WO2025142589A1 - Compound or salt or solvate thereof, use thereof, and method for producing same - Google Patents

Abstract

The present disclosure relates to compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof: in formula (I), X¹ and X² each independently are a radioactive halogen nuclide, hydrogen, or deuterium, R¹, R², and R³ each independently are hydrogen or deuterium, at least one of X¹, X² _, R¹, R², and R³ is deuterium, at least one of X¹ and X² is a radioactive halogen nuclide, and Y is a methyl group and an isopropyl group.

Description

Compounds or salts or solvates thereof, their uses and methods for producing them

The present invention relates to a compound or a salt or solvate thereof, their use, and a method for producing the same.

　Metabotropic glutamate receptor 1 (mGluR1) is a G protein-coupled receptor normally expressed in the central nervous system and contributes to learning or memory formation or neuronal development. Ectopic mGluR1 is carcinogenic, and is presumed to activate the mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways independent of B-Raf or N-Ras, inducing cancer in melanocytes. It has also been reported that mGluR1 is not expressed in normal skin melanocytes or peripheral organs, but if abnormal expression is induced in melanocytes, melanoma will form with almost 100% probability. It is also known to be frequently expressed in many types of cancer, including human melanoma, breast cancer, pancreatic cancer, and colon cancer, and mGluR1 is expected to be a promising target for the development of cancer diagnosis or treatment.

The present inventors have developed small molecule PET tracers targeting receptors on various tissues, and have succeeded in developing a small molecule PET tracer ( ^18F -FITM) for mGluR1 (Non-Patent Document 1). Using knowledge of the pharmacokinetics of this tracer, we have also succeeded in developing ^211At -AITM labeled with ^211At , an alpha-emitting nuclide, and have obtained knowledge that can be used as a small molecule radiotherapeutic drug (Non-Patent Documents 2 and 3). However, there have been no reports on the development of a method for modifying the backbone structure that can contribute to further metabolic stability of the compound, particularly a technology that can be applied to radiotherapeutic drugs.

One method for improving the metabolic stability of a compound is to use a stable isotope. Deuterium is the most commonly used isotope. Compounds containing deuterium have been actively researched in recent years, and many reports have been published on their ability to improve the metabolic stability of drugs. For example, Non-Patent Document 4 reports compounds containing deuterium as candidates for radiopharmaceuticals.

Xie L., Fujinaga M., Zhang M-R., et al., Int J Cancer. 2014; 135:1582-1859 Xie L., Hanyu, M., Fujinaga M., Zhang M-R., et al., J. Nucl. Med. 2019;61:242-248 Xie L., Hanyu, M., Fujinaga M., Zhang M-R., et al., Cell Reports Medicine, 2023;4: 100960 Klenner, MA, Pascali G., Fraser BH, Darwish TA., Nucl. Bio. Med., 2021: 96-97; 112-147

Non-Patent Document 4 reports findings regarding labeling reactions after deuteration of aliphatic and alicyclic hydrocarbons. However, it is known that the introduction reaction of radioactive halogen nuclides into aliphatic and alicyclic hydrocarbons, especially when At is used, hardly any labeling reaction proceeds. This is because the nucleophilicity of At is much smaller than other radioactive halogen nuclides, and furthermore, the bond energy of carbon-At in the hydrocarbon is much smaller than the carbon-radioactive halogen nuclides in other hydrocarbons, reducing the stability of the compound.

In addition, while there has been much research into the introduction of radioactive halogen nuclides into aromatic or heteroaromatic rings, there has been no research into improving the metabolic stability of the compound skeleton due to the difficulty of developing small molecule radiopharmaceuticals that contain radioactive halogen nuclides.

To date, no radioactive halogen compounds have been reported that contain deuterium on an aromatic or heteroaromatic ring.

One aspect of the present invention is to provide a radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, and the like, which has improved metabolic stability.

The inventors have conducted extensive research to achieve the above object. As a result, they have discovered that by reacting a compound having a deuterated aromatic ring or heteroaromatic ring with a radioactive halogen nuclide under specific conditions, it is possible to obtain a radioactive halogen compound having a radioactive halogen nuclide and deuterium on the aromatic ring or heteroaromatic ring. They have also discovered that the metabolic stability of the obtained compound is improved, which has led to the completion of the present invention.

式（Ｉ）中、
　Ｘ^１およびＸ^２はそれぞれ独立して放射性ハロゲン核種、水素または重水素であり、
　Ｒ^１、Ｒ^２およびＲ^３はそれぞれ独立して水素または重水素であり、
　Ｘ^１、Ｘ^２ _、Ｒ^１、Ｒ^２およびＲ^３のうちの少なくとも１つは重水素であり、
　Ｘ^１およびＸ^２のうち少なくとも１つは放射性ハロゲン核種であり、
　Ｙはメチル基およびイソプロピル基である。 A compound according to one aspect of the present invention is a compound of formula (I), a pharma- ceutically acceptable salt, or a solvate thereof:

In formula (I),
^X1 and ^X2 are each independently a radioactive halogen nuclide, hydrogen or deuterium;
R ¹ , R ² and R ³ are each independently hydrogen or deuterium;
At least one of X ¹ , X ² _, R ¹ , R ² and R ³ is deuterium;
At least one of ^X1 and ^X2 is a radioactive halogen nuclide;
Y is a methyl group and an isopropyl group.

In addition, a manufacturing method according to one embodiment of the present invention is a method for manufacturing a radiolabeled deuterated aromatic carbonyl compound, a medicamentarily acceptable salt thereof, or a solvate thereof, comprising a labeling step of labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide by subjecting the aromatic carbonyl compound, in which at least one hydrogen atom on the aromatic ring or heteroaromatic ring has been substituted with deuterium, to an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower, with a radioactive halogen nuclide.

According to one aspect of the present invention, it is possible to provide a radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, which has improved metabolic stability.

