JP2003102698A - Nuclear magnetic resonance image diagnosing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a nuclear magnetic resonance image diagnosing agent which is high in the degree of relaxation of T2, less affects an organism in spite of a large amount of rapid administration and makes it possible to obtain stable tissue perfusion information in the nuclear magnetic resonance imaging or nuclear magnetic resonance spectroscopy. SOLUTION: The nuclear magnetic resonance image diagnosing agent is an aqueous solution containing a molecule having a hydrogen atom directly bonded with a quadrupole nucleus within the molecule as an effective component and having a property for admitting living body, in which the degree of relaxation of T2 of the aqueous solution is >=0.1 s<-1> atom%<-1> .

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nuclear magnetic resonance imaging diagnostic agent capable of obtaining in vivo tissue perfusion information in nuclear magnetic resonance diagnosis such as nuclear magnetic resonance imaging or nuclear magnetic resonance spectroscopy.

[0002]

2. Description of the Related Art Conventionally, various radioisotopes or radiopharmaceuticals have been used as contrast agents for diagnosing in vivo tissue perfusion information, for example, blood flow information of the brain, liver, kidneys, muscles, and even tumors. Positron emission computer tomography (PET) or single photon emission computer tomography (S
PECT). However, since these methods use radioactive elements, there are problems that they may be exposed to radiation and that the supply of radioactive elements must be based on manufacturing by a nuclear reactor or a cyclotron. In addition, there is a limitation in use that the actual diagnosis must be made within the radioactivity controlled area.

Diagnosis of tissue perfusion that does not use radioactive elements, for example, a method of measuring cerebral blood flow, includes nuclear magnetic resonance imaging using paramagnetic metal complex or iron oxide particles as a contrast agent. After these contrast agents are administered from the blood vessel into the body, the migration from the blood vessel into the tissue is slow and gradually distributed, so the migration rate of the contrast agent into the tissue due to a single circulation (Extraction Fraction) is more than 1. Is also small. An inspection method using PET using ¹⁵ O-H ₂ O is an example of an inspection method that overcomes such drawbacks. Extraction Fraction is the most important method for this inspection.
It is said to be the standard method for cerebral blood flow test. However, since this method also uses a radioisotope, it has the above-mentioned problems such as radiation exposure and limitation in use.

On the other hand, regarding the proton of the hydrogen atom directly bonded to the quadrupole nucleus of ¹⁴ N, ³³ S, ¹⁷ O, etc., due to the scalar bond interaction between the quadrupole nucleus and the hydrogen proton,
It is known that it is possible to obtain contrast (contrast) in nuclear magnetic resonance imaging by utilizing the phenomenon that the transverse relaxation time (T2) of hydrogen protons and the longitudinal relaxation time (T1ρ) of the rotating coordinate system are shortened. ing. That is, by utilizing this phenomenon, the distribution and concentration of water obtained by concentrating water (H ₂ ¹⁷ O) in which oxygen in the molecule is replaced with ¹⁷ O is determined by nuclear magnetic resonance imaging using protons of hydrogen atoms as detection nuclei. It is possible to measure the in-vivo tissue perfusion information by detecting with. This method is described above
It is noted that it overcomes the supply of the administered compound, the radiation exposure, the limitation on use, and the low versatility of the inspection device, which are constraints in performing the inspection by PET using ¹⁵ O-H ₂ O.

In nuclear magnetic resonance imaging using the proton of the hydrogen atom as a detection nucleus, the quadrupole nucleus which is each stable isotope is an element whose natural abundance ratio is small, so that M
To be used as an RI contrast agent, it is necessary to administer a large amount of concentrated quadrupole nuclei into the body. For example, in order to use H ₂ ¹⁷ O-concentrated water as an MRI contrast agent, it is necessary to administer several tens to several hundred mL or more per adult. Further, in order to obtain information on tissue perfusion in the living body, it is necessary to know the distribution kinetics of the administered nuclear magnetic resonance imaging diagnostic agent, and therefore it is necessary to administer the contrast agent relatively rapidly, that is, the bolus administration.

