Radiolabeled compounds and their uses

Abstract

The purpose of the present invention is to provide a drug which specifically binds to PSMA, which is effective in treatment and diagnosis of tumors or cancers that express PSMA, such as treatment and diagnosis of prostate cancer, especially castration-resistant prostate cancer (CRPC), and further especially castration-resistant prostate cancer with metastasis (mCRPC), and which does not produce any side effects due to accumulation in the kidney and salivary glands.　The present invention provides a radiolabeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The present invention is represented by formula (I). (I) [In the formula, each symbol is as defined in the description.]

Description

[Technical Field]

[0001] The present invention relates to radiolabeled compounds useful as therapeutic and / or diagnostic agents for prostate cancer, and to a method for producing the same. [Background technology]

[0002] Prostate cancer is the most common cancer in men, and if detected early, it has a good prognosis (5-year survival rate of over 95%). Initial treatment involves radical or partial resection of the primary tumor, or radiation therapy. Hormone therapy with drugs is also an effective treatment. However, recurrence or metastasis over time is not uncommon. After recurrence, hormone therapy may initially be effective, but it gradually becomes resistant, leading to castration-resistant prostate cancer (CRPC), and especially castration-resistant prostate cancer with metastasis (mCRPC), which becomes extremely difficult to treat. The development of drugs effective in the treatment and diagnosis of such CRPC is desired.

[0003] Prostate-specific membrane antigen (PSMA) is attracting attention as a target molecule for prostate cancer. PSMA is highly expressed not only in primary prostate cancer lesions but also in recurrent lesions and metastatic lesions in lymph nodes and bones. Therefore, it is suggested that drugs that specifically bind to PSMA may be effective in the treatment and diagnosis of CRPC and mCRPC. It should be noted that PSMA is also expressed in the kidneys and salivary glands in normal tissues, so it is important that drugs that specifically bind to PSMA do not cause side effects due to accumulation in the kidneys and salivary glands.

[0004] Targeting PSMA 177 Lu (beta-emitting radionuclide) and 225 Drugs labeled with Ac (alpha-emitting radionuclide) have been reported (Patent Document 1). While the former drug has some effect in treating CRPC patients, it is known that there are still cancer patients who cannot be treated with this drug. The latter drug, which is expected to have a stronger therapeutic effect, has been reported to have side effects on the salivary glands, and side effects on renal function due to the progeny radionuclides have also been suggested.

[0005] Being the same alpha-ray emitting nuclide 211 At has a half-life that is 225 shorter than that of Ac ( 211 At: 7.2 hours, 225 Ac: 10 days), 211 drugs labeled with At have a short duration of action, allowing for outpatient treatment. Additionally, since it is a short-lived nuclide, it has the advantage of a lower risk of prolonged side effects, and its usefulness as a new anticancer agent is expected. With PSMA as the target molecule 211 various drugs labeled with At (an alpha-ray emitting nuclide) have been reported (Patent Documents 2 and 3, Non-Patent Documents 1 and 2). However, there are issues regarding optimization of pharmacokinetics and side effects caused by renal accumulation, and no drug has progressed to the clinical trial stage at present.

[0006] Furthermore, with PSMA as the target molecule 18 it has been reported that F-labeled drugs are useful as PET diagnostic imaging agents (Patent Document 4).

PRIOR ART DOCUMENTS

PATENT DOCUMENTS

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

NON-PATENT DOCUMENTS

[0008]

Non-Patent Document 1

Non-Patent Document 2

SUMMARY OF THE INVENTION

[0009] The present invention aims to provide a drug that specifically binds to PSMA and is effective in the treatment and diagnosis of tumors or cancers that express PSMA, such as prostate cancer, particularly castration-resistant prostate cancer (CRPC), and especially castration-resistant prostate cancer with metastasis (mCRPC), and that does not cause side effects due to accumulation in the kidneys or salivary glands. [Means for solving the problem]

[0010] As a result of diligent research to solve the above problems, the inventors have found that a novel radiolabeled compound represented by the following formula (I) specifically binds to PSMA and is effective in the treatment and diagnosis of tumors or cancers that express PSMA, such as prostate cancer, in particular castration-resistant prostate cancer (CRPC), and especially castration-resistant prostate cancer with metastasis (mCRPC), and does not cause side effects due to accumulation in the kidneys or salivary glands, thus completing the invention.

[0011] In other words, the present invention is as follows: [1] A radiolabeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as radiolabeled compound (I)).

[0012] [ka]

[0013] [In the formula, p1 unit -CO-A 1 -NH- independently represents an amino acid residue; p2 units -CO-A 2 -NH- independently represents an amino acid residue; L 1 This is a single bond, or -CO-(CH2) m1 -CO- (where m1 represents an integer from 1 to 6) is shown; L 2This is a single bond, or -NH-(CH2) m2 The formula represents -CH(COOH)-NH- (where m² represents an integer from 1 to 6); Ar is C 6-14 It shows an aryl group; q R 1 These are, independently, hydrogen atoms and C 1-6 Represents an alkyl group or an amino group; q R 2 These are, independently, hydrogen atoms or C 1-6 This indicates an alkyl group; n R 3 These are, independently, C 1-6 This indicates an alkyl group or a hydroxyl group; X is 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Shows radionuclides selected from Br; p1 represents an integer between 0 and 3; p2 represents an integer between 0 and 3; q represents an integer between 0 and 3; n represents an integer between 0 and 3.

[0014] [2] L 1 and L 2 The compounds described in [1] above or their pharmaceutically acceptable salts thereof, wherein both are single bonds. [3] L 1 ga-CO-(CH2) m1 -CO- (wherein m1 is equivalent to [1] above), and L 2 -ga-NH-(CH2) m2 A compound described in [1] above or a pharmaceutically acceptable salt thereof, wherein the compound is -CH(COOH)-NH- (wherein m2 is the same as in [1] above).

[0015] [4] p1-CO-A 1A compound described in any of [1] to [3] above, wherein at least one of the -NH- groups is a glutamic acid residue, or a pharmaceutically acceptable salt thereof. [5] A compound or pharmaceutically acceptable salt thereof described in any of [1] to [4] above, wherein p1 is an integer between 0 and 2.

[0016] [6] p2-CO-A 2 A compound described in any of [1] to [5] above, wherein at least one of the -NH- groups is a glycinic acid residue, or a pharmaceutically acceptable salt thereof. [7] A compound or pharmaceutically acceptable salt thereof described in any of [1] to [6] above, wherein p2 is 0 or 1.

[0017] [8] A compound according to any of [1] to [7] above, wherein Ar is a phenyl group, or a pharmaceutically acceptable salt thereof. [9] R 1 and R 2 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to [8], wherein the compound is a hydrogen atom.

[10] A compound or a pharmaceutically acceptable salt thereof described in any of [1] to [9] above, wherein q is an integer from 1 to 3.

[0018]

[11] A pharmaceutical composition comprising any of the compounds described in [1] to

[10] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[12] A therapeutic agent for tumors or cancers expressing prostate-specific membrane antigen (PSMA), comprising any of the compounds described in [1] to

[10] above or a pharmaceutically acceptable salt thereof.