FIG. 2 shows an HPLC chart of the reaction mixture obtained in the condition study of Example 2. FIG. 2 shows an HPLC chart of ²¹¹ At-AITM-D4 obtained in Example 3. FIG. 2 shows the Radio TLC chart of ²¹¹ At-AITM-D4 obtained in Example 3. FIG. 1 shows the results of evaluating the stability of ^211At -AITM-D4 to serum. FIG. 1 shows the results of measuring the amount of cellular uptake of ^211At -AITM-D4. FIG. 1 shows the results of measuring the cellular distribution of ^211At -AITM-D4. FIG. 1 shows Radio TLC charts of ¹²³ I-Py[D4] and ¹²³ I-Py after purification. FIG. 1 shows Radio TLC charts of ²¹¹ At-Py[D4] and ²¹¹ At-Py after purification. FIG. 1 shows the results of a stability test of ¹²³ I-Py[D4] and ²¹¹ At-Py[D4].

[Definition of terms, etc.]
As used herein, the term "aromatic ring or heteroaromatic ring is deuterated" refers to at least one hydrogen atom on the aromatic ring or heteroaromatic ring being replaced with deuterium.

As used herein, the term "heteroaromatic ring" refers to an aromatic ring containing at least one heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of heteroaromatic rings include π-electron rich and π-electron deficient aromatic heterocycles, such as a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a furan ring, a thiophene ring, a thiazole ring, a pyrrole ring, an imidazole ring, and an oxazole ring.

In this specification, a "radioactive halogen nuclide" is a radioactive isotope of a halogen element. Examples of halogen elements include fluorine (F), chlorine (Cl), bromine (Br), iodine (I) and astatine (At).

As used herein, "pharmaceutical acceptable salts" refers to salts that are not harmful to living animals, particularly mammals. Pharmaceutically acceptable salts can be formed using non-toxic acids or bases, including inorganic acids or bases, or organic acids or bases. Pharmaceutically acceptable salts include acid addition salts and base addition salts.

Examples of acidic salts include salts with alkali metals such as sodium, potassium, and lithium; salts with alkaline earth metals such as calcium and magnesium; metal salts such as aluminum and zinc; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, diethanolamine, ethylenediamine, dicyclohexylamine, procaine, chloroprocaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, meglumine (N-methylglucamine), etc.

Basic salts include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

As used herein, the term "solvate" refers to a solvate formed by the association of one or more solvent molecules with a compound according to one aspect of the present invention. Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates. Solvates also include hydrates.

In this specification, when isomers exist, "a compound or a pharma- ceutical acceptable salt thereof" includes all isomers in one embodiment of the present invention, and also includes hydrates, solvates, and all crystal forms. Examples of isomers include optical isomers, geometric isomers, and tautomers.

In this specification, "A and/or B" is a concept that includes both A and B and A or B, and can be rephrased as "at least one of A and B." In addition, in this specification, "~" means a range that includes both the numerical values at both ends.

式（Ｉ）中、
　Ｘ^１およびＸ^２はそれぞれ独立して放射性ハロゲン核種、水素または重水素であり、
　Ｒ^１、Ｒ^２およびＲ^３はそれぞれ独立して水素または重水素であり、
　Ｘ^１、Ｘ^２ _、Ｒ^１、Ｒ^２およびＲ^３のうちの少なくとも１つは重水素であり、
　Ｘ^１およびＸ^２のうち少なくとも１つは放射性ハロゲン核種であり、
　Ｙはメチル基およびイソプロピル基である。 Compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof
One aspect of the present invention is a compound of the following formula (I), or a pharma- ceutical acceptable salt or solvate thereof (hereinafter, these may be collectively referred to as "the compound (I)").

In formula (I),
^X1 and ^X2 are each independently a radioactive halogen nuclide, hydrogen or deuterium;
R ¹ , R ² and R ³ are each independently hydrogen or deuterium;
At least one of X ¹ , X ² _, R ¹ , R ² and R ³ is deuterium;
At least one of ^X1 and ^X2 is a radioactive halogen nuclide;
Y is a methyl group and an isopropyl group.

Compound (I) has high metabolic stability. The metabolic stability can be measured, for example, by mixing the target compound with a biological sample such as blood (e.g., serum) and allowing to stand for a certain period of time (e.g., 24 hours at 37°C), and then calculating the proportion of the unchanged target compound in the biological sample (amount of the unchanged target compound in the biological sample/total amount of the target compound in the biological sample). When the proportion of the unchanged target compound is 80% or more, the metabolic stability of the target compound is high, and it is preferable that the proportion is 90% or more.

Examples of the radioactive halogen nuclide of the compound (I) include ¹⁸ F, ^34m Cl, ³⁶ Cl, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸⁰ Br, ⁸² Br, ¹²³ I, ¹²⁴ I, ^{125 I, 131} I, ²¹¹ At, etc. When the compound (I) is used as a radioactive diagnostic drug ^, the radioactive halogen nuclide is preferably ¹²³ I, ¹⁸ F, ⁷⁶ Br, ¹²⁴ I. When the compound (I) is used as a radioactive therapeutic drug, the radioactive halogen nuclide is preferably ²¹¹ At, ⁷⁷ Br, ¹³¹ I.

In order to improve the structural stability and metabolic stability of the compound (I), it is preferable that the two hydrogen atoms adjacent to the radioactive halogen nuclide on the aromatic ring are replaced with deuterium.For example, when ^X1 is a radioactive halogen nuclide, it is preferable that ^X2 and ^R3 are each deuterium.In addition, when ^X2 is a radioactive halogen nuclide, it is preferable that ^X1 and ^R1 are each deuterium.

　式（ＩＡ）中、Ｄは重水素である。 From the viewpoint of further improving the structural stability and metabolic stability of the present compound (I), it is more preferable that one of ^X1 and ^X2 is ^211At and the other is deuterium, and ^R1 , ^R2 and ^R3 are each deuterium. A more preferable example of the present compound (I) is a compound of the following formula (IA).

In formula (IA), D is deuterium.

