WO2003028769A1

WO2003028769A1 - Diagnostic reagent for nuclear magnetic resonance imagination

Info

Publication number: WO2003028769A1
Application number: PCT/JP2002/009872
Authority: WO
Inventors: Akihiro Otsuka; Akira Nakatani; Kumiko Iwai
Original assignee: Nihon Medi-Physics Co., Ltd.
Priority date: 2001-09-28
Filing date: 2002-09-25
Publication date: 2003-04-10
Also published as: JP2003102698A

Abstract

A diagnostic reagent for nuclear magnetic resonance imagination, characterized in that it is an aqueous solution being acceptable to an organism and containing, as an active component, a molecule having a hydrogen atom bonded directly with a quadrupole nucleus, wherein the aqueous solution exhibits a T2 relaxation degree of 0.1 s-1atom%-1 or more. The diagnostic reagent for nuclear magnetic resonance imagination has an enhanced T2 relaxation degree and exhibits a little effect on an organism even when administrated rapidly in a large amount, and thus can be used for obtaining stable information on the tissue perfusion in nuclear magnetic resonance imaging or nuclear magnetic resonance spectroscopy.

Description

Description Nuclear magnetic resonance imaging diagnostics Technical field

The present invention relates to a diagnostic agent for nuclear magnetic resonance imaging capable of obtaining tissue perfusion information in a living body in a nuclear magnetic resonance diagnosis such as nuclear magnetic resonance imaging or nuclear magnetic resonance spectroscopy.

Background art

Conventionally, diagnosis of tissue perfusion information in a living body, for example, blood flow information of the brain, liver, kidney, muscle, and even tumors, has been performed using various radioisotopes or radiopharmaceuticals as a contrast agent. It is performed by positron emission computed tomography (PET) or single photon emission computed tomography (S PECT). However, these methods have problems such as the possibility of exposure to radiation due to the use of radioactive elements, and the fact that the supply of radioactive elements must be based on production by a reactor / cyclotron. . There is also a limitation on use that the actual diagnosis must be made in a radioactively controlled area.

Diagnosis of tissue perfusion without using radioactive elements, such as a method for measuring cerebral blood flow, includes nuclear magnetic resonance imaging using a paramagnetic metal complex or iron oxide particles as a contrast agent. After these contrast agents are injected into the body from the blood vessels, the movement from the blood vessels into the fibrous tissue is slow and gradually distributed. Therefore, the ratio of the contrast medium into the tissues by a single circulation (Extraction Fraction) Is less than 1. As such a detection查方that overcomes the drawbacks include test查法by PET using ^{1 5} 0- H ₂ 0. In this test method, the Extraction Fraction is closest to 1, and is considered to be the standard method for cerebral blood flow tests. However, since this method also uses radioisotopes, there are the above-mentioned problems such as exposure to radiation and restrictions on use. On the other hand, regarding the proton of the hydrogen atom directly bonded to the quadrupole nucleus such as ¹⁴ N, ³³ S, ¹⁷ O, etc., the scalar bond interaction between the quadrupole nucleus and the hydrogen proton causes By taking advantage of the phenomenon that the transverse relaxation time (T 2) of hydrogen protons and the longitudinal relaxation time (T ip) of the rotating coordinate system are shortened, it is possible to obtain contrast in nuclear magnetic resonance imaging. It is known that there is. Specifically, utilizing this phenomenon, the biodistribution and concentration of water and concentrated water obtained by replacing the oxygen in the molecule ^{_{^{1 7 O (H 2 1 7}}} 0), nuclear magnetic where the protons of the hydrogen atom and detection nuclei Detection by resonance imaging makes it possible to measure tissue perfusion information in a living body. This method overcomes supply, radiation exposure, Usage limits, the TeiHiroshi for of the test device of the constraints and going on, administered compound in performing inspection by PET with "O-H ₂ O as described above It is noted as something to do.

In nuclear magnetic resonance imaging using the proton of the hydrogen atom as a detection nucleus, quadrupolar nuclei, which are stable isotopes, are elements having a low natural abundance ratio. It is necessary to administer a relatively large amount of a concentrated polar nucleus into the body. For example, in order to use the water was concentrated H ₂ ^{1 7} O as MR I contrast agents, need to be administered several hundred m L over tens m per adult human. Also, in order to obtain tissue perfusion information in the living body, it is necessary to know the distribution dynamics of the administered nuclear magnetic resonance imaging agent.Therefore, it is necessary to administer the contrast agent relatively quickly, that is, to administer B o 1 us. is there.