[13] The therapeutic agent described in

[12] above, wherein the tumor or cancer expressing PSMA is prostate cancer.

[14] A diagnostic agent for tumors or cancers expressing prostate-specific membrane antigen (PSMA), comprising any of the compounds described in [1] to

[10] above or a pharmaceutically acceptable salt thereof.

[15] The diagnostic agent described in

[14] above, wherein the tumor or cancer expressing PSMA is prostate cancer.

[0019]

[16] Compounds represented by formula (II) or salts thereof (hereinafter also referred to as boronic acid compounds (II)).

[0020] [ka]

[0021] [In the formula, p1 unit -CO-A 1 -NH- independently represents an amino acid residue; p2 units -CO-A 2 -NH- independently represents an amino acid residue; L 1 This is a single bond, or -CO-(CH2) m1 -CO- (where m1 represents an integer from 1 to 6) is shown; L 2 This is a single bond, or -NH-(CH2) m2 The formula represents -CH(COOH)-NH- (where m² represents an integer from 1 to 6); Ar is C 6-14 It shows an aryl group; q R 1 These are, independently, hydrogen atoms and C 1-6 Represents an alkyl group or an amino group; q R 2 These are, independently, hydrogen atoms or C 1-6 This indicates an alkyl group; n R 3 These are, independently, C 1-6 This indicates an alkyl group or a hydroxyl group; Y represents a boryl group (-B(OH)2) or its ester group; p1 represents an integer between 0 and 3; p2 represents an integer between 0 and 3; q represents an integer between 0 and 3; n represents an integer between 0 and 3.

[17] The compound or salt thereof described in

[16] above, wherein Y is a boryl group (-B(OH)2) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group.

[0022]

[18] A method for producing a radiolabeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0023] [ka]

[0024] [In the formula, p1 unit -CO-A 1 -NH- independently represents an amino acid residue; p2 units -CO-A 2 -NH- independently represents an amino acid residue; L 1 This is a single bond, or -CO-(CH2) m1 -CO- (where m1 represents an integer from 1 to 6) is shown; L 2 This is a single bond, or -NH-(CH2) m2 The formula represents -CH(COOH)-NH- (where m² represents an integer from 1 to 6); Ar is C 6-14 It shows an aryl group; q R 1 These are, independently, hydrogen atoms and C 1-6 Represents an alkyl group or an amino group; q R 2 These are, independently, hydrogen atoms or C 1-6 This indicates an alkyl group; n R 3 These are, independently, C 1-6 This indicates an alkyl group or a hydroxyl group; X is 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77Br and 76 Shows radionuclides selected from Br; Y represents a boryl group (-B(OH)2) or its ester group; p1 represents an integer between 0 and 3; p2 represents an integer between 0 and 3; q represents an integer between 0 and 3; n represents an integer between 0 and 3. Step 1: The compound represented by formula (II) or a salt thereof is heated in water in the presence of a reagent selected from alkali metal iodide, alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide. 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 A step of reacting a radionuclide selected from Br with a radioactively labeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0025] According to the present invention, it is possible to provide a radiolabeled compound that specifically binds to PSMA and is effective in the treatment and diagnosis of tumors or cancers that express PSMA, such as prostate cancer, in particular castration-resistant prostate cancer (CRPC), and especially castration-resistant prostate cancer with metastasis (mCRPC), and does not exhibit side effects due to accumulation in the kidneys or salivary glands. [Brief explanation of the drawing]

[0026] [Figure 1] Figure 1 shows the analysis results of the reaction solution and eluate in Example 3 using thin-layer chromatography (TLC). Figure 1(a) shows the analysis results of the reaction solution, and Figure 1(b) shows the analysis results of the eluate. [Figure 2]Figure 2 shows the analysis results of the reaction solution and eluate in Example 4 using thin-layer chromatography (TLC). Figure 2(a) shows the analysis results of the reaction solution, and Figure 2(b) shows the analysis results of the eluate. [Figure 3] Figure 3 shows the analysis results of the reaction solution and eluate in Example 7 using thin-layer chromatography (TLC). Figure 3(a) shows the analysis results of the reaction solution, and Figure 3(b) shows the analysis results of the eluate. [Figure 4] Figure 4 shows the analysis results of the reaction solution and eluate in Example 8 using thin-layer chromatography (TLC). Figure 4(a) shows the analysis results of the reaction solution, and Figure 4(b) shows the analysis results of the eluate. [Figure 5] Figure 5 shows imaging of human prostate cancer transplanted mice using compound 3 in Test Example 1. [Figure 6] Figure 6 shows the therapeutic effect of compound 3 on human prostate cancer transplanted mice in Test Example 2. [Figure 7] Figure 7 shows the in vivo distribution of compound 3 in normal mice in Test Example 3. Figure 7(a) shows the radioactive distribution rate, and Figure 7(b) shows the radioactivity distribution rate per gram of organ weight. [Figure 8] Figure 8 shows the in vivo distribution of compound 3 in human prostate cancer transplanted mice in Test Example 3. Figure 8(a) shows the radioactive distribution rate, and Figure 8(b) shows the radioactivity distribution rate per gram of organ weight. [Figure 9] Figure 9 shows the in vivo distribution of compound 4 in normal mice in Test Example 3. Figure 9(a) shows the radioactivity distribution rate, and Figure 9(b) shows the radioactivity distribution rate per gram of organ weight. [Figure 10] Figure 10 shows the in vivo distribution of compound 7 in human prostate cancer transplanted mice in Test Example 3. Figure 10(a) shows the radioactivity distribution rate, and Figure 10(b) shows the radioactivity distribution rate per gram of organ weight. [Figure 11]Figure 11 shows the in vivo distribution of compound 8 in normal mice in Test Example 3. Figure 11(a) shows the radioactivity distribution rate, and Figure 11(b) shows the radioactivity distribution rate per gram of organ weight. [Figure 12] Figure 12 shows the therapeutic effect of compound 3 on human prostate cancer transplanted mice in Test Example 4. Figure 12(a) shows the change in tumor size, and Figure 12(b) shows the change in body weight. [Figure 13] Figure 13 shows the therapeutic effect of compound 7 on human prostate cancer transplanted mice in Test Example 4. Figure 13(a) shows the change in tumor size, and Figure 13(b) shows the change in body weight. [Figure 14] Figure 14 shows the therapeutic effect of compound 8 on human prostate cancer transplanted mice in Test Example 4. Figure 14(a) shows the change in tumor size, and Figure 14(b) shows the change in body weight. [Modes for carrying out the invention]

[0027] The present invention will be described in detail below. In this specification, "C 1-3 Examples of alkyl groups include methyl, ethyl, propyl, and isopropyl. In this specification, "C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Preferably, "C 1-3 It is an alkyl group. In this specification, "C 6-14 Examples of "aryl groups" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

[0028] In this specification, "amino acid residue" means a divalent group obtained by removing H from the amino group and OH from the carboxyl group of an amino acid. The amino acid in the amino acid residue is not particularly limited as long as it has an amino group and a carboxyl group, and may be a natural (L-type), unnatural (D-type), or artificial amino acid. Furthermore, the above amino acid may be any of α-amino acids, β-amino acids, γ-amino acids, etc. It may also be a cyclic amino acid as shown below.