Compound (I) can be produced by the method for producing a radiolabeled deuterated aromatic carbonyl compound, a medicamentously acceptable salt thereof, or a solvate thereof, which will be described later.

[Radioactive therapeutic or diagnostic agent]
A radiotherapeutic agent or radiodiagnostic agent containing the present compound (I) as an active ingredient is also included in one aspect of the present invention.

The radiotherapeutic or diagnostic agent may be contained in a medicament acceptable carrier. The medicament acceptable carrier is not particularly limited, but may be, for example, sterile water, saline, normal saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection.

The above radioactive therapeutic agents or radioactive diagnostic agents can be preferably used for the treatment or diagnosis of diseases involving cells expressing metabotropic glutamate receptor 1 (mGluR1) (particularly cells expressing it at a high level). They can also be preferably used for the treatment or diagnosis of cancer (tumor), and in particular, for the treatment or diagnosis of cancer (tumor) expressing mGluR1.

Examples of diseases involving cells expressing mGluR1 (especially cells that express it highly) include cancer (tumors) and fatty liver. Examples of cancers (tumors) that express mGluR1 highly include melanoma, breast cancer, pancreatic cancer, colon cancer, glioma, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, gastric cancer, thyroid cancer, thymic cancer, renal cell carcinoma, chromophobe renal cell carcinoma, testicular germ cell cancer, endometrial cancer, sarcoma, and uterine sarcoma.

The radioactive therapeutic drug or radioactive diagnostic drug is not particularly limited, but can be administered, for example, parenterally, intravenously, or intraperitoneally. The compound (I) may be a single substance, or may be supported by a DDS (drug delivery system). The radioactive therapeutic drug or radioactive diagnostic drug may consist of only the compound (I).

The dosage of the compound (I) may be appropriately determined depending on the type of substance used, the age, weight, health condition, sex, and diet of the subject to be administered, the number of administrations, and the route of administration, etc.

　An aspect of the present invention also includes a method for diagnosing or treating a disease involving cells expressing mGluR1 using the above radioactive therapeutic agent or radioactive diagnostic agent. An aspect of the present invention also includes a method for diagnosing or treating cancer using the above radioactive therapeutic agent or radioactive diagnostic agent. The diagnostic or therapeutic method includes a step of administering the above radioactive therapeutic agent or radioactive diagnostic agent to a subject.

The administration route is not particularly limited and may be selected from common drug administration routes such as parenteral administration, intravenous administration, or intraperitoneal administration.

A method for diagnosing cancer will now be described. The method for diagnosing cancer using the radioactive diagnostic agent further includes detecting a compound that has accumulated in the cancer. There are no particular limitations on the method for detecting the compound, but it is preferable to use a radiation detector that detects radiation emitted from the radioactive halogen nuclide in the compound (I). For example, a positron emission tomography (PET) is an example of such a radiation detector. Compounds that have accumulated in tumors can also be detected by nuclear magnetic resonance imaging (MRI) or hyperpolarized nuclear magnetic resonance.

When the radioactive diagnostic agent is used in a cancer diagnosis method, the dose to be administered to the subject may be appropriately determined depending on the detection method used to detect compounds accumulated in the cancer.

The results of detecting compounds accumulated in cancer are preferably output as an image. In other words, one aspect of the present invention includes a cancer imaging method (imaging method) that uses the above radioactive diagnostic agent. Also, one aspect of the present invention includes a cancer imaging agent (imaging agent) that uses the above radioactive diagnostic agent.

A method of treating cancer using the above radioactive therapeutic drug will now be described. The above radioactive therapeutic drug is administered to the subject so that an amount of active ingredient that results in a radioactivity concentration that exerts a therapeutic effect on cancer is administered to the subject. In general, in order to exert a sufficient therapeutic effect on cancer, it is preferable to set the dosage of the radioactive therapeutic drug so that the radioactivity concentration is higher than that of the above radioactive diagnostic drug.

[Method for producing a radiolabeled deuterated aromatic carbonyl compound, a pharma- ceutical acceptable salt thereof, or a solvate thereof]
A method for producing a radiolabeled deuterated aromatic carbonyl compound, a pharma- ceutical acceptable salt thereof, or a solvate thereof (hereinafter, these may be collectively referred to as a "method for producing a radiolabeled deuterated aromatic carbonyl compound") is also included in one aspect of the present invention.

The method for producing a radioactively labeled deuterated aromatic carbonyl compound includes a labeling step in which an aromatic carbonyl compound in which at least one hydrogen on an aromatic ring or a heteroaromatic ring is replaced with deuterium is subjected to an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower with a radioactive halogen nuclide, thereby labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide. Hereinafter, the "aromatic carbonyl compound in which at least one hydrogen on an aromatic ring or a heteroaromatic ring is replaced with deuterium" may be referred to as the "labeled precursor".

The labeled precursor has at least one hydrogen atom on the aromatic ring or heteroaromatic ring substituted with deuterium. The aromatic ring or heteroaromatic ring of the labeled precursor is labeled with a radioactive halogen nuclide by an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower with the radioactive halogen nuclide. By this labeling, a radioactive halogen compound having a radioactive halogen nuclide and deuterium on the aromatic ring or heteroaromatic ring can be produced.

　Deuteration of the aromatic or heteroaromatic ring in the above-mentioned labeled precursor can be carried out by methods well known to those skilled in the art.

In order to facilitate the introduction of a radioactive halogen nuclide onto the aromatic ring or heteroaromatic ring of the labeling precursor, it is preferable that the aromatic ring or heteroaromatic ring of the labeling precursor has a radioactive halogen nuclide introduction group.

