JP2014122177A - Method of producing radioactive iodine labeling precursor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique which can prevent mixing of non-radioactive iodine compounds into a labeling precursor of iodometomidate.SOLUTION: A method of producing a radioactive iodine labeling precursor includes a step to synthesize a labeling precursor of radioactive iodine-labeled iodometomidate from 1-[1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylic acid methyl ester.

Description

  The present invention relates to a method for producing a radioiodine labeled precursor.

  Primary aldosteronism (PA) is known as a disease that develops due to abnormal adrenal glands. Primary aldosteronism is a disease that causes hypertension and hypokalemia due to excessive production of aldosterone by a tumor in the adrenal cortex. Many primary aldosteronisms have tumors on either the right or left side, and surgery is possible on one side, while treatment with pharmacotherapy is used on both sides. Therefore, when primary aldosteronism develops, a local diagnosis of whether the tumor is on one side or on both sides is necessary to determine the treatment strategy.

  As this localization diagnosis, computed tomography (CT), adrenal scintigraphy using adosterol, and adrenal vein sampling (AVS) are used.

  However, functional diagnosis is not possible in principle in CT. Therefore, it is impossible to distinguish nonfunctional adenoma from aldosterone-producing adenoma even if a lesion is found in the adrenal gland.

  In addition, adrenal scintigraphy using adsterol is complicated because it requires pretreatment with dexamethasone and the test period is long. In addition, in recent years, it has been clarified that the accumulation of adosterol in adrenal scintigraphy depends on the size of adrenal adenoma rather than the ability to produce aldosterone. Therefore, the diagnostic method using adosterol is considered to be extremely low in accuracy as a PA local diagnosis (Non-patent Document 1).

  At the time of this application, AVS is regarded as the gold standard for confirming the site of aldosterone hypersecretion lesions (Non-patent Document 2). However, AVS is a method of collecting blood by inserting a catheter into the adrenal vein, which imposes a heavy burden on the patient side, such as requiring hospitalization and anesthesia, and requires advanced techniques on the part of the doctor.

Therefore, in recent years, attempts have been made to image adrenal adenomas by single photon tomography (SPECT) or positron emission tomography (PET) aiming at local diagnosis of noninvasive aldosterone-producing adenoma instead of AVS. For example, Non-Patent Document 3 describes that an adrenal adenoma was imaged with ¹²³ I-labeled iodomethomidate. Non-Patent Document 3 also reports that ¹²³ I-labeled iodomethomidate has higher selectivity for steroid 11β-hydroxylase (CYP11B1) than aldosterone synthase (CYP11B2).

  As a method for synthesizing radioactive iodomethomidate, a method of performing a radioiodination reaction using trimethylstannylated metomidate as a labeling precursor is known (Non-patent Document 4). Non-patent document 5 also reports on a method for synthesizing trimethylstannylated metomidate.

Nomura K, et al. The Journal of Clinical Endocrinology & Metabolism, 1990, Vol. 71, p. 825-830 Nishikawa T, et al. , Endocrine Journal, 2011, Vol. 58, no. 9, p. 711-721 Stefanie Hahner, et al. , Journal of Clinical Endocrinology & Metabolism, 2008, Vol. 93, no. 6, p. 2358-2365 A. Schirbel et al. Radiochim. Acta, 2004, 92, Vol. 92, p. 297-303 Friedrich Hammerschmidt et al. , Monatshefte fur Chemie, Vol. 136, p. 229-239

  However, in the methods described in Non-Patent Documents 4 and 5, the labeling precursor trimethylstannylated metomidate is obtained by an iodine-tin exchange reaction using non-radioactive iodomethomidate. Therefore, only by purification by recrystallization of Non-Patent Document 4 or purification by flash column chromatography of Non-Patent Document 5, non-radioactive iodomethomidate as a raw material or non-product generated as a by-product is used as a labeling precursor. Radioiodine compounds are mixed. When a radioiodination reaction is performed with a labeled precursor mixed with a nonradioactive iodine compound, a radioiodine labeled iodomethomidate coexisting with the nonradioactive iodometomidate is obtained. Therefore, when the accumulation in the steroid 11β-hydroxylase is evaluated by the radioactive iodomethomidate obtained by the methods of Non-Patent Documents 4 and 5, problems such as a decrease in quantitative accuracy and an increase in dose occur.

