JPS5995288A - Novel radioactive iodospiroperidol and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is group shown by the formula II; X is radioactive iodine). EXAMPLE:[<125>I]-8-[4-( 4-Fluoro-2-iodophenyl )-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro [4,5]decan-4-one[(<125>I)-2-iodospiroperidol]. USE:A diagnostic of unclear medicine of dopamine acceptor, or radioactive drug. PROCESS:A 2-aminospiroperidol shown by the formula III is diazotized to give a diazo compound shown by the formula IV (Z<-> is halogeous ion, or HSO4<->), which is reacted with a radioactive metal iodide salt preferably at -5-30 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) C, where K represents a group represented by the formula, and X represents a radioactive iodine atom. ) The present invention relates to a novel radioactive 2-iodospiroperidol represented by Te and a method for producing the same.

The compound of the present invention is a new compound that has not been described in any literature, and has a high affinity for dopamine receptors, and is extremely useful as a nuclear medicine diagnostic agent for dopamine receptors and as a radiopharmaceutical. be.

In recent years, it has been discovered that the amount of dopamine receptors changes in brain pathological conditions (e.g. Parkinson's exposure, schizophrenia, etc.) compared to normal people, and the relationship between dopamine receptors and various brain diseases has been discovered. This relationship has been attracting attention in the fields of medicine and pharmacy.

Against this background, there is a strong desire for the emergence of nuclear medicine diagnostic agents and radiopharmaceuticals that target dopamine receptors.

The present inventors conducted research with the aim of developing dopamine receptor-directed diagnostic agents and radiopharmaceuticals that have radioactive iodine in their molecules, and found that the novel iodine compound represented by the general formula (I) found that it has high affinity and specifically binds to it. In addition, the compound (1) of the present invention is P-iodospiroperidol (J, Nuclear Medic.
ine.

2B (5), 100, (1982)), it has a much higher affinity for dopamine receptors, and has excellent properties as a radiodiagnostic agent and radiopharmaceutical directed toward dopamine receptors.

Therefore, by using the compound (I) of the present invention, not only can the presence of dopamine receptors in the human or animal brain and other organs and tissues be detected non-invasively, but also changes in the amount of receptors can be dynamically measured. It is very useful for nuclear medicine diagnosis and treatment of brain diseases, etc. It is also useful in this field because of the relationship between breast cancer and other cancers and dopamine receptors.

The method for producing the compound of the present invention will be explained below.

The compound of the present invention represented by the general formula (I) can be produced by a general synthesis method for radioactive iodine compounds, for example, according to Method A or Method B shown below.

[Method A]

An amino compound represented by the general formula (II) H2 (wherein K is as defined above) is mixed with an acid such as dilute sulfuric acid or dilute hydrochloric acid in a suitable solvent such as tetrahydrofuran, dioxane or acetonitrile. is reacted with an alkali metal nitrite salt in the presence of the general formula (m) (representing the anion shown) to form a diazonium salt.

Then, the compound (III) is reacted with a radioactive iodine metal salt to obtain the compound of the present invention represented by the general formula (I). This reaction was carried out at -5 to 30°C.The obtained compound (I) was subjected to thin layer chromatography (T
LC) or high performance liquid chromatography (HPLC)
It can be purified by general methods such as.

[Method B]

A halogen compound represented by the general formula (IV) (wherein k is as described above and Y represents a halogen atom) is dissolved in a suitable solvent such as acetonitrile, dimethylformamide, ethylene glycol, or ethylene glycol noether derivative. The exchange reaction with a radioactive iodine metal salt is carried out using a solvent such as , an ether derivative of diethylene glycol or water at a reaction temperature of 50 to 180°C. The obtained compound (I) can be purified by a common method such as TLC or HPLC.

In the present invention, radioactive iodine atoms include, for example, I
-128, I-125, 1-1111-182, etc. are exemplified, and 1-128 is preferred. The radioactive iodine metal salt means the above-mentioned metal salt of radioactive iodine, and its chemical form may be one that provides radioactive I ions, but is preferably an alkali salt such as sodium iodide, potassium iodide, or lithium iodide. It is a metal salt. General formula (
Examples of the halogen ion in m) include anions such as chlorine, bromine, and iodine, and examples of the halogen atom in general formula (Iv) include fluorine, chlorine, bromine, and iodine atoms. can.