[0029] [ka]

[0030] [Each symbol in the formula has the same meaning as described above.] Examples of α-amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, arginine, histidine, glutamine, asparagine, phenylalanine, tyrosine, α-methyltyrosine, tryptophan, ornithine, thyroxine, proline, 3,4-dihydroxyphenylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine, α-aminobutyric acid, norvaline, norleucine, homonorleucine, 1,2,4-triazole-3-alanine, 2-aminoadipic acid, propargylglycine, allylglycine, α-cyclobutylmethylglycine, 6-azidonorleucine, 4-azidophenylalanine, 4-fluoroglutamic acid, 4-iodophenylalanine, etc. Examples of β-amino acids include β-alanine and 3-aminoadipic acid; Examples of γ-amino acids include γ-aminobutyric acid; Examples include: If an amino acid has a functional group in its side chain, that functional group may be protected / modified.

[0031] In this specification, "boryl group (-B(OH)2)" is also referred to as the dihydroxyboryl group. In this specification, "ester group of a boryl group" includes, for example, the following groups.

[0032] [ka]

[0033] [In the formula, R 4 C 1-6 This indicates an alkyl group. In this specification, "protected amino acid residue" means an amino acid residue in which a functional group is protected, if the amino acid residue has a functional group. If it has an amino group, it is protected with an amino protecting group such as a tert-butoxycarbonyl group (Boc group), and if it has a carboxyl group, it is protected with a carboxy protecting group such as a tert-butyl group. These protecting groups are appropriately selected depending on other protecting groups, the type of resin used for solid-phase synthesis, the synthesis strategy, etc. In this specification, "protected hydroxyl group" refers to a hydroxyl group protected by a "hydroxy protecting group," and examples of "hydroxy protecting groups" include benzyl group, p-methoxybenzyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group, trityl group, tert-butyl group, tert-butyldimethylsilyl group, tetrahydropyranyl group, and the like. In this specification, "protected amino group" refers to an amino group protected by an "amino protecting group," and examples of "amino protecting groups" include the 9-fluorenylmethyloxycarbonyl group (Fmoc group), the Boc group, and the benzyloxycarbonyl group (Cbz group). In this specification, "carboxyprotecting group" refers to, for example, a tert-butyl group, a benzyl group, or C 1-2 Examples include alkyl groups (methyl group, ethyl group) and diphenylmethyl group.

[0034] The radiolabeled compound (I) of the present invention is the compound shown below.

[0035] [ka]

[0036] [Each symbol in the formula has the same definition as described above.] p1 groups of -CO-A 1 -NH- each independently represent an amino acid residue. In one embodiment, the amino acid residue is preferably a glutamic acid residue (Glu). In one embodiment, among the p1 amino acid residues, at least one is preferably a glutamic acid residue. In another embodiment, among the p1 amino acid residues, at least two are preferably glutamic acid residues. The configuration of the amino acid residue is not particularly limited, and may be any of D-form, L-form, and DL-form (that is, any of R-form, S-form, and R / S-form). p1 represents an integer of 0 to 3. In one embodiment, p1 is preferably an integer of 0 to 2. In one embodiment, -(CO-A 1 -NH)p1- is preferably a single bond, or -L-Glu-L-Glu- or -D-Glu-D-Glu-.

[0037] p2 groups of -CO-A 2 -NH- each independently represent an amino acid residue. In one embodiment, the amino acid residue is preferably a glycine residue (Gly). In one embodiment, among the p2 amino acid residues, at least one is preferably a glycine residue. The configuration of the amino acid residue is not particularly limited, and may be any of D-form, L-form, and DL-form (that is, any of R-form, S-form, and R / S-form). p2 represents an integer of 0 to 3. In one embodiment, p2 is preferably 0 or 1. In one embodiment, -(CO-A 2 -NH)p2- is preferably a single bond, or -Gly-.

[0038] L 1 is a single bond, or -CO-(CH2) m1-CO- (wherein m1 represents an integer of 1 to 6). In one embodiment, m1 is preferably 2 or 3, particularly preferably 2. L 2 represents a single bond, or -NH-(CH2) m2 -CH(COOH)-NH- (wherein m2 represents an integer of 1 to 6). In one embodiment, m2 is preferably an integer of 3 to 5, particularly preferably 4. L 1 and L 2 preferred combinations include (1) L 1 and L 2 are both single bonds, (2) L 1 is -CO-(CH2) m1 -CO- (wherein m1 has the same definition as above), and L 2 is -NH-(CH2) m2 -CH(COOH)-NH- (wherein m2 has the same definition as above), and the like.

[0039] q R 1 each independently represent a hydrogen atom, C 1-6 alkyl group (e.g., methyl) or an amino group. In one embodiment, R 1 is preferably a hydrogen atom. q R 2 each independently represent a hydrogen atom or C 1-6 alkyl group (e.g., methyl). In one embodiment, R 2 is preferably a hydrogen atom. q represents an integer of 0 to 3. In one embodiment, q is preferably an integer of 1 to 3, more preferably 1.

[0040] Ar represents C 6-14 aryl group. In one embodiment, Ar is preferably a phenyl group. n R 3 These are, independently, C 1-6 This indicates an alkyl group (e.g., methyl) or a hydroxyl group. n represents an integer between 0 and 3. In one embodiment, n is preferably 0.

[0041] X is 211 At (α-ray emitting nuclide), 210 At (α-ray emitting nuclide), 131 I (beta-emitting radionuclide), 125 I (X-ray emitting radionuclide), 124 I (positron-emitting nuclide), 123 I (γ-ray emitting nuclide), 77 Br (Auger electron-emitting radionuclide) and 76 This shows the radioactive nuclide selected from Br (positron-emitting nuclide). The half-lives of these radionuclides are: 211 At 7.2 hours, 210 At 8.3 hours, 131 I on 8.04 125 I was 59.4 days old. 124 I on April 2nd, 123 I was 13.2 hours, 77 Br for 57 hours, 76 Br is 16 hours. The bond position of X on Ar is not particularly limited, but for example, when Ar is a phenyl group, the 3rd or 4th position is preferred.

[0042] Naphthylalanine residue in formula (I)

[0043] [ka]

[0044] The three-dimensional configuration is not particularly restricted and may be D-body, L-body, or DL-body (i.e., R-body, S-body, or R / S-body).

[0045] Also, the lysine-glutamic acid residue in formula (I)

[0046] [ka]

[0047] The three-dimensional arrangement is not particularly restricted and any of the following three-dimensional arrangements are acceptable.

[0048] [ka]

[0049] In one embodiment, the lysine-glutamic acid residue is

[0050] [ka]

[0051] It is preferable that this be the case. In other words, compound (I) is preferably compound (Ia) as shown below.