  This invention is made | formed in view of the said situation, and is providing the technique which can prevent mixing of nonradioactive iodine compounds, such as a nonradioactive iodomethomidate, with respect to the labeled precursor of iodomethomidate.

  According to the present invention, a step of synthesizing a radioiodine-labeled precursor represented by the following general formula (1) from methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate A process for producing a radioiodine labeled precursor is provided.

[In the formula, R is an integer having 1 to 6 carbon atoms in the alkyl chain and is a substituted or unsubstituted trialkylstannyl group or a substituted or unsubstituted triphenylstannyl group. ]

According to the present invention, a radioiodine-labeled precursor represented by the above general formula (1) is synthesized from methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate. And a process of
Synthesizing a radioiodine compound represented by the following general formula (2) from the radioiodine labeled precursor;
A method for producing a radioactive iodo compound is provided.

[In formula, X is a radioactive iodine atom. ]

  According to the present invention, stannylated metomidate is synthesized as a labeled precursor of radioactive iodomethomidate by bromine-tin exchange reaction, and a non-radioactive iodo compound is not used in the synthesis system of the labeled precursor. It is possible to obtain a labeled precursor of radioactive iodomethomidate that is not contaminated with an iodo compound.

It is a figure which shows an example of the manufacturing method of the labeling precursor of the radioiodine labeled iodoetomidate which concerns on this invention, and a non-radioactive iodoetomidate. It is a figure which shows an example of the manufacturing method of a radioiodine label iodoetomidate.

  Methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate is a compound represented by the following formula.

  1- [1- (4-Bromophenyl) ethyl] -1H-imidazole-5-carboxylate uses triphenylphosphine and azodicarboxylic acid ester and 1- (4-bromophenyl) ethanol and 4- It can be obtained by dehydration condensation with methyl imidazolecarboxylate.

  By using (S) -1- (4-bromophenyl) ethanol, methyl (R) -1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate can be obtained. . Also, by using (R) -1- (4-bromophenyl) ethanol, methyl (S) -1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate is obtained. Can do.

  Examples of the azodicarboxylic acid ester include diethyl azodicarboxylate, dibenzyl azodicarboxylate, dimethyl azodicarboxylate, diisopropyl azodicarboxylate, bis (2,2,2-trichloroethyl) azodicarboxylate, and bis (2 -Methoxyethyl) or di-tert-butyl azodicarboxylate.

  The dehydration condensation of 1- (4-bromophenyl) ethanol and methyl 4-imidazolecarboxylate is preferably carried out in a solvent, and as the solvent, for example, an organic solvent such as dichloromethane or tetrahydrofuran (THF) is used. Can do.

  1- [1- (4-Bromophenyl) ethyl] -1H-imidazole-5-carboxylate can synthesize stannylated metomidate represented by the above general formula (1) by bromine-tin exchange reaction. it can.

In the bromine-tin exchange reaction, a ditin compound represented by [Sn (R ¹ ) ₃ ] ₂ or a tin hydride compound represented by (R ² ) ₃ SnH can be used in the presence of a palladium catalyst. Wherein, R ¹ and R ² are integers from 1 to 6 carbon atoms, a substituted or unsubstituted alkyl group, or a phenyl group.