Examples of radioactive halogen nuclide-introducing groups include boronic acid, boronic acid esters, trialkylstannyl groups, trialkylsilyl groups, trialkylgermyl groups, chloro, bromo, iodo, nitro groups, trimethylammonium trifluoromethanesulfonate, sulfonic acid groups, iodonium salts, and iodonium ylide groups. In terms of the relative ease with which radioactive halogens can be introduced, the radioactive halogen nuclide-introducing groups are preferably trialkylstannyl groups and boronic acid esters. In terms of the high reactivity with electrophiles and the ability to carry out Sn-halogen substitution reactions at low reaction temperatures, the radioactive halogen nuclide-introducing groups are more preferably trialkylstannyl groups. Examples of trialkylstannyl groups include tri(C1-C4 alkyl)stannyl groups, with tributylstannyl groups being more preferred. Examples of trialkylsilyl groups include tri(C1-C4 alkyl)silyl groups, with trimethylsilyl groups being more preferred. Examples of C1-C4 alkyl groups include methyl, ethyl, propyl, and butyl groups.

For example, an aromatic carbonyl compound having a radioactive halogen nuclide-introducing group on the aromatic ring or heteroaromatic ring can be obtained by a substitution reaction between an aromatic carbonyl compound in which the hydrogen on the aromatic ring or heteroaromatic ring is replaced with a halogen element and a radioactive halogen nuclide-introducing group.

In order to further improve the structural stability of a radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, when the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound has a radioactive halogen nuclide-introducing group, it is preferable that two hydrogen atoms adjacent to the radioactive halogen nuclide-introducing group on the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound are replaced with deuterium, and it is more preferable that each hydrogen atom on the aromatic ring or heteroaromatic ring is replaced with deuterium.

式（ＩＩ）中、
　Ｘ^１１およびＸ^１２はそれぞれ独立して放射性ハロゲン核種導入基、水素または重水素であり、
　Ｒ^１１、Ｒ^１２、およびＲ^１３はそれぞれ独立して水素または重水素であり、
　Ｘ^１１、Ｘ^１２ _、Ｒ^１１、Ｒ^１２およびＲ^１３のうちの少なくとも１つは重水素であり、
　Ｘ^１１およびＸ^１２のうち少なくとも１つは放射性ハロゲン核種導入基であり、
　Ｙはメチル基およびイソプロピル基であり、
　前記放射性ハロゲン核種導入基は、ボロン酸、ボロン酸エステル、トリアルキルスタニル基、トリアルキルシリル基、トリアルキルゲルミル基、クロロ、ブロモ、ヨード、ニトロ基、トリメチルアンモニウムトリフルオロメタンスルホン酸塩、スルホン酸基、ヨードニウム塩、ヨードニウムイリド基である。 An example of the label precursor is a compound of the following formula (II):

In formula (II),
^X11 and ^X12 are each independently a radioactive halogen nuclide introducing group, hydrogen or deuterium;
R ¹¹ , R ¹² , and R ¹³ are each independently hydrogen or deuterium;
At least one of X ¹¹ , X ¹² _, R ¹¹ , R ¹² and R ¹³ is deuterium;
At least one of X ¹¹ and X ¹² is a radioactive halogen nuclide-introducing group;
Y is a methyl group and an isopropyl group;
The radioactive halogen nuclide-introducing group is a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, a chloro, a bromo, an iodo, a nitro group, a trimethylammonium trifluoromethanesulfonate salt, a sulfonic acid group, an iodonium salt, or an iodonium ylide group.

From the viewpoint of structural stability of the aromatic ring labeled with a radioactive halogen nuclide, it is preferred that one of X ¹¹ and X ¹² is the radioactive halogen nuclide-introducing group, the other is deuterium, and R ¹¹ , R ¹² and R ¹³ are each deuterium.

The compound (I) can be produced by labeling the aromatic ring on the compound of formula (II) above with a radioactive halogen nuclide.

Examples of solvents used in the labeling process include methanol (MeOH), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), etc. Solvents may be used alone or in combination of two or more.

The labeling process utilizes an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction. In particular, it is preferable to carry out the aromatic electrophilic substitution reaction in the presence of an acid and an oxidizing agent.

Examples of the acid include carboxylic acid and sulfonic acid. Examples of the carboxylic acid include formic acid, acetic acid, trifluoroacetic acid, citric acid, gluconic acid, lactic acid, oxalic acid, and tartaric acid. Examples of the sulfonic acid include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. From the viewpoint of activating the oxidizing agent and improving the solubility of the substrate, the acid is preferably acetic acid or formic acid. One type of acid may be used alone, or two or more types may be used in combination. An acid may be added to the solvent in an amount of 0.01% to 10% of the reaction solvent amount, preferably 0.1% to 7.0%, and more preferably 0.5% to 2.0%. Note that % is by mass.

Examples of the oxidizing agent include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, OXONE (registered trademark), chloramine-T, metachloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl hydroperoxide, bis(trimethylsilyl)peroxide, N-chlorosaccharin, N-bromosaccharin, and N-iodosaccharin. In terms of high activity when halogen cation species are formed by oxidation of halide ions and solubility in solvents, the oxidizing agent is preferably an N-halogen succinimide, and more preferably N-chlorosuccinimide. The oxidizing agent may be used alone or in combination of two or more kinds. The labeling step may be carried out by adding an oxidizing agent to the solvent at a concentration of 0.05 mg/mL to 10 mg/mL relative to the radioactivity of ^211At , preferably the oxidizing agent concentration is 0.5 mg/mL to 7.5 mg/mL, more preferably the oxidizing agent concentration is 1.0 mg/mL to 2.0 mg/mL.

The reaction temperature in the labeling step is 50°C or higher and 220°C or lower. The reaction temperature may be selected depending on the type of solvent used in the labeling step. In terms of improving the reaction efficiency of the aromatic electrophilic substitution reaction or aromatic nucleophilic substitution reaction, the reaction temperature is preferably 60°C or higher, and more preferably 70°C or higher. In addition, the reaction temperature is preferably 200°C or lower, more preferably 150°C or lower, and even more preferably 80°C or lower.