However, a relatively large amount of injection is
When lus is administered, biological information such as blood pressure and heart rate may fluctuate, and further, such biological information may fluctuate to change tissue perfusion information obtained by image diagnosis. For example, in the case of cerebral blood flow, it is known that the blood vessel diameter changes as blood pressure changes due to the mechanism that keeps the blood flow velocity constant, and as a result, cerebral blood flow changes. On the other hand, when the blood pressure fluctuation is large, the mechanism for keeping the blood flow velocity constant does not work, and the blood flow velocity itself fluctuates. As another example, in the case of myocardial blood flow, when acquiring a nuclear magnetic resonance diagnostic image by cardiac synchronization, the timing of cardiac synchronization changes due to changes in the heartbeat, and the information of the collected diagnostic image itself is normal. It is known to be different from time. When such changes in biological information occur, accurate myocardial blood flow diagnosis cannot be performed. That is, due to the change in the biological information associated with the rapid and large-scale administration of the contrast agent as described above, the in-vivo tissue perfusion information changes, and it is possible to obtain the tissue perfusion information that does not reflect the state before administration of the diagnostic agent. There is a nature. Therefore, it is necessary to suppress the influence on the image diagnosis due to the perturbation of biological information as much as possible.

[0007] In fact, several reports have been made as examples of administration of water enriched with H ₂ ¹⁷ O to warm-blooded animals.
Hopkins et al. Utilize the phenomenon that the relaxation time of hydrogen protons is shortened by the above-mentioned scalar bond interaction.
H for the cerebral infarction model of ongolian gerbils
₂ ¹⁷ O water with a concentration of 41 to 50 atom%,
% To 2% (converted to human: 360 to 12
(00 mL) was administered intraperitoneally, and the infarct site was detected by the T2-weighted spin echo method (ALHopkins et al. Mag.
n. Reson. Med., 22, 167, 1991). In addition, Tailor et al. Administers 0.2 mL of water with an H ₂ ¹⁷ O concentration of 29 atom% (converted to human: 48 mL) to the rat in the carotid artery and calculates the H ₂ ¹⁷ O concentration in the brain by the T1ρ dispersion method. (9thISMRM 18th ESMRMB joint annual meeting, Pr
oc.Inth.Soc.Mag.Reson.Med 9,356, 2001). However, in all of these reports, a large amount of H ₂ ¹⁷ O-enriched water is administered as it is, and the problems in clinical diagnosis use such as the above-mentioned effects on the living body due to large-scale administration are not taken into consideration. There remains a problem as a method for performing image diagnosis of various tissue perfusion information. In addition, according to the report by Tailor et al., In order to efficiently distribute the H ₂ ¹⁷ O-enriched water to the target tissue, the carotid artery is administered at a smaller dose than that reported by Hopkins et al. But
There is a problem as a clinical application in which it is necessary not to invasively burden the patient.

Further, Ronen, etc., H ₂ ¹⁷ O concentration 41
A physiological saline solution containing ˜50 atom% of water was intravenously administered to a rat, and the H ₂ ¹⁷ O concentration in blood was determined by a combined ¹⁷ O nuclear irradiation method (I. Ronen et al., Proc. Natl. Acad. . S
ci. USA., 95, 12934, 1998). Although physiological saline is used in this report, as in the above-mentioned report, the H ₂ ¹⁷ O concentration in blood after administration is merely measured, and tissue perfusion of animals by administration of a contrast agent is merely measured. We have not considered changes in information at all. Moreover, since none of the above-mentioned documents considers the application to actual clinical diagnosis, the necessity of administration of a contrast agent having a high T2 relaxation degree effective for image diagnosis is not examined at all. .

As described above, the use of a nuclear magnetic resonance imaging diagnostic agent containing a molecule containing a hydrogen atom directly bonded to a quadrupole nucleus as an active ingredient, represented by water enriched with H ₂ ¹⁷ O, as a contrast agent. It is considered that the form needs to be administered to a living body in a large amount and rapidly. However, until now, due to changes in biological information such as up-down fluctuation of blood pressure, increase / decrease of heartbeat, irregularity, etc., which are expected due to usage forms such as rapid large-volume administration of the diagnostic imaging agent, and changes in these biological information. No study has been made to suppress changes in tissue perfusion information. Similarly, the contrast agent having T2 relaxivity effective for image diagnosis in clinical applications has not been examined.

[0010]

In view of the above situation, the present invention has a high degree of T2 relaxation and has little effect on the living body even when a large amount of rapid administration is performed in the diagnosis of nuclear magnetic resonance. Therefore, stable tissue perfusion information can be obtained. An object of the present invention is to provide a nuclear magnetic resonance imaging diagnostic agent containing a molecule having a hydrogen atom directly bonded to a quadrupole nucleus.