[0052] [ka]

[0053] [Each symbol in the formula has the same meaning as described above.]

[0054] Specific examples of radiolabeled compounds (I) include the following:

[0055] [ka]

[0056] [ka]

[0057] [In the formula, X is equivalent to the above.]

[0058] The compound represented by formula (I) may also be in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include, for example, if the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), ammonium salts, etc., and if the compound has a basic functional group, salts with inorganic acids such as hydrogen chloride, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid.

[0059] The chiral carbon atom in the radiolabeled compound (I) may be D-coordinate or L-coordinate. The radiolabeled compound (I) has optical isomers based on the chiral carbon atom, but any optical isomer, or any mixture thereof in any proportion, is included in the radiolabeled compound (I).

[0060] The method for producing the radiolabeled compound (I) of the present invention is described below. In this specification, when the raw material compound is a salt, such salts include, for example, metal salts (e.g., alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt), ammonium salts, salts with organic bases (e.g., trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine), salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid), and salts with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid).

[0061] The radiolabeled compound (I) can be produced by a method comprising the following step 1.

[0062] [ka]

[0063] [Each symbol in the formula has the same meaning as described above.] Y represents a boryl group (-B(OH)2) or its ester group. Y is preferably a boryl group (-B(OH)2) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group (pinacol ester group).

[0064] Step 1 involves ferric acid compound (II) in water in the presence of a reagent selected from alkali metal iodide, alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide. 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 This is a step in which a radioactive nuclide selected from Br is reacted to obtain a radiolabeled compound (I).

[0065] Boronic acid compound (II) is a novel compound. In one embodiment, the boronic acid compound (II) is preferably the boronic acid compound (IIa) shown below.

[0066] [ka]

[0067] [Each symbol in the formula has the same meaning as described above.]

[0068] Specific examples of boronic acid compounds (II) include the following:

[0069] [ka]

[0070] [ka]

[0071] Boronic acid compound (II) can be produced by the method described later. Since the reaction in this process takes place in water, the boronic acid compound (II) may be in free form or salt form as long as it is soluble in water. Alternatively, it may be used dissolved in a weakly basic aqueous solution such as sodium bicarbonate solution.

[0072] Examples of alkali metal iodides include potassium iodide and sodium iodide, with potassium iodide being particularly preferred. Examples of alkali metal bromides include sodium bromide and potassium bromide.

[0073] Suitable combinations of radionuclides and the above reagents include: (1) Radioactive nuclides 211 Tom or 210 At, and the above reagent is selected from potassium iodide, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide; (2) Radioactive nuclides 123 I, 124 I, 125 I or 131 I is a combination in which the above reagent is selected from N-bromosuccinimide and N-chlorosuccinimide; (3) Radioactive nuclides 76 Br or 77 A combination in which the reagent is Br and the reagent is N-chlorosuccinimide; These are some examples. The above reagents may be used individually or in combination of two or more. The above reagents are usually used in aqueous solution form. A preferred embodiment is a radionuclide 211 Tom or 131 The reagent is I, and the reagent is selected from potassium iodide and N-bromosuccinimide. A more preferred embodiment is, Radioactive nuclides 211 A configuration in which At is present and the reagent is potassium iodide, and the radionuclide is131 Embodiment in which I and the reagent is N-bromosuccinimide These are some examples.

[0074] The above reagent should be used in an amount sufficient to oxidize or reduce the radionuclide. It is usually used in large excess relative to the radionuclide, but from the viewpoint of reaction efficiency and economic efficiency, it is preferably used at a concentration of 0.0001 to 0.2 mol / L, more preferably 0.001 to 0.1 mol / L.

[0075] Radioactive nuclides are typically used in reactions in aqueous solution form. If necessary, an alkaline aqueous solution such as sodium hydroxide or a buffer solution may be added to the aqueous solution to stabilize the radioactive nuclide. Radioactive nuclides 211 In the case of At, helium particles accelerated to 28 MeV in a cyclotron are irradiated onto bismuth. 209 Bi(α,2n) 211 Due to the nuclear reaction of At 211 After manufacturing At, the target substance 209 Bi melts when heated, 211 At is evaporated and collected in a cooling trap, and then dissolved in water, 211 Prepare the stock solution. If necessary, 211 For the purpose of stabilizing At, an alkaline aqueous solution such as sodium hydroxide or a buffer solution may be added. Radioactive nuclides 210 In the case of At, helium particles accelerated to over 29 MeV in a cyclotron are irradiated onto bismuth. 209 Bi(α,3n) 210 Due to the nuclear reaction of At 210 After manufacturing At, perform the same operation as described above. 210 Prepare an aqueous solution of At. Radioactive nuclides 123 In the case of I, Na 123 It is available as an aqueous solution. Radioactive nuclides 124 In case I, proton particles accelerated by a cyclotron are irradiated onto tellurium. 124 Te(p,n) 124 Due to the nuclear reaction of I 124After manufacturing I, the target substance 124 Dissolve Te, 124 Prepare a sodium hydroxide solution of I. Radioactive nuclides 125 In the case of I, Na 125 It is available as an aqueous solution. Radioactive nuclides 131 In the case of I, Na 131 It is available as an aqueous solution. Radioactive nuclides 76 In the case of Br, proton particles accelerated by a cyclotron are irradiated onto tellurium. 76 Se(p,n) 76 Due to the nuclear reaction of Br 76 After producing Br, the target substance 76 Dissolve Se, 76 Prepare a sodium hydroxide solution of Br. Radioactive nuclides 77 In the case of Br, proton particles accelerated by a cyclotron are irradiated onto tellurium. 77 Se(p,n) 77 Due to the nuclear reaction of Br 77 After producing Br, the target substance 77 Dissolve Se, 77 Prepare a sodium hydroxide solution of Br. 211 At has a half-life of 7.2 hours. 210 At has a half-life of 8.3 hours. 123 I has a half-life of 13.2 hours. 76 Since Br has a short half-life of 16 hours, the radioactive nuclide must be used in the reaction immediately after preparation. On the other hand, 124 I has a half-life of 4.2 days. 125 I has a half-life of 59.4 days. 131 I has a half-life of 8.04 days. 77 Although Br has a relatively long half-life of 57 hours, it is preferable to use these radionuclides in the reaction as soon as possible after preparation.

[0076] Boronic acid compounds (II) are usually used in large excess relative to radionuclides, but from the viewpoint of reaction efficiency and economic efficiency, they are preferably used at a concentration of 0.00001 mol / l to 0.5 mol / l, more preferably 0.0001 mol / l to 0.2 mol / l, per 1 Bq to 1,000 GBq of radionuclides.

[0077] The above reaction is carried out by mixing the boronic acid compound (II), the reagent, and the radionuclide, and there are no particular restrictions on the order in which these are mixed. Preferably, the reaction is carried out by adding an aqueous solution of the radionuclide to an aqueous solution of the boronic acid compound (II), followed by an aqueous solution of the reagent, or by adding an aqueous solution of the reagent to an aqueous solution of the boronic acid compound (II), followed by an aqueous solution of the radionuclide, and more preferably by adding an aqueous solution of the radionuclide to an aqueous solution of the boronic acid compound (II), followed by an aqueous solution of the reagent.