The reaction time in the labeling step can be appropriately selected depending on the aromatic carbonyl compound, the radioactive halogen nuclide, the type or amount of the solvent or reagent used in the labeling step, etc. For example, the reaction time may be 5 minutes or more and 120 minutes or less, preferably 10 minutes or more and 60 minutes or less, and more preferably 15 minutes or more and 20 minutes or less.

Methods for determining the radiochemical purity of radiolabeled deuterated aromatic carbonyl compounds include analysis by HPLC or Radio-TLC.

[Method of producing a radiotherapeutic or diagnostic agent]
An aspect of the present invention also includes a method for producing a radioactive therapeutic agent or a radioactive diagnostic agent, the method comprising the step of producing a radioactively labeled deuterated aromatic carbonyl compound, a medicamentously acceptable salt thereof, or a solvate thereof by the above-mentioned method for producing a radioactively labeled deuterated aromatic carbonyl compound.

式（Ｉ）中、
　Ｘ^１およびＸ^２はそれぞれ独立して放射性ハロゲン核種、水素または重水素であり、
　Ｒ^１、Ｒ^２およびＲ^３はそれぞれ独立して水素または重水素であり、
　Ｘ^１、Ｘ^２ _、Ｒ^１、Ｒ^２およびＲ^３のうちの少なくとも１つは重水素であり、
　Ｘ^１およびＸ^２のうち少なくとも１つは放射性ハロゲン核種であり、
　Ｙはメチル基およびイソプロピル基である。 〔summary〕
The compound according to aspect 1 of the present invention, or a pharma- ceutically acceptable salt or solvate thereof, is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof:

In formula (I),
^X1 and ^X2 are each independently a radioactive halogen nuclide, hydrogen or deuterium;
R ¹ , R ² and R ³ are each independently hydrogen or deuterium;
At least one of X ¹ , X ² _, R ¹ , R ² and R ³ is deuterium;
At least one of ^X1 and ^X2 is a radioactive halogen nuclide;
Y is a methyl group and an isopropyl group.

The compound according to aspect 2 of the present invention may be the compound according to aspect 1 of the present invention, wherein the radioactive halogen nuclide is ²¹¹ At.

The compound according to aspect 3 of the present invention may be the compound according to aspect 1 or 2 of the present invention, in which one of X ¹ and X ² is ²¹¹ At and the other is deuterium, and R ¹ , R ² and R ³ are each deuterium.

The radiotherapeutic or radiodiagnostic agent according to aspect 4 of the present invention contains, as an active ingredient, any of the compounds according to aspects 1 to 3 of the present invention, a medicamentously acceptable salt thereof, or a solvate thereof.

The method for producing a radiolabeled deuterated aromatic carbonyl compound, a medicamentously acceptable salt thereof, or a solvate thereof according to aspect 5 of the present invention includes a labeling step of labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide by subjecting an aromatic carbonyl compound in which at least one hydrogen atom on the aromatic ring or heteroaromatic ring has been replaced with deuterium to an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower with a radioactive halogen nuclide.

In the manufacturing method according to aspect 6 of the present invention, in aspect 5 of the present invention, the labeling step may be carried out in the presence of an acid and an oxidizing agent.

The manufacturing method according to aspect 7 of the present invention is the same as in aspect 5 or 6 of the present invention, in which the aromatic carbonyl compound has a radioactive halogen nuclide-introducing group on the aromatic ring or heteroaromatic ring, and the radioactive halogen nuclide-introducing group may be selected from boronic acid, boronic acid ester, trialkylstannyl group, trialkylsilyl group, trialkylgermyl group, chloro, bromo, iodo, nitro group, trimethylammonium trifluoromethanesulfonate, sulfonic acid group, iodonium salt, or iodonium ylide group.

式（ＩＩ）中、
　Ｘ^１１およびＸ^１２はそれぞれ独立して放射性ハロゲン核種導入基、水素または重水素であり、
　Ｒ^１１、Ｒ^１２、およびＲ^１３はそれぞれ独立して水素または重水素であり、
　Ｘ^１１、Ｘ^１２ _、Ｒ^１１、Ｒ^１２およびＲ^１３のうちの少なくとも１つは重水素であり、
　Ｘ^１１およびＸ^１２のうち少なくとも１つは放射性ハロゲン核種導入基であり、
　Ｙはメチル基およびイソプロピル基であり、
　前記放射性ハロゲン核種導入基は、ボロン酸、ボロン酸エステル、トリアルキルスタニル基、トリアルキルシリル基、トリアルキルゲルミル基、クロロ、ブロモ、ヨード、ニトロ基、トリメチルアンモニウムトリフルオロメタンスルホン酸塩、スルホン酸基、ヨードニウム塩、ヨードニウムイリド基である。 In the production method according to an eighth aspect of the present invention, in any one of the fifth to seventh aspects of the present invention, the aromatic carbonyl compound may be a compound of the following formula (II):

In formula (II),
^X11 and ^X12 are each independently a radioactive halogen nuclide introducing group, hydrogen or deuterium;
R ¹¹ , R ¹² , and R ¹³ are each independently hydrogen or deuterium;
At least one of X ¹¹ , X ¹² _, R ¹¹ , R ¹² and R ¹³ is deuterium;
At least one of X ¹¹ and X ¹² is a radioactive halogen nuclide-introducing group;
Y is a methyl group and an isopropyl group;
The radioactive halogen nuclide-introducing group is a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, a chloro, a bromo, an iodo, a nitro group, a trimethylammonium trifluoromethanesulfonate salt, a sulfonic acid group, an iodonium salt, or an iodonium ylide group.

A production method according to a ninth aspect of the present invention is the method according to the eighth aspect of the present invention, wherein one of X ¹¹ and X ¹² is the radioactive halogen nuclide introducing group, the other is deuterium, and R ¹¹ , R ¹² and R ¹³ are each deuterium.

The method for producing a radioactive therapeutic agent or radioactive diagnostic agent according to aspect 10 of the present invention includes the step of producing a radioactively labeled deuterated aromatic carbonyl compound, a medicamentously acceptable salt thereof, or a solvate thereof by any one of the production methods according to aspects 5 to 9 of the present invention.