[0011]

The present invention is a biocompatible aqueous solution containing, as an active ingredient, a molecule having a hydrogen atom directly bonded to a quadrupole nucleus in the molecule, and the T2 relaxation degree of the aqueous solution. Is 0.1 s ^-1 atom% ^-1 or more, and a nuclear magnetic resonance imaging diagnostic agent is provided. Also,
The present invention is a biocompatible aqueous solution containing a molecule having a hydrogen atom directly bonded to a quadrupole nucleus in the molecule as an active ingredient, and having a property of suppressing a change in biological information in rapid mass administration. Provided is a characteristic nuclear magnetic resonance imaging diagnostic agent.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The nuclear magnetic resonance imaging diagnostic agent in the present invention is a biocompatible aqueous solution containing a molecule having a hydrogen atom directly bonded to a quadrupole nucleus in the molecule, and T2 of the aqueous solution. It is a nuclear magnetic resonance imaging agent characterized by having a relaxation degree of 0.1 s ^-1 atom% ^-1 or more. Further, the nuclear magnetic resonance imaging diagnostic agent in the present invention is a biocompatible aqueous solution containing a molecule having a hydrogen atom directly bonded to a quadrupole nucleus in the molecule as an active ingredient, and bioinformation in rapid mass administration. It is a nuclear magnetic resonance imaging agent characterized by having the property of suppressing changes in Examples of the quadrupole nucleus include ¹⁴ N, ³³ S, ¹⁷ O, and the like. The bond between the quadrupole nucleus and a hydrogen atom is, for example, —OH bond of alcohols, sugars and water, —NH bond of amino acids, or cysteine. Examples thereof include -SH bond of some amino acids. A biocompatible aqueous solution is an aqueous solution containing a pharmaceutically acceptable component, preferably a biocompatible ion selected from biological components and a salt thereof selected from biological components. . Examples of the pharmaceutically acceptable component include various sugars and various amino acids, and biocompatible ions selected from biological components and salts thereof selected from biological components. Examples of biocompatible ionic species include inorganic ions such as sodium ions, potassium ions, calcium ions and hydrogen ions, organic ions such as carbonic acid, and the like. More preferably, it is selected from inorganic ions.

As an example of the composition of a preferable nuclear magnetic resonance imaging diagnostic agent, for example, 0.09 to 0.26 mol / L sodium ion is added to water containing H ₂ ¹⁷ O as an active ingredient to obtain a hydrogen ion concentration. Is converted to pH of 5.0 to
A composition adjusted to 8.5 is included. With such a composition, it is possible to suppress a change in tissue perfusion information in the living body due to a change in biological information being suppressed. Moreover, the reduction rate of the T2 relaxation time (ms) per 1 atom% of the quadrupole nucleus, that is, the T2 relaxation degree is 0.1 s ^−1.
It is possible to obtain a nuclear magnetic resonance imaging agent having a value of not less than atom% ^−1, which is suitable for image diagnosis.

The dose and rate of administration of the nuclear magnetic resonance imaging agent in the present invention are within the range that the object of the present invention can be achieved. The enrichment of quadrupole nuclei contained in the imaging agent or the nucleus serving as a measuring means. It can be appropriately selected depending on the type of magnetic resonance imaging. For example, an MRI contrast agent is usually required to be administered in an amount of several tens to several hundreds of mL per adult, but such an amount of the drug is rapidly administered to a living body, that is, even if a large amount is rapidly administered, the biological information changes. It is preferable for the nuclear magnetic resonance imaging agent to have no influence. Here, rapid large-scale administration usually means several tens of mL per adult.
This means that several hundred mL of the drug is administered at a rate of 0.3 mL / sec or more. By using the nuclear magnetic resonance imaging diagnostic agent of the present invention, blood pressure fluctuation, which is one of biological information, can be kept below 20% even if rapid large-volume administration is performed. Further, the administration method is not particularly limited, and it is preferable to administer according to the administration route necessary for obtaining the intended information. For example, administration may be performed through arteries, veins, and indwelling catheters. Preferably, intravenous administration or the like is performed.

The nuclear magnetic resonance imaging diagnostic agent in the present invention is
Nuclear magnetic resonance imaging with protons as the detection nuclei, or by detecting with quadrupole nuclei containing active ingredient molecules as the detection nuclei or with nuclear magnetic resonance spectroscopy, the distribution is monitored,
It can be used to detect the necessary biometric information. For the sequence used for imaging, see the proton T
The method is not limited to any one as long as it is selected from 2 or the imaging method that reflects the reduction of the T1ρ relaxation time, and can be appropriately selected according to the purpose. For example, spin echo method T2
The emphasis method and various T1ρ emphasis methods are selected.

[0016]

EXAMPLES The present invention will now be specifically described with reference to examples, but the present invention is not limited to these.