The bromine-tin exchange reaction of methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate is preferably 1- [1- (4-bromophenyl) ethyl] -1H— It can be an alkylstannylation reaction of methyl imidazole-5-carboxylate. In this alkylstannylation reaction, as a ditin compound, R ¹ is an integer having 1 to 6 carbon atoms, a substituted or unsubstituted alkyl group, preferably an integer having 1 to 4 carbon atoms, A ditin compound which is a substituted alkyl group can be used. Further, as the tin hydride compound, R ² is an integer having 1 to 6 carbon atoms and is a substituted or unsubstituted alkyl group, preferably an integer having 1 to 4 carbon atoms, and an unsubstituted alkyl group. Certain tin hydride compounds can be used. Thereby, R in the general formula (1) is an integer having 1 to 6 carbon atoms in the alkyl chain, and a substituted or unsubstituted trialkylstannyl group, preferably an alkyl chain having 1 to 4 carbon atoms. A stannylated metomidate can be synthesized which is an integer of and an unsubstituted trialkylstannyl group.

  Examples of the ditin compound include hexamethyldistin, hexaethyldistin, hexabutyldistin, hexaphenyldistin, hexa (4-chlorophenyl) distin, hexa (4-fluorophenyl) distin, and hexatolyldistin. Can be used.

  As the tin hydride compound, for example, trialkyltin hydride such as tributyltin hydride, triphenyltin hydride, or the like can be used.

  As the palladium catalyst, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), or the like can be used.

  The bromine-tin exchange reaction of methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate is preferably carried out in the presence of a base. As the base, trialkylamines such as triethylamine and triisopropylamine can be used.

  The bromine-tin exchange reaction of methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate is preferably carried out in a solvent, and an organic solvent such as toluene is used as the solvent. be able to.

  (R) -1- [1- (4-Bromophenyl) ethyl] -1H-imidazole-5-carboxylate is used to perform bromine-tin exchange reaction, which is represented by the following general formula (11). (R) stannylated metomidate can be obtained.

In general formula (11), R is an integer having 1 to 6 carbon atoms in the alkyl chain, and is a substituted or unsubstituted trialkylstannyl group or a substituted or unsubstituted triphenylstannyl group.

  Further, by performing bromine-tin exchange reaction using methyl (S) -1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate, the following general formula (12) The (S) stannylated metomidate represented can be obtained.

In General Formula (12), R is an integer having 1 to 6 carbon atoms in the alkyl chain, and is a substituted or unsubstituted trialkylstannyl group or a substituted or unsubstituted triphenylstannyl group.

  The compound represented by the general formula (1) can be used as a labeling precursor of radioiodine-labeled iodomethomidate. That is, the radioiodine labeled iodomethomidate represented by the following general formula (2) can be obtained by subjecting the compound represented by the general formula (1) to a radioiodination reaction.

By subjecting the compound represented by the general formula (11) to a radioiodination reaction, an (R) -form radioiodine labeled iodomethomidate represented by the following general formula (21) can be obtained.

  In addition, by subjecting the compound represented by the general formula (12) to a radioiodination reaction, an (S) -form radioiodine labeled iodomethomidate represented by the following general formula (22) can be obtained.

In the general formulas (2), (21) and (22), X is a radioactive iodine atom, and X is preferably ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I.

  The radioiodination reaction can be performed by reacting an alkali metal radioiodide and an oxidizing agent under acidic conditions. As the alkali metal radioactive iodide, for example, a sodium compound of radioactive iodine or a potassium compound of radioactive iodine can be used. As the oxidizing agent, for example, chloramine-T, hydrogen peroxide solution, peracetic acid, N-chlorosuccinimide, N-bromosuccinimide and the like can be used.

  The radioiodine-labeled iodomethomidate synthesized in this way has high selectivity for steroid 11β-hydroxylase (CYP11B1) and can therefore be used as a CYP11B1 inhibitor. The radioactive iodo-labeled iodomethomidate produced by the method of the present invention theoretically has no non-radioactive iodomethomidate, and therefore, a CYP11B1 inhibitor excellent in quantitative accuracy when used as an in-vivo test agent or an in-vitro test agent. Can be. In addition, since there is no non-radioactive iodomethomidate, competition for binding to CYP11B1 is eliminated, so that accumulation of radioiodine-labeled iodomethomidate can be evaluated with a smaller dose than in the conventional method.