[0078] The above reaction is carried out in water, that is, in a system that does not contain organic solvents. The above reaction is carried out at 0 to 95°C, preferably 10 to 80°C. The reaction time is 1 minute to 3 hours, preferably 1 minute to 1 hour. The end of the reaction is confirmed by thin-layer chromatography (TLC) analysis, specifically by the disappearance of the free radionuclides.

[0079] In the production method of the present invention, radiolabeled compound (I) can be obtained with a high radiochemical yield of 60% or more, particularly 80% or more, and especially 90% or more. After the reaction is complete, the reaction solution does not contain organic solvents or toxic reagents, so the radiolabeled compound (I) can be immediately formulated into an injectable drug or the like without isolation. The reaction between boronic acid compounds (II) and radionuclides is an electrophilic substitution reaction and / or a nucleophilic substitution reaction. In particular, because the introduction site of the radionuclide in boronic acid compounds (II) is a benzene ring, 211 Tom or 210 In the case of At, it can be successfully introduced into the benzene ring.

[0080] Furthermore, in order to remove by-products, the radiolabeled compound (I) may be purified as necessary. This purification is preferably carried out by a solid-phase extraction column. A solid-phase extraction column that is commonly used in the art can be used.

[0081] Furthermore, after the above purification, ascorbic acid or ascorbate may be added to achieve a final concentration of 0.01% to 10%, preferably 0.1% to 5%. This suppresses the degradation of the radiolabeled compound (I) and allows for its long-term retention.

[0082] Boronic acid compound (II) can be produced by a method comprising the following steps 2 and 3.

[0083] [ka]

[0084] [In the formula, p1 unit -CO-A 1p -NH- independently indicates a protected amino acid residue; p2 units -CO-A 2p -NH- independently indicates a protected amino acid residue; L 2p This is a single bond, or -NH-(CH2) m2 -CH(COOP 1 )-NH-(wherein, P 1 ) indicates a protecting group for the carboxyl group, and m2 is equivalent to the above. q R 1p These are, independently, hydrogen atoms and C 1-6 Represents an alkyl group or a protected amino group; n R 3p These are, independently, C 1-6 It indicates an alkyl group or a protected hydroxyl group; P 2 and P 3 These independently each represent a protecting group for the carboxyl group. RL- indicates a group derived from a solid-phase synthesis resin. All other symbols have the same meaning as described above.

[0085] P 1 Preferably, it is a diphenylmethyl group. P 2 and P 3 Preferably, it is a tert-butyl group. Suitable solid-phase synthesis resins for groups derived from solid-phase synthesis resins, indicated by RL-, include Wang resin and the like.

[0086] Step 2 is the process of reacting compound (V) with compound (IV) to obtain compound (III). This reaction is carried out by solid-phase synthesis.

[0087] Compound (V) is prepared by a common solid-phase synthesis method widely used in peptide synthesis, or by a known synthesis method. After preparation, it is subjected to step 2 by solid-phase synthesis without deresination. Compound (IV) may be a commercially available product or may be prepared by a known synthetic method. The amount of compound (IV) used is usually 1.5 to 4.0 moles, preferably 3.0 moles or more, per mole of compound (V).

[0088] The reaction may be carried out in the presence of a coupling agent, or it may be carried out in the presence of a base after converting compound (IV) to a reactive derivative (e.g., an acid chloride). Examples of condensing agents include hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium (PyBOP), hexafluorophosphate (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium (BOP), and diisopropylcarbodiimide (DIC). Among these, PyBOP is preferred. The amount of condensing agent used is usually 1 mole per mole of compound (IV). When the reaction is carried out in the presence of a coupling agent, it may also be carried out in the presence of a base. Examples of bases include diisopropylethylamine (DIEA) and triethylamine (TEA). When PyBOP is used as the coupling agent, DIEA is preferably used. The amount of base agent used is usually 1 to 2 moles per mole of compound (IV).

[0089] Solvents used in solid-phase synthesis include N-methyl-2-pyrrolidone (NMP) and dimethylformamide (DMF). Solid-phase synthesis is typically carried out by reacting the cells at a temperature in the range of 0 to 60°C, preferably in the range of 10 to 40°C, for a period of 1 to 24 hours, preferably 3 to 12 hours. The compound (III) obtained in this way is washed and then subjected to step 3.

[0090] Step 3 is a step in which compound (III) is subjected to deprotection and deresination to obtain boronic acid compound (II). The deprotection and deresination methods are appropriately selected according to the type of protective group and resin. For example, the carboxyl protecting group (P 1 , P 2 , P 3 (etc.) are tert-butyl groups, diphenylmethyl groups, etc., and protected amino acid residues (-CO-A 1p -NH-, -CO-A 2p When the carboxyl protecting group of -NH- is a tert-butyl group and RL- is a group derived from Wang resin, boronic acid compound (II) can be obtained by treating compound (III) under acidic conditions. Examples of treatments under acidic conditions include acid treatment with trifluoroacetic acid, etc. After the reaction is complete, the solid-phase synthesis resin is removed and the mixture is concentrated to obtain boronic acid compound (II). If necessary, it may be purified by HPLC or other methods.

[0091] The reaction conditions, such as the solvent and reaction temperature, in each step of the manufacturing method of the present invention described above will be described in detail as representative examples in the examples below, but are not necessarily limited to those, and those skilled in the art can appropriately select them based on general knowledge of organic synthesis.

[0092] The radiolabeled compound (I) produced in this manner specifically binds to prostate-specific membrane antigen (PSMA), is then taken up into cells, and accumulates stably. Thus, since the radiolabeled compound (I) targets cells expressing PSMA, the radiolabeled compound (I) containing a therapeutically effective radionuclide may be useful in treating tumors or cancers that express PSMA. Examples of therapeutically effective radionuclides include: 211 At, 210 At, 131 I, 125 I and 77 Br is one example. Furthermore, since the radiolabeled compound (I) targets cells expressing PSMA, the radiolabeled compound (I) containing imaging-effective radionuclides can image tumors or cancers expressing PSMA, and thus may be useful for diagnosis. Imaging-effective radionuclides include: 211 At, 131 I, 124 I, 123 I, 77 Br and 76 Br is one example. 211 At, 131 I, 124 I, 123 I, 77 Br and 76 Compounds (I) radiolabeled with radionuclides selected from Br are used for imaging by positron emission tomography (PET) or single-photon emission tomography (SPECT). Furthermore, the radiolabeled compound (I) can treat or diagnose tumors or cancers expressing PSMA with minimal side effects due to accumulation in the kidneys or salivary glands.