Reference Example 1 La with an aqueous solution of calcium chloride
Measurement of change in biometric information of botton Distilled water for injection was added to 1.65 g of calcium chloride dihydrate to make exactly 100 mL, to prepare a 1.2% calcium chloride solution. Prepared 1.2% calcium chloride solution 1
mL was rapidly administered to SD rats (male, 8 weeks old) through a femoral vein catheter for about 3 seconds, and changes in blood pressure and heart rate were examined. Blood pressure and heart rate were measured invasively from the femoral artery using a blood pressure measuring unit AP-641G manufactured by Nihon Kohden Co., Ltd. and a heart rate measuring instrument AT-601G. As a result, the maximum blood pressure value was about 10 before administration.
Approximately 150 mm from 0 mmHg to approximately 6 seconds after administration
Increased to Hg. Further, even after about 16 seconds when the equilibrium was almost reached, the maximum blood pressure was about 120 mmHg, which was about 20% higher than that before administration. based on the above results,
It was revealed that rapid administration of 1.2% calcium chloride solution changes biological information.

Reference Example 2 Administration of aqueous sodium chloride solution
Measurement of changes in biological information of rats Exactly 10% by adding water for injection to 0.9 g of sodium chloride
The volume was adjusted to 0 mL to prepare a 0.9% sodium chloride solution.
1 mL of the prepared 0.9% sodium chloride solution was rapidly administered to SD rats (male, 8 weeks old) through a femoral vein catheter over about 3 seconds, and changes in blood pressure and heart rate were examined. Blood pressure and heart rate are measured by Nihon Kohden Co., Ltd. blood pressure measuring unit AP-641G and heart rate measuring instrument AT-601G.
Was used for invasive measurement from the femoral artery. In rats administered with 0.9% sodium chloride solution, the maximum blood pressure value changed from about 100 mmHg before administration to about 90 mmHg for about 3 seconds after administration,
It gradually recovered, and after about 10 seconds, it returned to the value before administration.

Example 1 Administration of aqueous sodium chloride solution
Measurement of changes in the biological information of rats Exactly 100 by adding water for injection to 15 g of sodium chloride
A 15% sodium chloride solution was prepared in mL. Separately, add water for injection to 10 g of sodium chloride to make exactly 1
The volume was adjusted to 00 mL to prepare a 10% sodium chloride solution.
Water for injection was added to 2 mL of 10% sodium chloride solution to make exactly 10 mL, to give a 2% sodium chloride solution. Furthermore, water for injection was added to 1 mL of a 15% sodium chloride solution to make exactly 10 mL, to give a 1.5% sodium chloride solution. Prepared 2% sodium chloride solution and 1.5%
1.4 mL of sodium chloride solution for each SD
Rats (male, 18 weeks old, about 500 g) were rapidly administered through a femoral vein catheter for about 3 seconds, and changes in blood pressure and heart rate were examined. Blood pressure and heart rate were measured invasively from the femoral artery using a blood pressure measuring unit AP-641G manufactured by Nihon Kohden Co., Ltd. and a heart rate measuring instrument AT-601G. In rats treated with 2% sodium chloride solution,
About 10 seconds after the administration, the value of the maximum blood pressure changed from about 110 mmHg before administration to about 85 mmHg,
After about 20 seconds, it had recovered to the value before administration. On the other hand, 1.5
% Rat, the maximum blood pressure value was about 110 mmHg before administration,
About 6 seconds after administration, it changes to about 95 mmHg, about 2
It returned to the value before administration after 0 seconds. based on the above results,
It was confirmed that the fluctuation range of blood pressure depends on the concentration of the sodium chloride solution to be administered, and that the 2% sodium chloride solution is as large as about 23% of the value before the administration.

Example 2 0.9% sodium chloride solution
And H ₂ ¹⁷ O concentration of 5 atom% water as a solvent 0.9%
Preparation of Sodium Chloride Solution To 1.8 g of sodium chloride was added distilled water for injection to 100
It was made into mL and it was a 1.8% sodium chloride solution. 1.8
% Sodium chloride solution 0.5 mL and H ₂ ¹⁷ O concentration 2
0.25 mL of 0.2 atom% water and 0.25 mL of distilled water for injection were mixed to prepare a 0.9% sodium chloride solution using H ₂ ¹⁷ O concentration of 5 atom% water as a solvent.
Further, 0.5 mL of a 1.8% sodium chloride solution and 0.5 mL of distilled water for injection were mixed to prepare a 0.9% sodium chloride solution.