  Moreover, the radioiodine labeled iodomethomidate synthesized in this way may form a pharmacologically acceptable salt. Moreover, you may prepare the pharmaceutical which contains a radioiodine labeled iodomethomidate or its salt as an active ingredient.

  When preparing radioiodine-labeled iodomethomidate as a CYP11B1 inhibitor or CYP11B2 inhibitor, or when preparing as a pharmaceutical, after synthesis of radioiodine-labeled iodomethomidate, unreacted radioiodide ions and insoluble impurities are removed. It is desirable to purify by a membrane filter, a column packed with various packing materials, HPLC or the like.

  The pharmaceutical containing the radioiodine-labeled iodomethomidate or a salt thereof may be formulated into a form suitable for administration into a living body, but is preferably parenterally, that is, administered by injection. More preferably. Such compositions may optionally contain additional components such as pH adjusters, pharmaceutically acceptable solubilizers, stabilizers or antioxidants.

A pharmaceutical containing radioiodinated iodomethomidate or a salt thereof is useful as an imaging agent for diagnostic imaging using single photon tomography (SPECT) or positron tomography (PET). When used for SPECT image diagnosis, iodomethomidate wherein X is ¹²³ I in the general formula (2) is preferred. When used for diagnostic imaging for PET, iodomethomidate wherein X is ¹²⁴ I in the general formula (2) is preferred. A pharmaceutical containing a radioiodine-labeled iodomethomidate or a salt thereof can be preferably used as an imaging agent for adrenal adenoma.

  EXAMPLES Hereinafter, although an Example is described and this invention is demonstrated in more detail, this invention is not limited to these content.

Abbreviations in the following examples are as follows.
Compound 1: (S) -1- (4-Bromophenyl) ethanol Compound 2: (R)-(+)-1- [1- (4-Bromophenyl) ethyl] -1H-imidazole-5-carboxylate methyl SnMTO: (R)-(+)-1- [1- (4-trimethylstannylphenyl) ethyl] -1H-imidazole-5-carboxylate methyl IMTO: (R)-(+)-1- [1- (4-Iodophenyl) ethyl] -1H-imidazole-5-carboxylate methyl

Example 1 Synthesis of SnMTO SnMTO was synthesized according to the scheme shown in FIG.

(1) Synthesis of Compound 2 Methyl 4-imidazolecarboxylate (2.89 g, manufactured by Wako Pure Chemical Industries, Ltd.) and triphenylphosphine (7.21 g, manufactured by Kanto Chemical Co., Ltd.) were mixed at room temperature ( And dissolved in dehydrated tetrahydrofuran (65 mL, manufactured by Kanto Chemical Co., Ltd.) at a temperature of 32 ° C., a solution of Compound 1 (4.60 g, manufactured by SynQuest and Aldrich) in dehydrated tetrahydrofuran (40 mL, manufactured by the same above) I picked it up. Next, a solution of ditert-butyl azodicarboxylate (6.33 g, manufactured by Aldrich) in dehydrated tetrahydrofuran (40 mL, manufactured by the same above) was plucked over 10 minutes. Then, after reacting at room temperature all day and night, dehydrated tetrahydrofuran (7 mL, same as above) of triphenylphosphine (1.30 g, same as above) and di-tert-butyl azodicarboxylate (1.14 g, same as above) Further solutions were added in this order and allowed to react for 1 hour at room temperature. Thereafter, the mixture was concentrated, diethyl ether (100 mL) was added to the residue, and the precipitated powder was filtered and washed with diethyl ether (75 mL). The filtrate was concentrated, diethyl ether (20 mL) and hexane (30 mL) were added to the residue, the precipitated powder was filtered, and washed with a mixed solution (50 mL) of diethyl ether: hexane (3: 1). The filtrate was concentrated, and the residue was roughly purified by silica gel column chromatography (spherical neutral silica gel, hexane: ethyl acetate = 2: 1), and further purified by silica gel column chromatography (spherical neutral silica gel, methylene chloride). Compound 2 was obtained as a pale yellow viscous oil (3.79 g, yield 53.7% from Compound 1). It was confirmed that ¹ H-NMR of Compound 2 is the same as ¹ H-NMR of Compound of Non-Patent Document 5, wherein ((R) -12).