However, when a relatively large amount of an injection is administered with B o 1 us, biological information such as blood pressure and heart rate may fluctuate, and furthermore, such biological information fluctuates, which can be obtained by diagnostic imaging. Tissue perfusion information may change. For example, in the case of cerebral blood flow, it is known that the blood vessel diameter changes with fluctuations in blood pressure because a mechanism that keeps the blood flow velocity constant works. As a result, a change in cerebral blood flow occurs. On the other hand, when the blood pressure fluctuation is large, the mechanism for keeping the blood flow velocity constant becomes ineffective, and the blood flow velocity itself fluctuates. As another example, in the case of myocardial blood flow, when acquiring a new magnetic resonance image by cardiac synchronization, the timing of the cardiac synchronization changes due to a change in the heartbeat, and the information of the collected diagnostic image itself is lost. It is known that it will be different from normal. If such changes in biological information occur, accurate diagnosis of myocardial blood flow becomes impossible. That is, due to the fluctuation of biological information accompanying the rapid mass administration of the contrast agent as described above, the tissue perfusion information in the living body changes. As a result, tissue perfusion information that does not reflect the state before administration of the diagnostic agent may be obtained. Therefore, it is necessary to minimize the effect of perturbation of biological information on diagnostic imaging.

Indeed, as an example of the administration of water was concentrated H ₂ ^{1 7} 0 blooded animal, several reports have been made. The Ho Pkins like using a phenomenon that the relaxation time of the hydrogen protons is shortened by the scalar coupling interaction described above, Mo ngoliangerbi 1 s cerebral infarction model H ₂ ¹ 'O concentration. 41 to 50 the atom% of the water, Amount equivalent to 0.6% to 2% of body weight (converted to human: 360 to 1,200 mL) is intraperitoneally administered, and the infarcted area is detected by T2-weighted spin echo method (A. Hopkins et al.) .Magn. Reson. Med., 22, 167, 1991). Further, Ta i 1 or the like is H ₂ ^{1 7} 〇 concentration 29 at om% water 0. 2 mL (converted to human: 48 mL) was administered in the carotid artery in rats, the brain by T lp disperser Ji Yeon method is calculated the H ₂ ^{1 7} 0 concentration (9th ISMRM 18th ESMRMB joint annual meeting , Pro Inth. Soc. Mag. Reson. Med 9, 356, 2001).

However, any in these reports are also administered the water was concentrated H ₂ ^{1 7} 0 as a large amount, does not consider the problems of clinical diagnosis utilizing such effects on the living body by a large dose as described above, There remains a problem as a method for performing image diagnosis of accurate tissue perfusion information. Further, in the report by T Ailor etc., in order to efficiently distribute the water was concentrated H ₂ ^{1 7} 0 to the target tissue, it is performed in a class arterial administration in smaller dose as compared with reports of such Ho Pkins However, this method is problematic in clinical applications where it is necessary to avoid invasive burden on the patient.

Furthermore, Ro nen, etc., physiological saline solution containing H ₂ ^{1 7} O concentration. 41 to 50 the atom% of the water, and administered intravenously to rats, the blood H ₂ ^{1 7} O concentration by ¹⁷ O nuclear irradiation combined method (I. Ronen et al., Proc. Natl. Acad. Sci. USA., 95, 12934, 1998). In this report, although physiological saline was used, as in the above-mentioned report, it merely measured the ⁷ O concentration in blood after administration, and tissue perfusion of animals by administration of a contrast agent was performed. No consideration is given to changes in information. Moreover, none of the above-mentioned documents considers the application of a contrast agent having a high T2 relaxivity, which is effective for image diagnosis, since it does not consider the application to actual clinical diagnosis. Not being discussed.

Use of this manner, typified by water was concentrated H ₂ ^{1 7} 〇, as a contrast medium for nuclear magnetic resonance imaging agent which comprises, as an active ingredient a molecule containing quadrupolar nuclei and hydrogen atoms bonded directly The form will need to be administered to the organism in large quantities and rapidly. However, up to now, changes in biological information such as up-and-down fluctuations in blood pressure, fluctuations in heart rate, irregularities, etc., which are expected due to usage patterns such as rapid mass administration of the diagnostic imaging agent, and these biological information No studies have been conducted to suppress changes in tissue perfusion information due to the change. Similarly, no study has been conducted on such a contrast agent having a T 2 relaxation that is effective for diagnostic imaging in clinical applications.

Disclosure of the invention

In view of this situation, the present invention provides a quadrupolar nucleus for nuclear magnetic resonance diagnosis, which has a high T 2 relaxivity and has little effect on the living body even when a large amount is administered rapidly, and thus can obtain stable tissue perfusion information. It is an object of the present invention to provide a nuclear magnetic resonance imaging diagnostic agent comprising a molecule having a hydrogen atom directly bonded to a nuclear magnetic resonance imaging agent.