The radioactive 2-iodospiroperidol (I) obtained according to the present invention is intravenously injected into a patient, and a scintigram is taken over time or the radioactivity is measured by a probe method, and the compound (I) is injected into a specific organ. By measuring the uptake, it is possible to easily and accurately diagnose the site range of the lesion and the degree of the disease.

In addition, the radioactive 2-iodospiroperidol according to the present invention is useful for diagnosing brain diseases and breast cancer, and is also useful for diagnosing and treating various other diseases caused by changes in dopamine receptors.

The present invention will be explained in more detail with reference to Examples below.

Reference example 8-44- (4-fluoro-2-iodophenyl)-
4-oxobutyl]-1-phenyl 1.8.8-triazaspiro[4,5]decane-4-one (2-iodospiroperidol)
- Suspend in hydrochloric acid and acetonitrile, and add dropwise an aqueous solution of sodium nitrite (95rIIg) under water cooling. 5℃
After stirring for 80 minutes, an aqueous solution of potassium iodide (166~) is added dropwise to the resulting diazonium salt under water cooling. After the dropwise addition, the mixture was stirred at the same temperature for 1.5 hours. After the reaction, the mixture is made alkaline, extracted with a solvent, and the solvent is distilled off to obtain a crude product.

This product is purified by silica gel column chromatography to obtain 2-iodospiroperidol (427W).

Melting point = 170-175°C IR (CHCL3) crn: 1710 (C = 0) /
H-NMR (CDC28)S (ppm): 1.
40-8.18 (14H, m, methylene) 4.72
(2H,s, -HNCH2N'l: )6.81~7
．． 79 (8H, m, benzene ring H) mass spectrum (70eV) m/e: 521[:fly], 24
4 Example 1 [IF-8-[4-fluoro-2-iodophenyl]
-4-oxobutyl]-1-phenyl-1,8,8-triazaspiro[4°5]decane-4-one ([IF-2
-Iodospiroperidol) production using 2-aminospiroperidol (40μg)
A diazonium salt prepared using sulfuric acid and sodium nitrite was reacted with Na I (2 mCi) under ice cooling in the same manner as in the reference example, and the resulting crude product was analyzed using HPLC (column: Licrosorb RP-18). [125112-iodospiroperidol (1,4m
C1) is obtained. The TLC and HPLC Rf values of the ice crystals matched those of the specimen obtained in the reference example.

Example 2 Preparation of [128I]2-iodospiroperidol using Na I [IF-2-iodospiroperidol (
1,4mC1) is obtained. The TLC and HPLC Rf values of the crystal matched those of the standard sample obtained in the reference example.

Example 8 Production of 2-iodospiroperidole [1251] by exchange method. Dimethylformamide (10 aL) was added to 2-iodospiroperidol (8 μIn) synthesized by the method of Reference Example.
, Na”I (2,2mCi) was added, and a trace amount of 0.I
Add N sulfuric acid and heat.

After the reaction, the crude product was purified by HPLC, [126I]
-2-iodospiroperidol (Q, 9 mCi) is obtained. The ice crystals were determined by TLC and HPLC (7). The Rf value was consistent with the specimen obtained in the reference example.

7

Claims (1)

[Claims] (1) In the general formula C, R represents a group represented by the formula, and X represents a radioactive iodine atom. ) Radioactive 2-iodospiroperidol. (2) X is l-128, l-125, l-181. The radioactive iodine according to claim 1, which is an atom selected from the group of radioactive iodine isotopes consisting of 1-182.
Iodospiroperidol. (8) General formula (wherein, K represents a group represented by the formula) obtained by diazotizing 2-aminospiroperidol (wherein the technique is as described above, Z - represents a halogen ion or an anion represented by the formula H3O4-. represents a radioactive iodine atom.) A method for producing radioactive 2-iodospiroperidol represented by: (4) A method characterized by carrying out an exchange reaction of 2-halogenospiroperidol represented by the general formula (in the formula, Y represents a halogen atom and 艮 represents a group represented by the formula) with a radioactive iodine metal salt. A method for producing radioactive 2-iodospiroperidol represented by the general formula (wherein k is as described above and X represents a radioactive iodine atom).