(2) Synthesis of SnMTO To a solution of the compound 2 (2.70 g) obtained above in dehydrated toluene (30 mL, manufactured by Kanto Chemical Co., Ltd.) in a nitrogen stream at room temperature (25 ° C.), hexamethylditin (3 .4 mL, manufactured by Aldrich) was dehydrated over 3 minutes with dehydrated toluene (30 mL, manufactured above). Next, tetrakis (triphenylphosphine) palladium (0.50 g, manufactured by Aldrich) and triethylamine (13.8 mL, manufactured by Kishida Chemical Co., Ltd.) were added in this order, and the mixture was heated to reflux overnight. Thereafter, the mixture was filtered through Celite, washed with toluene (100 mL), and concentrated. The residue was roughly purified by silica gel column chromatography (spherical neutral silica gel, hexane: ethyl acetate = 3: 1). Hexane (3 mL) was added to the obtained oily substance, filtered, and washed with hexane (7 mL). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (spherical neutral silica gel, hexane: ethyl acetate = 17: 7) to give SnMTO as a pale orange transparent viscous oil (1.47 g, collected from compound 2). (42.8% rate). ¹ H-NMR of SnMTO was confirmed to be the same as the ¹ H-NMR of Compound of Non-Patent Document 4 (5). The specific rotation [α] was + 73.45 ° (c = 2, acetone).

Example 2: Unlabeled compound synthesis of IMTO To a solution of SnMTO (0.24 g) obtained in Example 1 in methylene chloride (4.6 mL, manufactured by Kanto Chemical Co., Inc.) under ice-cooling (4 ° C), Iodine (271 mg, manufactured by Kanto Chemical Co., Inc.) was added in portions over 20 minutes and reacted at 4 ° C. for 5 minutes. Then, quench with saturated aqueous sodium carbonate (5 mL) and saturated aqueous sodium thiosulfate (5 mL), add methylene chloride (5 mL), separate the organic layer, and wash with water (10 mL) and saturated aqueous sodium chloride (10 mL). And dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (spherical neutral silica gel, hexane: ethyl acetate = 7: 5) to obtain IMTO as a pale yellow transparent viscous oil (0.19 g, yield from SnMTO 87.2%). It was. ¹ H-NMR of IMTO was confirmed to be the same as the ¹ H-NMR of Compound of Non-Patent Document 4 (4). The specific rotation [α] was + 75.82 ° (c = 1, acetone).

Example ^3: [123 I] along the scheme shown in labeling synthesis Figure 2 IMTO, was synthesized ^[123 I] IMTO from SnMTO obtained in Example 1. Specifically, 170 μL of 1 mol / L hydrochloric acid, 60 μL of [ ¹²³ I] sodium iodide in 1249 MBq, and 10 μL of 30% (W / V) hydrogen peroxide solution were added to 90 μL of an SnMTO ethanol solution (concentration: 1 mg / mL). The mixture was allowed to stand at room temperature for 10 minutes, and then subjected to HPLC under the following conditions to fractionate [ ¹²³ I] IMTO fraction. It was confirmed that [ ¹²³ I] IMTO was obtained by agreeing with the HPLC retention time of the unlabeled product obtained in Example 2.
<HPLC conditions>
Column: CAPCELL PAK C18
MG-II (trade name, Shiseido, 4.6 x 150 mm)
Mobile phase: methanol / water / diethylamine = 60/40 / 0.2
Flow rate: 1.5 mL / min Detector: UV-visible absorptiometer (detection wavelength: 254 nm) and radioactivity detector (RAYTEST STEFFI type)
Retention time: 9.3 minutes