The following examples are provided to further explain the embodiments of the present invention. Of course, the present invention is not limited to the following examples, and various details are possible. Furthermore, the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. The technical scope of the present invention also includes embodiments obtained by appropriately combining the technical means disclosed. Furthermore, all of the documents described in this specification are incorporated by reference.

Example 1 Preparation of a labeled precursor incorporating ²¹¹ At A labeled precursor incorporating ²¹¹ At (Compound 5) was prepared according to the following procedure.

(Synthesis of compound 3)

Compound 1 (500 mg, 2.44 mmol) was dissolved in dichloromethane (7 mL), DMF (3 drops) was added dropwise, and the mixture was stirred at 0°C for 5 min. Oxalyl chloride (315 mL, 3.66 mmol) was added dropwise at room temperature (1°C to 30°C), and the mixture was stirred for 4 h and the solvent was evaporated. Toluene (15 mL), triethylamine (1.02 mL, 7.32 mmol), and compound 2 synthesized by the method described in Fujinaga M., Zhang M-R., et al., J. Med. Chem., 2012, pp2342-2352 were added to the residue in sequence, and the mixture was stirred at 100°C for 5 h. Water (50 mL) was added to the reaction mixture, and the reaction product was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated saline (50 mL x 3) and then dried over anhydrous sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified using silica gel column chromatography (hexane:ethyl acetate = 5:1 + triethylamine (0.1%)) to obtain white crystals. (260 mg, 26%)

The NMR analysis of compound 3 gave the following results:
1H NMR (CDCl ₃ ): d 3.76 (3H, s), 8.06 (1H, s), 8.13 (1H, s), 8.95 (1H, s)

(Synthesis of compound 4)

Potassium carbonate (131 mg, 0.95 mmol) and 1,4-dioxane (10 mL) were added to compound 3 (260 mg, 0.63 mmol), followed by isopropylamine (1 mL). The reaction solution was heated to 80°C, and isopropylamine (1 mL) was added every 3 hours and stirred for 10 hours. Water (50 mL) was added to the reaction mixture, and the reactants were extracted with dichloromethane (30 mL x 3). The organic layer was washed with saturated saline (30 mL x 3) and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (hexane:ethyl acetate=1:2 + triethylamine (0.1%)) to obtain cream-colored crystals. (225 mg, 82%)

The NMR analysis of compound 4 gave the following results:
1H NMR (CDCl ₃ ): d 1.29 (6H, d, J = 6.6 Hz), 3.74 (3H, s), 4.12 (1H, br), 4.87 (1H, br), 7.05 (1H, s), 7.92 (1H, s), 8.57 (1H, s)

(Synthesis of compound 5)

After adding compound 4 (218 mg, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol), the atmosphere in the reaction vessel was replaced with nitrogen, and bis(tributyltin) (348 mg, 0.6 mmol) and 1,4-dioxane (7 mL) were added, followed by heating and stirring at 100°C for 8 hours. Water (30 mL) was added to the reaction mixture, and the reactants were extracted with dichloromethane (30 mL x 3). The organic layer was washed with saturated saline (30 mL x 3) and then dried over anhydrous sodium sulfate. After filtering off the sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (hexane:ethyl acetate = 1:2 + triethylamine (0.1%)) to obtain an oily product. (46 mg, 14%)

The NMR analysis of compound 5 gave the following results:
1H NMR (CDCl ₃ ): d 0.90 (9H, t, J=7.4 Hz), 1.10 (6H, t, J=7.7 Hz), 1.29 (6H, t, J=6.2 Hz), 1.28-1.42 (6H, m), 1.50-1.61 (6H, m), 3.77 (3H, s), 4.13 (1H, br), 4.92 (1H, br), 7.07 (1H, s), 7.95 (1H, s), 8.58 (1H, s)

Example 2: Study of reaction temperature for preparation of ²¹¹ At-AITM-D4 The conditions for preparing a compound ( ²¹¹ At-AITM-D4) in which ²¹¹ At was introduced into compound 5 were studied. ²¹¹ At in a glass vial was extracted with 460 μL of 2 mg/mL N-chlorosuccinimide/methanol solution. Two reaction solutions were prepared by adding 200 μL of ²¹¹ At solution to 100 μL of 3% acetic acid/methanol solution containing compound 5 at a concentration of 1 mg/mL. After leaving the solution at room temperature (1°C to 30°C) and 70°C for 20 minutes, the reaction was terminated by adding 50 μL of 2 mg/mL sodium sulfite aqueous solution. The labeling efficiency was measured by RadioHPLC.

The HPLC conditions were set as follows:
Flow rate: 1 mL/min
Mobile phase A: 0.1% TEA acetonitrile/water mixture (acetonitrile:water = 50:50)
Mobile phase B: 0.1% TEA acetonitrile solution (acetonitrile 100%)
Elution conditions: Mobile phase A 100% (starting 0 minutes) → Mobile phase B 100% (starting 20 minutes)
Column temperature: room temperature Column: CAPCELL PAK UG80, 5mm, 4.6 mm ID 250mm

The HPLC chart is shown in Figure 1. The labeling efficiencies at room temperature (1°C to 30°C) and 70°C were calculated from the HPLC area ratio to be 39% and 88%, respectively. From the above, it was found that the reaction temperature for ^211At -AITM-D4 is preferably 70°C.