The present invention is a raw i ^ m-soluble aqueous solution containing, as an active ingredient, a molecule having a hydrogen atom directly bonded to a quadrupole nucleus in the molecule, and the aqueous solution has a T 2 relaxation of 0.1 s. — ¹ atom ^ / o— Provides a nuclear magnetic resonance diagnostic imaging agent characterized by being ¹ or more.

Further, the present invention is a biocompatible aqueous solution containing as an active ingredient a molecule having a hydrogen atom directly bonded to a quadrupolar nucleus in a molecule, and is capable of transforming biological information in rapid mass administration. Provided is a diagnostic agent for nuclear magnetic resonance imaging characterized by having a suppressing property.

According to the present invention, it is possible to obtain stable tissue perfusion information with high T 2 relaxation and little effect on a living body even when a large amount is rapidly administered in nuclear magnetic resonance imaging or nuclear magnetic resonance spectroscopy. It is possible to provide a nuclear magnetic resonance imaging diagnostic agent containing, as an active ingredient, a molecule containing a hydrogen atom directly bonded to a quadrupolar nucleus.

BEST MODE FOR CARRYING OUT THE INVENTION

The nuclear magnetic resonance imaging diagnostic agent according to the present invention comprises water directly bonded to a quadrupolar nucleus in the molecule. A nuclear magnetic resonance imaging diagnostic agent comprising a biocompatible aqueous solution containing a molecule having an elemental atom, wherein the aqueous solution has a T 2 relaxation of at least 1 s—to myo— ¹ . It is.

Further, the nuclear magnetic resonance imaging diagnostic agent of the present invention is a biocompatible aqueous solution containing, as an active ingredient, a molecule having a hydrogen atom directly bonded to a quadrupolar nucleus. It is a nuclear magnetic resonance imaging diagnostic agent characterized by having the property of suppressing the change of the nuclear magnetic resonance.

The quadrupolar nuclei ^{^{1 4 N, 3 3 S,}} 1 7 0 and the like, binding of the quadrupolar nuclei and hydrogen atoms, such as alcohols, primary OH bond of sugars及Pi water, one NH amino acids Bonding, one SH bonding of some amino acids including cysteine, and the like. The aqueous solution having bioacceptability is an aqueous solution containing a pharmaceutically acceptable component, preferably an ion having bioacceptability selected from biological components, and a salt thereof selected from biological components. It is. Pharmaceutically acceptable components include various sugars and various amino acids, etc., and bio-tolerant ions selected from biological components and salts thereof selected from biological components. Examples of ionic species having bioacceptability include inorganic ions such as sodium ion, potassium ion, calcium ion and hydrogen ion, and organic ions such as carbonate. More preferably, it is selected from inorganic ions.

As an example of the composition of a preferred magnetic resonance imaging agent, for example, in water containing H ₂ ^{1 7} 0 as an active ingredient, 0. 0 9~0. 2 6 mo 1 / L Natoriumuio down added, A composition in which the hydrogen ion concentration is adjusted to 5.0 to 8.5 in terms of pH is exemplified.

With such a composition, it is possible to suppress the change in the tissue perfusion information in the living body due to the suppression of the change in the biological information. In addition, it is suitable for diagnostic imaging that the reduction rate of T2 relaxation time (ms) per atom% of quadrupolar nucleus, that is, the T2 relaxation degree is 0.1 IS- ¹ atom% ^-1 or more. A nuclear magnetic resonance imaging diagnostic agent exhibiting a value can be obtained.

The dosage and administration rate of the nuclear magnetic resonance imaging agent in the present invention are within the range that can achieve the object of the present invention, and the enrichment or measurement of the quadrupolar nucleus contained in the imaging agent can be performed. It can be appropriately selected according to the type of nuclear magnetic resonance imaging used as a means. For example, it is usually necessary to administer tens to hundreds of mL of an MRI contrast agent per adult, but such an amount of the drug is rapidly administered to a living body, that is, even if a large amount is administered, biometric information is not obtained. It is preferable that the agent does not affect the change as a diagnostic agent for nuclear magnetic resonance imaging. Here, rapid large dose administration usually means administration of several tens to several hundred ml of a drug per adult 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 at less than 20% even when a rapid mass 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 target information. For example, for arteries and veins, administration may be carried out from the indwelling force table. Preferably, intravenous administration or the like is performed.