A solution obtained by adding 10 mL of water to the fraction was passed through a reverse-phase column (trade name: Sep-Pak (registered trademark) Lights C18 Cartridges, manufactured by Waters, 130 mg of filler filling agent), and [ ¹²³ I] IMTO Was adsorbed and collected on the column. The column was washed with 20 mL of water and then 1 mL of ethanol was passed through to elute [ ¹²³ I] IMTO. The amount of radioactivity obtained was 841 MBq immediately after the synthesis, and the time required for the synthesis of [ ¹²³ I] IMTO from SnMTO was 54 minutes. Moreover, when the analysis by the following conditions was conducted, the radiochemical purity was 97%.
<TLC analysis conditions>
TLC plate: Silica Gel 60 F254 (product name, manufactured by Merck & Co., Inc.)
Developing phase: Hexane / ethyl acetate = 1/1 (V / V)
Detector: TLC scanner Gita Star (manufactured by raytest)

[Evaluation]
For [ ¹²³ I] IMTO obtained in Example 3, specific radioactivity is measured according to the conditions shown in Non-Patent Document 4. As a result, it is confirmed that the specific activity of [ ¹²³ I] IMTO obtained in Example 3 is higher than the specific activity 50 GBq / μmol of [ ¹²³ I] IMTO described in Non-Patent Document 4.

Claims (9)

Radioiodine labeling comprising the step of synthesizing a radioiodine labeling precursor represented by the following general formula (1) from methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate A method for producing a precursor.
[In the formula, R is an integer having 1 to 6 carbon atoms in the alkyl chain and is a substituted or unsubstituted trialkylstannyl group or a substituted or unsubstituted triphenylstannyl group. ]   Performing said step of synthesizing said radioiodine labeled precursor comprising performing a trialkylstannylation reaction of methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate; The manufacturing method of the radioiodine label precursor of Claim 1. The method for producing a radioiodine labeled precursor according to claim 1 or 2, wherein the radioiodine labeled precursor is used for producing a radioiodine compound represented by the following general formula (2).
[In formula, X is a radioactive iodine atom. ] The method for producing a radioiodine labeled precursor according to claim 3, wherein the radioactive iodine atom is ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I.   The radioiodine-labeled precursor according to claim 3 or 4, wherein the radioiodine-labeled precursor is used to produce a steroid 11β-hydroxylase (CYP11B1) inhibitor represented by the general formula (2). Manufacturing method.   The said radioiodine labeling precursor is used in order to manufacture the pharmaceutical which contains the radioiodine compound or its salt represented by the said General formula (2) as an active ingredient. A method for producing a radioiodine-labeled precursor.   The method for producing a radioiodine-labeled precursor according to claim 6, wherein the medicine is an imaging agent for diagnostic imaging for single photon tomography (SPECT).   The method for producing a radioiodine labeled precursor according to claim 6, wherein the medicine is an imaging agent for diagnostic imaging for positron tomography (PET). Synthesizing a radioiodine-labeled precursor represented by the following general formula (1) from methyl 1- [1- (4-bromophenyl) ethyl] -1H-imidazole-5-carboxylate;
Synthesizing a radioiodine compound represented by the following general formula (2) from the radioiodine labeled precursor;
A method for producing a radioactive iodo compound, comprising:
[In the formula, R is an integer having 1 to 6 carbon atoms in the alkyl chain and is a substituted or unsubstituted trialkylstannyl group or a substituted or unsubstituted triphenylstannyl group. ]
[In formula, X is a radioactive iodine atom. ]