることが分かる。言い換えると間質相の値の変化は時系列解析により高い精度で予測可能であることを示しており、我々の作業仮説を立証する重要な根拠を示している。
以上の結果から、TK1を生体に投与した後、間質相に相当する期間について、腫脹の進行を予測した部位の蛍光強度を経時的に測定することで、その後の蛍光強度の推移が予測可能であり、その蛍光強度の推移がその部位における腫脹の進行に関連することが明らかになった。従ってTK1は、ICGを用いては行うことができない腫脹の予測に用いることができることが分かった。
Claims (25)
- 下記化学式1で示されるシクロデキストリン結合インドシアニン化合物。
- インドシアニンのナフチル基の少なくとも一部がシクロデキストリンの空洞に包接されることを特徴とする、下記化学式2で示されるシクロデキストリン結合インドシアニン化合物。
- 請求項1に記載のシクロデキストリン結合インドシアニン化合物であって、下記化学式3で示されるシクロデキストリン結合インドシアニン化合物。
- 請求項2に記載のシクロデキストリン結合インドシアニン化合物であって、下記化学式4で示されるシクロデキストリン結合インドシアニン化合物。
- (1)インドシアニンカルボン酸化合物とアミノシクロデキストリンとを溶媒中で混合する工程と、(2)脱水縮合剤を加えて脱水縮合反応させる工程とを含むことを特徴とする、請求項1、3、5、7、9、11のいずれか1つに記載のシクロデキストリン結合インドシアニン化合物の化学合成法。
- 請求項1、3、5、7、9、11のいずれか1つに記載のシクロデキストリン結合インドシアニン化合物を、水中で包接反応させることを特徴とする請求項2、4、6、8、10、12のいずれか1つに記載のシクロデキストリン結合インドシアニン化合物の化学合成法。
- 請求項1乃至12のいずれか1つに記載のシクロデキストリン結合インドシアニン化合物の精製法であって、該化合物をHClを含有する溶媒で溶出するカラムクロマトグラフィーによる精製法。
- 請求項1乃至12のいずれか1つに記載のシクロデキストリン結合インドシアニン化合物を含む水溶液である体内に注入して用いられる診断用組成物。
- 実質的にヨウ素を含まない請求項16に記載の診断用組成物。
- 請求項16又は17に記載の診断用組成物を投与した生体の一部について、前記シクロデキストリン結合インドシアニン化合物に励起光を照射する励起光照射手段と、
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を測定する蛍光強度測定手段と、
前記蛍光強度測定手段から経時的に取得した前記蛍光強度からその蛍光強度の経時変化を求めることにより前記シクロデキストリン結合インドシアニン化合物が前記生体の一部において間質液中に移行する速度及び/又は前記間質外に移行する速度を算出する生体内動態算出手段と、
を有する前記シクロデキストリン結合インドシアニン化合物の生体内動態測定装置。 - 請求項16又は17に記載の診断用組成物を投与した生体の一部について、前記シクロデキストリン結合インドシアニン化合物に励起光を照射する励起光照射手段と、
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を二次元的に取得して前記シクロデキストリン結合インドシアニン化合物の生体内における分布状態データを得る蛍光イメージング手段と、
前記シクロデキストリン結合インドシアニン化合物が発する前記蛍光波長以外の波長の光の強度を二次元的に取得して前記生体の一部についての形態データを得る形態イメージング手段と、
前記形態イメージング手段により得られた前記形態データに前記蛍光イメージング手段により得られた前記分布状態データを重ね合わせて前記生体の一部における前記シクロデキストリン結合インドシアニン化合物の分布状態を表示する表示手段と、
を有する循環可視化装置。 - 前記表示手段は前記生体の一部において前記シクロデキストリン結合インドシアニン化合物の分布量が所定の基準より低い部分を壊死部分として表示する請求項19に記載の循環可視化装置。
- 前記生体の一部において間質液内外に移行する速度から前記生体の一部において以後に進行する腫脹の程度を予測する腫脹進行予測手段を有する請求項18に記載の生体内動態測定装置。
- 前記腫脹進行予測手段は、前記診断用組成物を投与されてから、前記シクロデキストリン結合インドシアニン化合物が全身の血液中に分散するまでの時間である所定時間経過以降における前記間質液中への移行速度の大きさに応じた程度の腫脹の進行を予測する請求項21に記載の生体内動態測定装置。
- 請求項16又は17に記載の診断用組成物を投与した生体の一部及び対照部位について、前記シクロデキストリン結合インドシアニン化合物に励起光を照射する励起光照射手段と、