The diagnostic agent for nuclear magnetic resonance imaging of the present invention is used for nuclear magnetic resonance imaging using protons as detection nuclei, nuclear magnetic resonance imaging using nuclear quadrupoles containing active ingredient molecules as detection nuclei, or nuclear magnetic resonance spectroscopy. By monitoring the distribution, the distribution can be monitored and used to detect necessary biological information. The sequence used for imaging is not limited to any method as long as it is selected from an imaging method that reflects the T 2 or T lp relaxation time of protons, and can be appropriately selected according to the purpose. For example, a spin echo method T2 emphasis method, various T1p emphasis methods, and the like are selected.

Example

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Reference Example 1 Measurement of changes in biological information of rats by aqueous solution of calcium chloride

Distilled water for injection was added to 1.65 g of Shiridani calcium dihydrate to make exactly 10 OmL, and a 1.2% Shiridani calcium solution was prepared. The prepared 1.2% calcium chloride solution (lmL) was rapidly administered to an SD rat (oss, 8 weeks old) from a femoral vein catheter over about 3 seconds to examine changes in blood pressure and heart rate. The blood pressure and the heart rate were measured invasively from the femoral artery using a blood pressure measurement unit AP-641 G and a heart rate meter AT-601 G manufactured by Nihon Kohden Corporation. As a result, the value of systolic blood pressure increased from about 10 OmmHg before administration to about 150 mmHg over about 6 seconds after administration. Also, about 16 seconds after the equilibrium was almost reached, the systolic blood pressure was about 120 mmHg, and the blood pressure increased about 20% from that before administration. From the above results, it became clear that the rapid administration of the 1.2% calcium salt solution changed the biological information.

Reference Example 2 Measurement of changes in biological information of rats by administration of aqueous sodium chloride solution

Water for injection was added to 0.9 g of Shiridani sodium to make exactly 10 OmL, and a 0.9% Shiridani sodium solution was prepared. 1 mL of the prepared 0.9% sodium chloride solution was rapidly administered to an SD rat (oss, 8 weeks old) from a femoral vein catheter for about 3 seconds to examine changes in blood pressure and heart rate . The blood pressure and the heart rate were measured invasively from the femoral artery using a blood pressure measurement unit AP-641 G and a heart rate monitor AT-601 G manufactured by Nihon Kohden Corporation.

In rats treated with 0.9% sodium chloride solution, the value of systolic blood pressure changed from about 10 OmmHg before administration to about 9 OmmHg for about 3 seconds after administration, but gradually recovered. After about 10 seconds, it returned to the value before administration. Example 1 Measurement of changes in biological information of rats by administration of sodium salt solution

Water for injection was added to 15 g of sodium chloride to make exactly lOOmL, and a 15% sodium chloride solution was prepared. Separately, water for injection was added to 10 g of sodium salt solution to make exactly 100 mL, and a 10% sodium chloride solution was prepared. Water for injection was added to 2 mL of a 10% sodium chloride solution to make exactly 1 OmL, thereby obtaining a 2% sodium chloride solution. Further, water for injection was added to 1 mL of a 15% sodium chloride solution to make exactly 10 mL, thereby obtaining a 1.5% sodium chloride solution. Transfer 1.4 mL each of the prepared 2% sodium chloride solution and 1.5% sodium chloride solution to separate SD rats (oss, 18 weeks old, about 500 g), and thigh The drug was rapidly administered from an intravenous catheter over about 3 seconds, and the changes in blood pressure and heart rate were examined. Blood pressure and heart rate were measured openly from the femoral artery using a blood pressure measurement unit AP-641G and a heart rate meter AT-601G manufactured by Nihon Kohden Corporation.

In rats administered 2% sodium chloride solution, the value of systolic blood pressure fluctuated from about 11 OmmHg before administration to about 85 mmHg over about 10 seconds after administration. After about 20 seconds, the value had recovered to the value before administration. On the other hand, in rats to which 1.5% sodium chloride solution was administered, the value of systolic blood pressure changed from about 11 OmmHg before administration to about 95 mmHg for about 6 seconds after administration, and about 20 seconds after administration. Had recovered to the value of Based on the above results, the range of fluctuation of blood pressure depends on the concentration of the sodium chloride solution to be administered, and the value of the 2% sodium salt solution was as large as about 23% of the value before administration. confirmed.