　ガラスバイアル中の²¹¹Atに2 mg/mL N-クロロスクシンイミド/メタノール溶液200μL、化合物5の濃度が1 mg/mLの3% 酢酸/メタノール溶液100μLを加えた。反応液を70℃にて20分間静置した後、2 mg/mL亜硫酸ナトリウム水溶液50μLを加えて反応を終了した後、蒸留水1 mLを加えた。精製はRadioHPLCにて行い保持時間16分前後を分取した。分取した溶液を濃縮した後、生理食塩水：2mg/mLアスコルビン酸ナトリウム水溶液：Tween80（85:14:1）200-300μLで再溶解し、²¹¹At-AITM-D4注射剤を得た。全工程時間は1.5時間、放射化学的収率42.2±2.7％（合成終了時、n=5）、放射化学的純度99%以上であった。精製した²¹¹At-AITM-D4のRadioHPLCおよびRadioTLCチャートをそれぞれ、図2および図3に示す。HPLCの条件は実施例2と同様の条件に設定した。 Example 3: Labeling synthesis of ^211At -AITM-D4

200μL of 2 mg/mL N-chlorosuccinimide/methanol solution and 100μL of 3% acetic acid/methanol solution with a concentration of 1 mg/mL of compound 5 were added to ²¹¹ At in a glass vial. After the reaction solution was left at 70℃ for 20 minutes, 50μL of 2 mg/mL sodium sulfite aqueous solution was added to terminate the reaction, and then 1 mL of distilled water was added. Purification was performed by RadioHPLC and the retention time was about 16 minutes was separated. The separated solution was concentrated and then redissolved in 200-300μL of physiological saline: 2 mg/mL sodium ascorbate aqueous solution: Tween 80 (85:14:1) to obtain ²¹¹ At-AITM-D4 injection. The total process time was 1.5 hours, the radiochemical yield was 42.2±2.7% (at the end of synthesis, n=5), and the radiochemical purity was 99% or more. RadioHPLC and RadioTLC charts of the purified ²¹¹ At-AITM-D4 are shown in Figure 2 and Figure 3, respectively. The HPLC conditions were set to the same as those in Example 2.

Example 4: Stability test of ²¹¹ At-AITM-D4 The stability in serum was measured using ²¹¹ At-AITM-D4 prepared in Example 3. 2 MBq of ²¹¹ At-AITM-D4 was mixed with 30 μL of mouse serum and left to stand at 37° C. for 24 hours. 1 μL of serum was supported on a TLC and developed using ethyl acetate as a solvent. After drying, detection was performed using a RadioTLC scanner. The results are shown in FIG. 4. After 24 hours, the proportion of unchanged ²¹¹ At-AITM-D4 in serum was 90.6 ± 1.3% (n = 5), and the proportion of unchanged ²¹¹ At-AITM was 78.5 ± 1.0% (n = 3). Statistical analysis of the comparison with ²¹¹ At-AITM whose aromatic ring is not deuterated showed p < 0.0001, and the stability in serum was improved by 11%. It was revealed that the proportion of the unchanged substance was significantly increased due to the effect of deuterium-doping the aromatic ring.

Example 5: Cellular uptake and distribution of ^211At -AITM-D4 Transplantable B16Fl0 melanoma cells in C57BL/6J mice were obtained from the American Type Culture Collection. B16Fl0 cells were maintained and passaged in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, penicillin (100 U/mL), and streptomycin (0.1 mg/mL). B16F10 melanoma cells (5× ¹⁰⁴ cells) were seeded in a 24-well plate and cultured for 24 hours as adherent cells. ²¹¹ At-AITM-D4 (18.5 kBq/mL) prepared in Example 3 and binding inhibitor FITM (4-fluoro-N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide) were added to the cells at a concentration of 10 mmol/L and allowed to stand at 37°C for 1 hour. After removing the supernatant, the cells were washed with phosphate-buffered saline (PBS) and then lysed with 0.2 mol/L NaOH. Radioactivity was measured using a γ-counter (PerkinElmer), and the protein content of the cell lysate was quantified using a protein assay kit (Bio-RAD). The amount of uptake into the cells was calculated as the amount of radioactivity used per protein weight (mg) (%ICD/mg protein). The measurement results of the amount of uptake into the cells are shown in Figure 5. The amount of cellular uptake after 1 hour for ^211At -AITM was 20.64±2.97 (%ICD/mg protein), whereas for ^211At -AITM-D4 it was 57.61±8.38 (%ICD/mg protein), a 2.5-fold increase in cellular uptake. The results of cellular distribution are shown in Figure 6. It was also confirmed that the internalization rate of ^211At -AITM-D4 was higher than that of 211At-AITM-D4.

Example 6 Preparation of ¹²³ I-Py[D4] Na ¹²³ I was purchased from PDR Pharma. 1 mg of 3-pyridine-d4-boronic acid was added with 40 μL of acetonitrile, 15 μL of a methanol solution containing 1 mg of Cu(OTf) ₂ (Py) ₄ and 355 μg of 3,4,7,8-tetramethyl-1,10-phenanthroline, and 50 μL of the above-prepared Na ¹²³ I methanol solution, and left to stand at 70° C. for 20 minutes. The reaction solution was added to 10 mL of water and collected in a Sep-PAK C18 light column, and the column was washed with 10 mL of water, and the target product was recovered with 300 μL of ethanol. After drying the EtOH, the target product ( ¹²³ I-Py[D4]) was obtained by redissolving in physiological saline. ^123I -Py[D4] is a compound in which four hydrogen atoms on the pyridine ring of pyridine are replaced with deuterium and further labeled with ^123I . The radiochemical yield was 96.3% and the radiochemical purity was 97.8%. The RadioTLC chart after purification is shown on the left in Figure 7.

[Example 7] Preparation of ¹²³ I-Py ¹²³ I-Py was synthesized in the same manner as in Example 6, with a radiochemical yield of 96.2% and a radiochemical purity of 96.2%. The RadioTLC chart after purification is shown on the right side of Figure 7. ¹²³ I-Py is pyridine labeled with ¹²³ I.