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を測定する蛍光強度測定手段と、
前記蛍光強度測定手段から経時的に取得した前記蛍光強度からその蛍光強度の経時変化を求めることにより前記シクロデキストリン結合インドシアニン化合物が前記生体の一部において間質液中に移行する速度及び/又は前記間質外に移行する速度を算出する生体内動態算出手段と、
前記生体の一部において間質液内外に移行する速度から前記生体の一部において以後に進行する腫脹の程度を予測する腫脹進行予測手段とを有し、
前記腫脹進行予測手段は、
前記診断用組成物を投与してから前記シクロデキストリン結合インドシアニン化合物が全身の血液中に分散するまでの時間である所定時間に至るまでの、前記生体の一部における蛍光強度の変化と前記対照部位における蛍光強度の変化とから、対照部位に流れる血流量と前記生体の一部における血流量との関係を求め、
前記所定時間経過以降における、前記対照部位における蛍光強度の変化を対照とした前記生体の一部における蛍光強度の変化の程度をその関係を用いて算出し、
算出した前記変化の程度の大きさに応じた腫脹の進行を予測する手段であることを特徴とする生体内動態測定装置。 - 請求項16又は請求項17に記載の診断用組成物を投与した生体の器官について、前記シクロデキストリン結合インドシアニン化合物に励起光を照射する励起光照射手段と、
前記励起光照射手段により励起された前記シクロデキストリン結合インドシアニン化合物が発する蛍光の強度を測定する蛍光強度測定手段と、
前記蛍光強度測定手段から経時的に取得した前記蛍光強度から前記器官における前記シクロデキストリン結合インドシアニン化合物の生体内動態を評価する生体内動態算出手段とを有することを特徴とする生体内動態測定装置。 - 前記器官は、腎臓、尿管、膀胱、及び尿道の何れかである請求項24に記載の生体内動態測定装置。
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JP2014005227A (ja) * | 2012-06-22 | 2014-01-16 | Mie Univ | 血管透過性亢進評価剤、血管透過性亢進評価方法、および血管透過性亢進評価装置 |
WO2021105888A1 (en) | 2019-11-27 | 2021-06-03 | Astellas Pharma, Inc. | Crystal of indocyanine compound |
WO2022202863A1 (ja) * | 2021-03-24 | 2022-09-29 | アステラス製薬株式会社 | がん造影用組成物 |
Also Published As
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US20170157273A1 (en) | 2017-06-08 |
US10086090B2 (en) | 2018-10-02 |
EP2530093B1 (en) | 2018-11-21 |
US20120302881A1 (en) | 2012-11-29 |
US9056131B2 (en) | 2015-06-16 |
US11344632B2 (en) | 2022-05-31 |
US20150152267A1 (en) | 2015-06-04 |
US9844606B2 (en) | 2017-12-19 |
CN102770460A (zh) | 2012-11-07 |
US10350310B2 (en) | 2019-07-16 |
PT2530093T (pt) | 2018-12-28 |
HUE041616T2 (hu) | 2019-05-28 |
EP2530093A4 (en) | 2016-07-06 |
JPWO2011093098A1 (ja) | 2013-05-30 |
DK2530093T3 (en) | 2019-01-28 |
US20190262477A1 (en) | 2019-08-29 |
US20180353626A1 (en) | 2018-12-13 |
EP2530093A1 (en) | 2012-12-05 |
CN106977628A (zh) | 2017-07-25 |
PL2530093T3 (pl) | 2019-06-28 |
CN106977628B (zh) | 2021-04-13 |
ES2708697T3 (es) | 2019-04-10 |
JP5721234B2 (ja) | 2015-05-20 |
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