Example 2 0.9% sodium chloride solution and H ₉ ¹⁷ . Preparation of 0.9% sodium chloride solution using 5 atom% water as solvent

Distilled water for injection was added to 1.8 g of sodium salt and made up to lOOmL to prepare a 1.8% sodium chloride solution. 0.5 mL of 1.8% salted sodium solution, 0.25 atom% of water with 0.22 atom% H ₂ ¹⁷ O and 0.25 mL of distilled water for injection were mixed, and H ₂ ¹ A 0.9% sodium chloride solution was prepared using water having a ⁷ O concentration of 5 atom% as a solvent. In addition, 0.5 mL of a 1.8% sodium salt solution and 0.5 mL of distilled water for injection were mixed to prepare a 0.9% sodium salt solution.

Example 3 H _-? ⁷ O concentration 5 the atom% of water measurements of the T 2 relaxation degree of 0.9% chloride sodium solution with a solvent

0.9% sodium chloride solution and H ₂ ¹⁷ O concentration obtained in Example 2

The hydrogen ion concentration was adjusted by bubbling argon gas and HC1 gas for each 0.9% sodium chloride solution using 5 atom% water as the solvent, and the transverse relaxation time of hydrogen protons at pH 3 to 8 T2 was measured.

The measurement was performed by a CMPG method using a JNM_FSE-60 type pulse NMR apparatus manufactured by JEOL Ltd. The measurement temperature was 37 ° C and the magnetic field strength was 1.5 T. Using the values of T 2 determined at each pH, it was calculated H ₂ ^{1 7} 〇 1 at om% per Rino the T 2 relaxation degree by the following equation. ·

Τ2 relaxivity = (1 / T 2 A- 1 / T 2 n) / (C-1 0.037)

Τ 2 A: T 2 of 0.9% sodium chloride solution using H ₂ O concentration 5 atom% water as solvent

T 2 n: T 2 of 0.9% sodium chloride solution

C: 0.9% sodium chloride dissolved in water with an H ₂ ¹⁷ O concentration of 5 atom% H ₂ ¹⁷ O concentration of liquid

From the results obtained, H ₂ ¹⁷ . Table 1 shows the results of calculating the value of T 2 relaxation in a 0.9% sodium chloride solution using water having a concentration of 5 atom% as a solvent. From this result, the p H 5. 0 or more, the value of the T 2 relaxation degree of the scalar binding interaction between the ^{1 7} 0 and hydrogen ^{protons, 0. 1 s- 1 at om%} - becomes ¹ or more, It was shown that the lateral relaxation time T2, which is effective for diagnostic imaging, can be reduced.

table 1

T 2 relaxivity in 0.9% sodium chloride solution using H ₂ ¹⁷ O concentration 5 atom% water as solvent

Hydrogen ion

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.0 Concentration (pH)

T 2 relaxation

0.88 1.1 0.92 0.93 0.95 0.49 0.17 0.038 0.017 0.0054 s atom%

Claims

The scope of the claims

1. 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 aqueous solution has a T 2 relaxation of 0.1 Is— ¹ atom%. ^A diagnostic agent for nuclear magnetic resonance imaging characterized by being at least ^one .

2. A biocompatible aqueous solution containing, as an active ingredient, a molecule having a hydrogen atom directly bonded to a quadrupole nucleus in its molecule, and has the property of suppressing changes in biological information during rapid mass administration. Nuclear magnetic resonance imaging diagnostic agent.

3. A biocompatible aqueous solution containing a molecule having a hydrogen atom directly bonded to a quadrupolar nucleus as an active ingredient and having a T2 relaxation of 0.1 s- ¹ atom% ^-1 or more. A nuclear magnetic resonance imaging diagnostic agent comprising an aqueous solution having a property of suppressing the change of biological information during rapid mass administration.

4. The diagnostic agent for nuclear magnetic resonance imaging according to claim 2, wherein the change in biological information upon rapid mass administration is a blood pressure fluctuation, and the blood pressure fluctuation is less than 20 ° / o.

5. The nuclear magnetic resonance imaging diagnostic agent 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.

6. The nuclear magnetic resonance imaging diagnostic agent according to claim 5, wherein the ion selected from the biological component 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 a sodium ion, a potassium ion, and a potassium ion.

8. The nuclear magnetic resonance imaging diagnostic agent according to claim 5, wherein the ion selected from the biological component is a sodium ion, and the sodium ion is contained in the range of 0.09 to 0.26 mO1 / L.

9. The diagnostic agent for nuclear magnetic resonance imaging according to any one of claims 1 to 8, wherein the pH is 5.0 to 8.5.

10. The nuclear magnetic resonance image according to any one of claims 1 to 9, wherein the quadrupolar nucleus is ¹⁷ mm.

11. active ingredients nuclear magnetic according to any of claims 1 a H ₂ ^{1 7} 〇 1 0 Resonance diagnostic imaging agent.