Example 8 Preparation of ²¹¹ At-Py[D4] ^50μL of 0.1 mol/L Na ₂ CO ₃ was added to 211 At in a glass vial, and after standing for 1 minute, 300μL of methanol was added. 40μL of acetonitrile, 15μL of a methanol solution containing 1mg of Cu(OTf) ₂ (Py) ₄ and 355μg of 3,4,7,8-tetramethyl-1,10-phenanthroline, and 150μL of the ²¹¹ At solution prepared above were added to 1mg of ₃ -pyridine-d 4 -boronic acid, and the mixture was left to stand at 70℃ for 20 minutes. The reaction solution was added to 10mL of water and collected in a Sep-PAK C18 light column, and the column was washed with 10mL of water, and the target product ( ²¹¹ At-Py[D4]) was collected with 300μL of ethanol. ²¹¹ At-Py[D4] is a compound in which the four hydrogen atoms on the pyridine ring of pyridine are replaced with deuterium and further labeled with ²¹¹ At. After drying the EtOH, the product was redissolved in saline to obtain the target compound. The radiochemical yield was 19.5%, and the radiochemical purity was 98.0%. The RadioTLC chart after purification is shown on the left in Figure 8.

[Example 9] Preparation of ²¹¹ At-Py ²¹¹ At-Py was synthesized in the same manner as in Example 8, with a radiochemical yield of 20.3% and a radiochemical purity of 95.6%. The RadioTLC chart after purification is shown on the right side of Figure 8. ²¹¹ At-Py is pyridine labeled with ²¹¹ At.

Example 10: Stability test of ^123I -Py[D4] and ^211At -Py[D4] The stability in serum was measured using deuterated pyridine with radioactive halogen and pyridine with radioactive halogen prepared in Examples 6 to 9. 2 MBq of the radioactive compound was mixed with 10 uL of mouse serum and allowed to stand at 37°C for 24 hours. 1 μl of the serum mixture was loaded onto a TLC and developed using ethyl acetate as a solvent. After drying, detection was performed using a RadioTLC scanner. The results are shown in Figure 9. After 24 hours, the proportion of unchanged compounds in serum was 96.9±0.1% (n=3) for ^123I -Py[D4] and ^95.1 ±0.6% (n=3) for 211At-Py[D4], whereas it was 93.4±0.9% (n=3) for ^123I -Py and 92.2±0.6% (n=3) for ^211At -Py. The statistical analysis for the iodine form was ns (Fig. 9, left), and the statistical analysis for the astatine form was p=0.0008 (Fig. 9, right). The deuterium-doped pyridine ring increased the proportion of unchanged compounds, demonstrating its effectiveness against astatine compounds.

Summary of the Examples
^211At -AITM-D4, a radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring, has been found to have high metabolic stability and to be useful as a radioactive diagnostic or radioactive therapeutic agent.

The present invention is applicable in the medical field, and in particular, to the diagnosis or treatment of diseases involving cells expressing mGluR1.

Claims (10)

A compound of formula (I), a pharma- ceutically acceptable salt thereof, or a solvate thereof:

In formula (I),
^X1 and ^X2 are each independently a radioactive halogen nuclide, hydrogen or deuterium;
R ¹ , R ² and R ³ are each independently hydrogen or deuterium;
At least one of X ¹ , X ² _, R ¹ , R ² and R ³ is deuterium;
At least one of ^X1 and ^X2 is a radioactive halogen nuclide;
Y is a methyl group and an isopropyl group. 2. The compound of claim 1, wherein the radioactive halogen nuclide is ²¹¹ At, or a pharma- ceutically acceptable salt or solvate thereof. One of ^X1 and ^X2 is ^211At and the other is deuterium;
3. The compound according to claim 1 or 2, wherein R ¹ , R ² and R ³ are each deuterium, or a pharma- ceutically acceptable salt or solvate thereof. A radiotherapeutic or radiodiagnostic agent comprising, as an active ingredient, the compound according to any one of claims 1 to 3, a medicamentously acceptable salt thereof, or a solvate thereof. A method for producing a radiolabeled deuterated aromatic carbonyl compound, its medicamentarily acceptable salt, or its solvate, comprising a labeling step of carrying out an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction between an aromatic carbonyl compound in which at least one hydrogen atom on an aromatic ring or a heteroaromatic ring is replaced with deuterium and a radioactive halogen nuclide at 50°C or higher and 220°C or lower, thereby labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide. The method of claim 5, wherein the labeling step is carried out in the presence of an acid and an oxidizing agent. The aromatic carbonyl compound has a radioactive halogen nuclide-introducing group on an aromatic ring or a heteroaromatic ring,
The method according to claim 5 or 6, wherein the radioactive halogen nuclide introducing group is selected from boronic acid, boronic acid ester, trialkylstannyl group, trialkylsilyl group, trialkylgermyl group, chloro, bromo, iodo, nitro group, trimethylammonium trifluoromethanesulfonate, sulfonic acid group, iodonium salt, or iodonium ylide group. The method according to any one of claims 5 to 7, wherein the aromatic carbonyl compound is a compound of the following formula (II):

In formula (II),
^X11 and ^X12 are each independently a radioactive halogen nuclide introducing group, hydrogen or deuterium;
R ¹¹ , R ¹² , and R ¹³ are each independently hydrogen or deuterium;
At least one of X ¹¹ , X ¹² _, R ¹¹ , R ¹² and R ¹³ is deuterium;
At least one of X ¹¹ and X ¹² is a radioactive halogen nuclide-introducing group;
Y is a methyl group and an isopropyl group;
The radioactive halogen nuclide-introducing group is a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, a chloro, a bromo, an iodo, a nitro group, a trimethylammonium trifluoromethanesulfonate salt, a sulfonic acid group, an iodonium salt, or an iodonium ylide group. One of ^X11 and ^Xs12 is the radioactive halogen nuclide introducing group, and the other is deuterium;
The method according to claim 8, wherein R ¹¹ , R ¹² and R ¹³ are each deuterium. A method for producing a radioactive therapeutic agent or a radioactive diagnostic agent, comprising a step of producing a radioactively labeled deuterated aromatic carbonyl compound, a medicamentously acceptable salt thereof, or a solvate thereof by the production method according to any one of claims 5 to 9.

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