Example 3 Water having an H ₂ ¹⁷ O concentration of 5 atom%
T2 Relaxation of 0.9% Sodium Chloride Solution Using Solvent
Measurement of 0.9% sodium chloride solution obtained in Example 2 and H
₂ ¹⁷ For O concentration 5 atom% of each water 0.9% sodium chloride solution as a solvent, by adjusting the hydrogen ion concentration by bubbling argon gas and HCl gas, transverse relaxation time of the hydrogen protons in pH3~8 T2 was measured. The measurement is JNM manufactured by JEOL Ltd.
It was carried out by the CPMG method using a -FSE-60 type pulse NMR apparatus. Measuring temperature is 37 ℃, magnetic field strength is 1.5T
And Using the value of T2 obtained at each pH, the T2 relaxation degree per H ₂ ¹⁷ O 1 atom% was calculated by the following formula. T2 relaxation degree = (1 / T2A-1 / T2n) / (C-0.
037) T2A: H ₂ ¹⁷ O concentration 5 atom% of T2 water 0.9% sodium chloride solution as a solvent T 2 n: T2 0.9% sodium chloride solution C: H ₂ ¹⁷ O concentration 5 atom% of water and the solvent And 0.9
% From H ₂ ¹⁷ O concentration results obtained sodium chloride solution, the result of the H ₂ ¹⁷ O concentration 5 atom% of water to calculate the value of T2 relaxivity in 0.9% sodium chloride solution as a solvent Table 1 Shown in. From this result,
At pH 5.0 or higher, the value of T2 relaxation degree due to the scalar bond interaction between ¹⁷ O and hydrogen protons is 0.1
It was s ^-1 atom% ^-1 or more, and it was shown that a lateral relaxation time T2 shortening effect effective for image diagnosis was provided.

[Table 1]

[0022]

INDUSTRIAL APPLICABILITY According to the present invention, T2 is used in nuclear magnetic resonance imaging or nuclear magnetic resonance spectroscopy.
A nucleus containing a molecule containing a hydrogen atom directly bonded to a quadrupole nucleus as an active ingredient, which has a high degree of relaxation, has little effect on the living body even when a large amount of rapid administration is performed, and can obtain stable tissue perfusion information. It has become possible to provide a magnetic resonance imaging diagnostic agent.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kumiko Iwai             Chiba Prefecture Sodegaura City Kitasode 3 No. 1 Japan Mezif             Physics drug discovery laboratory F-term (reference) 4C085 HH07 JJ02 KB30 LL01                 4C096 AA11 AA13 AA17 AB01 AB46                       AB50 AD19 FC14

Claims (11)

[Claims] 1. A biocompatible aqueous solution containing, as an active ingredient, a molecule having a hydrogen atom directly bonded to a quadrupole nucleus, and the T2 relaxation degree of the aqueous solution is 0.1 s ^−1.
A nuclear magnetic resonance imaging agent characterized by having an atom% ^-1 or more. 2. A biocompatible aqueous solution containing, as an active ingredient, a molecule having a hydrogen atom directly bound to a quadrupole nucleus, and having the property of suppressing changes in biological information in rapid mass administration. A magnetic resonance imaging diagnostic agent characterized by: 3. A biocompatible aqueous solution containing a molecule having a hydrogen atom directly bonded to a quadrupole nucleus as an active ingredient and having a T2 relaxation degree of 0.1 s ^-1 atom% ^-1 or more. And a nuclear magnetic resonance imaging agent characterized by comprising an aqueous solution having the property of suppressing changes in biological information during rapid and large-scale administration. 4. The diagnostic agent for nuclear magnetic resonance imaging according to claim 2 or 3, wherein the change in biological information in the rapid and large-scale administration is blood pressure change, and the blood pressure change is less than 20%. 5. The nuclear magnetic resonance imaging method according to claim 1, wherein the biocompatible aqueous solution is an aqueous solution containing ions selected from biological components and salts thereof selected from biological components. Agent. 6. The nuclear magnetic resonance imaging diagnostic agent according to claim 5, wherein the ion selected from the biological components is an inorganic ion. 7. The nuclear magnetic resonance imaging diagnostic agent according to claim 5, wherein the ions selected from the biological components are sodium ions, potassium ions and calcium ions. 8. The ion selected from biological components is sodium ion, and the sodium ion is 0.09-
The nuclear magnetic resonance imaging diagnostic agent according to claim 5, which contains 0.26 mol / L. 9. The nuclear magnetic resonance imaging diagnostic agent according to claim 1, which has a pH of 5.0 to 8.5. 10. The quadrupole nucleus is ¹⁷ O, as claimed in claim 1.
The nuclear magnetic resonance imaging diagnostic agent according to any one of 1. 11. The nuclear magnetic resonance imaging diagnostic agent according to claim 1, wherein the active ingredient is H ₂ ¹⁷ O.