[0093] Tumors or cancers that express PSMA include prostate cancer (including pre-metastatic prostate cancer), particularly castration-resistant prostate cancer (CRPC), and even more particularly castration-resistant prostate cancer with metastasis (mCRPC). Furthermore, since virtually all solid tumors express PSMA in neovascularization, it can also be used to treat or image almost all solid tumors, including brain tumors, head and neck cancers, lung cancers, mediastinal tumors, breast cancers, malignancies of the liver and biliary tract, pancreatic cancers, malignancies of the gastrointestinal tract such as the esophagus, stomach, and colon, malignancies of the kidneys and adrenal glands, malignancies of the urinary tract, bladder cancers, sarcomas, malignant melanomas, uterine and ovarian cancers, malignancies of the testes, and bone tumors. The dosage of radiolabeled compounds (I) used for therapeutic or diagnostic purposes is generally determined by the radionuclide used, the patient's weight, age, sex, treatment / diagnosis site, etc. For example, in human subjects, 211 The recommended single dose for the At-labeled compound (I) is approximately 100 MBq to 900 MBq.

[0094] The radiolabeled compound (I) is typically used as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is a biocompatible solution that takes sterility, pH, isotonicity, and stability into sufficient consideration, and may include any solvent, diluent (including sterile saline, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, Ringer's lactate injection, and other aqueous buffers), dispersion medium, coating, antimicrobial and antifungal agents, isotonic agents, etc. A pharmaceutically acceptable carrier may also include stabilizers, preservatives, antioxidants, or other additives known to those skilled in the art.

[0095] The dosage form of the pharmaceutical composition is not particularly limited, but it can be prepared as an orally administered pharmaceutical composition in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids, or as a parenterally administered pharmaceutical composition in the form of injections for intravenous, intramuscular, or subcutaneous administration, drips, transdermal agents, transmucosal agents, nasal drops, inhalants, suppositories, etc. These preparations can be prepared according to conventional methods. Preferably, they are liquid preparations for oral administration or injection. Such liquid formulations are prepared by dissolving radiolabeled compound (I) in water, but may also be dissolved in physiological saline or glucose solution as needed, and buffers and preservatives may be added. Furthermore, as mentioned above, reducing agents such as ascorbic acid may be further included. In particular, to manufacture injectable formulations, the active ingredient may be dissolved in distilled water for injection along with pH adjusters such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, monohydrogen phosphate, and dihydrogen dihydrogen phosphate, as needed, and isotonic agents such as sodium chloride and glucose, and then sterile filtered and filled into ampoules, or mannitol, dextrin, cyclodextrin, gelatin, etc. may be added and vacuum freeze-dried to prepare an injectable formulation that can be dissolved immediately before use. Alternatively, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may be added to the active ingredient and emulsified in water to prepare an emulsion for injection.

[0096] The half-life of the radioactive nuclide contained in the radiolabeled compound (I) is: 211 At 7.2 hours, 210 At 8.3 hours, 131 I on 8.04 125 I was 59.4 days old. 124 I on April 2nd, 123 I was 13.2 hours, 77 Br for 57 hours, 76 Given the short Br interval of 16 hours, it is desirable to prepare the pharmaceutical composition to contain the required amount of radiolabeled compound (I) immediately before administering it to the subject. [Examples]

[0097] The present invention will be further described in detail by the following embodiments, which are merely examples and do not limit the present invention, and may be modified without departing from the scope of the present invention. In the following examples, the radiochemical yield was calculated using the following formula. Radiochemical yield (%) = (Radioactivity of the target compound in the thin-layer plate / Total radioactivity of the thin-layer plate) × 100

[0098] The abbreviations are as follows: tBu: tert-butyl Fmoc: 9-Fluorenylmethyloxycarbonyl Alloc: Allyloxycarbonyl Naph: Naphthyl Ambz: 4-aminomethylbenzoyl Dpm: Diphenylmethyl Suc: succinyl (-CO-(CH2)-COOH) DCM: Dichloromethane DIEA: Diisopropylethylamine NMP: N-methyl-2-pyrrolidone TCM: Trichloromethane Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) DIC: Diisopropylcarbodiimide Oxyma: Cyano(hydroxyimino)ethyl acetate PyBOP: Hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium TFA: Trifluoroacetic acid TIS: Triisopropylsilane DMSO: Dimethyl sulfoxide DMF: Dimethylformamide

[0099] Example 1: Preparation of Compound 1 Under an Ar atmosphere, triphosgene (0.32 g, 1.1 mmol) was dissolved in DCM (80 mL), cooled to -78°C, and then a solution of HCl·HL-Glu(OtBu)-OtBu (0.80 g, 2.7 mmol) and DIEA (4.6 mL, 27 mmol) in DCM (24 mL) was added dropwise. After 30 minutes, the temperature was raised to room temperature, and HL-Lys(Alloc)-Wang resin, prepared by deprotecting Fmoc-L-Lys(Alloc)-Wang resin (0.54 mmol) with 20% piperidine / NMP, was added and the mixture was stirred for 1.5 hours. After washing the resin, Pd(PPh3)4 (94 mg, 0.08 mmol) and phenylsilane (3.3 mL, 27 mmol) were added to TCM (10 mL) and the mixture was stirred under an Ar atmosphere for 1 hour. After washing the resin, Fmoc-D-Ala(2-Naph)-OH, Fmoc-(4)Ambz-OH, Fmoc-D-Glu(OtBu), and Fmoc-D-Glu(OtBu) were sequentially condensed with DIC-Oxyma, and deprotected with 20% piperidine / NMP, repeating this process to extend the peptide chain. 0.22 mmol (40%) of the obtained resin was taken and mixed with 4-(carboxymethyl)phenylboronic acid (0.12 g, 0.68 mmol), PyBOP (0.35 g, 0.68 mmol), and DIEA (0.13 mL, 0.79 mmol) in NMP (15 mL). The mixture was stirred for 1.5 hours, and the resin was washed to obtain a protected peptide resin. To the obtained protected peptide resin, 30 mL of trifluoroacetic acid cocktail (TFA / TIS / H2O = 95 / 2.5 / 2.5) was added and the mixture was stirred at room temperature for 1 hour to deprotect and deresinize. After filtering off the resin, the trifluoroacetic acid solution was concentrated, and the crude peptide was solidified with diethyl ether and filtered off. Finally, the obtained crude peptide was dissolved in a 30% DMSO aqueous solution and purified by reverse-phase HPLC. The fraction containing the target product was freeze-dried to obtain compound 1 as a freeze-dried powder (yield: 54 mg, purity 99% or higher (HPLC method), molecular weight: observed value 1070.4 [M+H]). + , 1052.4[M-H2O+H] + (Theoretical value: 1070.4 [M+H]).

[0100] [ka]

[0101] Example 2: Preparation of Compound 2 Compound 2 was synthesized using the same procedure as in Example 1, except that Fmoc-D-Ala(2-Naph)-OH and Fmoc-D-Glu(OtBu) were replaced with Fmoc-L-Ala(2-Naph)-OH and Fmoc-L-Glu(OtBu) (Yield: 204 mg, Purity: 99% or higher (HPLC method), Molecular weight: Observed value 1070.3 [M+H]). + , 1052.4[M-H2O+H] + (Theoretical value: 1070.4 [M+H]).

[0102] [ka]

[0103] Example 3: Preparation of Compound 3 The powder of compound 1 obtained in Example 1 was dissolved in a 7% sodium bicarbonate aqueous solution to a concentration of 0.1 mg / mL. In 10 μL of the same solution... 211 20 μL (20 MBq) of an aqueous solution of At and 30 μL of an aqueous solution of 0.1 mol / L potassium iodide were added and reacted at 80°C for 1 hour. The reaction solution was injected into a solid-phase extraction cartridge (Oasis HLB, Waters), the cartridge was washed with 1 mL of water, and then 0.5 mL of an aqueous solution of 30% ethanol was injected into the cartridge to collect the eluate. The reaction solution and eluate were analyzed by thin-layer chromatography (TLC). Silica gel 60 (Merck) was used as the thin-layer plate, and it was developed with an acetonitrile / water mixture (2 / 1). The radioactivity on the developed thin-layer plate was exposed to an imaging plate (GE Healthcare) and analyzed with a bioimaging analyzer (BAS7000, GE Healthcare). The results are shown in Figure 1. From the TLC analysis of the reaction solution, the radiochemical yield of compound 3 was 58.0%, and the radiochemical purity of the eluate was 98.6%.

[0104] [ka]

[0105] Example 4: Preparation of Compound 4 The powder of Compound 2 obtained in Example 2 was dissolved in 7% aqueous sodium hydrogen carbonate solution to obtain a solution with a concentration of 0.1 mg / mL. To 10 μL of the same solution 211 20 μL of At aqueous solution (20 MBq) and 30 μL of 0.1 mol / L aqueous potassium iodide solution were added, and the mixture was reacted at 80°C for 1 hour. The reaction solution was injected into a solid-phase extraction cartridge (Oasis HLB, Waters), the cartridge was washed with 1 mL of water, then 0.5 mL of 30% aqueous ethanol solution was injected into the cartridge, and the eluate was collected. The above reaction solution and eluate were analyzed by thin-layer chromatography (TLC). A silica gel 60 (Merck) plate was used as the thin-layer plate, and development was performed with an acetonitrile / water mixed solution (2 / 1). Radioactivity on the developed thin-layer plate was exposed to an imaging plate (GE Healthcare) and analyzed with a bioimaging analyzer (BAS7000, GE Healthcare). The results are shown in Figure 2. From the results of TLC analysis of the reaction solution, the radiochemical yield of Compound 4 was 72.6%, and the radiochemical purity of the eluate was 99.9%.

[0106]

Chemical Structure

[0107] Reference Example 1: Synthesis of Fmoc-L-Lys(Suc)-ODpm HCl·Fmoc-L-Lys-ODpm (2.5 g, 4.4 mmol) was dissolved in DMF (20 mL), succinic anhydride (0.48 g, 4.8 mmol) and DIEA (0.82 mL, 4.8 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction solution, the mixture was washed with 0.2 N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Fmoc-L-Lys(Suc)-ODpm (2.1 g, 89%).

[0108]

Chemical Structure

[0109] Example 5: Preparation of Compound 5 Under an Ar atmosphere, triphosgene (0.42 g, 1.4 mmol) was dissolved in dichloromethane (90 mL) and cooled to -78°C. Then, a solution of HCl·HL-Glu(OtBu)-OtBu (1.0 g, 3.5 mmol) and DIEA (6.0 mL, 35 mmol) in dichloromethane (30 mL) was added dropwise. After 30 minutes, the temperature was raised to room temperature, and HL-Lys(Alloc)-Wang resin, prepared by deprotecting Fmoc-L-Lys(Alloc)-Wang resin (0.7 mmol) with 20% piperidine / NMP, was added and the mixture was stirred for 2 hours. After washing the resin, Pd(PPh3)4 (0.12 g, 0.11 mmol) and phenylsilane (4.3 mL, 35 mmol) were added to chloroform (10 mL) and the mixture was stirred under an Ar atmosphere for 1 hour. After washing the resin, Fmoc-D-Ala(2-Naph)-OH, Fmoc-(4)Ambz-OH, Fmoc-L-Lys(Suc)-ODpm (obtained in Reference Example 1), and Fmoc-Gly-OH were sequentially condensed with DIC-Oxyma, and deprotected with 20% piperidine / NMP, repeating the process to extend the peptide chain. Next, 4-(carboxymethyl)phenylboronic acid pinacol ester (0.55 g, 2.1 mmol), PyBOP (1.1 g, 2.1 mmol), and DIEA (0.42 mL, 2.5 mmol) were added to NMP (15 mL), and the mixture was stirred for 1 hour. The resin was then washed to obtain the protected peptide. 60 mL of trifluoroacetic acid cocktail (TFA / TIS / H2O=95 / 2.5 / 2.5) was added to the obtained protected peptide resin, and the mixture was stirred at room temperature for 1 hour to deprotect and remove the resin. After filtering off the resin, the solvent in the filtrate was removed under reduced pressure, and the residue was solidified and washed with diethyl ether. The resulting solid was dissolved in 10 mL of 50% aqueous acetic acid, stirred at room temperature for 40 minutes, and then purified by reverse-phase HPLC. The fraction containing the target product was freeze-dried to obtain compound 5 as a freeze-dried powder (yield 0.20 g, yield 26%, purity 98% or higher (HPLC method), molecular weight: observed value 1097.5 [M+H]). + , 1079.5[M-H2O+H]+ (Theoretical value: 1097.5 [M+H]).

[0110] [ka]

[0111] Example 6: Preparation of Compound 6 Compound 6 was synthesized using the same procedure as in Example 5, except that the extended peptide chain was changed from Fmoc-D-Ala(2-Naph)-OH, Fmoc-(4)Ambz-OH, Fmoc-L-Lys(Suc)-ODpm, Fmoc-Gly-OH to Fmoc-D-Ala(2-Naph)-OH, Fmoc-(4)Ambz-OH, Fmoc-D-Glu(OtBu)-OH, Fmoc-D-Glu(OtBu)-OH, Fmoc-L-Lys(Suc)-ODpm, Fmoc-Gly-OH (yield 0.28 g, yield 29%, purity 98% or higher (HPLC method), molecular weight: observed value 1353.5 [MH]). - , 1335.5[M-H2O-H] - (Theoretical value: 1353.5 [MH])

[0112] [ka]

[0113] Example 7: Preparation of Compound 7 The powder of compound 5 obtained in Example 5 was dissolved in a 7% sodium bicarbonate aqueous solution to a concentration of 0.1 mg / mL. 20 μL of this solution was mixed with 50 μL of a 7% sodium bicarbonate aqueous solution. 21116 μL (38.5 MBq) of an aqueous solution of At and 40 μL of a 0.1 mol / L potassium iodide aqueous solution were added and reacted at 80°C for 45 minutes. The reaction solution was injected into a solid-phase extraction cartridge (Oasis HLB, Waters), washed with 1 mL of water, and then 0.5 mL of a 20% ethanol aqueous solution and a 30% ethanol aqueous solution were sequentially injected into the cartridge to collect the eluate. The reaction solution and the 30% ethanol eluate were analyzed by thin-layer chromatography (TLC). A thin-layer plate was made of silica gel 60 (Merck) and developed with an acetonitrile / water mixture (2 / 1). The radioactivity on the developed thin-layer plate was exposed to an imaging plate (GE Healthcare) and analyzed with a bioimaging analyzer (BAS7000, GE Healthcare). The results are shown in Figure 3. From the TLC analysis of the reaction solution, the radiochemical yield of compound 7 was 67.4%, and the radiochemical purity of the eluate was 96.3%.

[0114] [ka]

[0115] Example 8: Preparation of Compound 8 The powder of compound 6 obtained in Example 6 was dissolved in a 7% sodium bicarbonate aqueous solution to a concentration of 0.1 mg / mL. 20 μL of this solution was mixed with 40 μL of a 7% sodium bicarbonate aqueous solution. 21122 μL (20 MBq) of an aqueous At solution and 40 μL of a 0.1 mol / L aqueous potassium iodide solution were added, and the reaction was allowed to proceed at 80°C for 45 minutes. The reaction solution was injected into a solid-phase extraction cartridge (Oasis HLB, Waters Corporation), the cartridge was washed with 1 mL of water, and then 0.5 mL of 20% aqueous ethanol solution was injected into the cartridge to collect the eluate. The aforementioned reaction solution and eluate were analyzed by thin-layer chromatography (TLC). Silica gel 60 (Merck KGaA) was used as the thin-layer plate, and development was performed with an acetonitrile / water mixed solution (2 / 1). Radioactivity on the thin-layer plate after development was exposed to an imaging plate (GE Healthcare) and analyzed with a bioimaging analyzer (BAS7000, GE Healthcare). The results are shown in Figure 4. Based on the results of TLC analysis of the reaction solution, the radiochemical yield of compound 8 was 61.5%, and the radiochemical purity of the eluate was 97.7%.

[0116]

Chemical Formula

[0117] Test Example 1: Imaging of human prostate cancer transplanted mice using compound 3. Human prostate cancer cells were transplanted subcutaneously into SCID mice (9 weeks old, male, n=5) (LNCaP, 0.5×10 7 cells / mouse), and the mice were then bred for one month. The mice were divided into a compound 3 administration group (n=3) and a control group (n=2). Mice in the compound 3 administration group were administered 0.43±0.01 MBq of compound 3 via the tail vein. The control group was administered physiological saline. Mice (n=3) in the compound 3 administration group were anesthetized by isoflurane inhalation at 3 hours and 24 hours after administration, and planar images were captured using a SPECT camera (E-cam, Siemens) (matrix size: 256×256, pixel size 1.2×1.2 mm, collimator: LEAP, energy window: 79 keV±20%, image acquisition time 10 minutes or 20 minutes). The results are shown in Figure 5. It was found that compound 3 accumulated at the tumor transplantation site (arrow) 3 hours after administration, and this accumulation persisted even after 24 hours. In addition, although compound 3 showed physiological accumulation in the kidneys, no non-specific accumulation in other organs was observed.

[0118] Test Example 2: Therapeutic study of human prostate cancer transplanted mice with compound 3 Mice in the compound 3 administration group (0.5 MBq, n=3) and the control group (CTL, n=2) of Test Example 1 were then reared for 3 weeks, and changes in tumor size were measured. Tumor size was standardized to the size at the time of drug administration, and the relative ratio of subsequent tumor sizes (Fold change) was calculated. The results are shown in Figure 6. The tumor size of the control group increased over time, becoming approximately 7 times larger after 3 weeks. On the other hand, the drug-administered group showed a tendency for tumor reduction immediately after administration, shrinking to 0.27 times its original size after 3 weeks. Dissection of the mice and blood biochemical tests revealed no significant difference in renal function marker levels between the control group and the drug-administered group. Furthermore, histopathological examination revealed no particular abnormalities in the kidneys, salivary glands, or thyroid gland of the drugs-administered mice. Based on these results, compound 3 is shown to be useful as a therapeutic agent for prostate cancer.

[0119] Test Example 3: In vivo distribution study in mice transplanted with human prostate cancer. Human prostate cancer cells were transplanted subcutaneously into SCID mice (9 weeks old, male, n=5) (LNCaP, 0.5x10 7 The mice were then reared for one month. Approximately 0.1 MBq of compound 3, 4, 7, or 8 was administered to tumor-transplanted mice or normal mice. Dissection was performed under isoflurane inhalation anesthesia at 3 and 24 hours after administration, and blood, urine, tumors, and various organs were collected. The radioactivity distribution rate (%ID) and the radioactivity distribution rate per gram of organ weight (%ID / g) were measured for each. The results are shown in Figures 7-11. Compounds 3 and 7 both showed marked accumulation in the tumors. Furthermore, all compounds 3, 4, 7, and 8 showed physiological accumulation in the kidneys.

[0120] Example 4: Therapeutic study of mice transplanted with human prostate cancer. Human prostate cancer cells were transplanted subcutaneously into SCID mice (9 weeks old, male, n=5) (LNCaP, 0.5x10 7The mice were then fed with the compound (individual mice / mouse) for one month. The tumor-transplanted mice were divided into two groups: a group administered compound 3, 7, or 8 (0.4 MBq or 1 MBq, n=3) and a control group (CTL, n=2 or 3). After three weeks of feeding, changes in tumor size and body weight were measured. The results are shown in Figures 12-14. The tumor size of the control group increased over time, while all groups administered compound 3, 7, or 8 showed an inhibitory effect on tumor growth. [Industrial applicability]

[0121] According to the present invention, it is possible to provide a radiolabeled compound that specifically binds to PSMA and is effective in the treatment and diagnosis of tumors or cancers that express PSMA, such as prostate cancer, in particular castration-resistant prostate cancer (CRPC), and especially castration-resistant prostate cancer with metastasis (mCRPC), and does not exhibit side effects due to accumulation in the kidneys or salivary glands.

[0122] This application is based on Japanese Patent Application No. 2021-125774, filed in Japan on July 30, 2021, the contents of which are fully incorporated herein.

Claims

1. A radiolabeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, p1 unit -CO-A １ -NH- independently represents an amino acid residue; p2 units of -CO-A ２ -NH- independently represents an amino acid residue; L １ This is a single bond, or -CO-(CH ２ ) ｍ１ -CO- (where m1 represents an integer from 1 to 6) is shown; L ２ This is a single bond, or -NH-(CH ２ ) ｍ２ -CH(COOH)-NH- (where m² represents an integer from 1 to 6) is shown; Ar is C ６－１４ represents an aryl group; q R １ These are, independently, hydrogen atoms and C １－６ Exhibiting an alkyl group or amino group; q R ２ These are, independently, hydrogen atoms or C １－６ The alkyl group was shown; n R ３ These are, independently, C １－６ Representing an alkyl group or hydroxyl group; X is, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ The radioactive nuclides selected from Br are shown; p1 represents an integer between 0 and 3; p2 represents an integer between 0 and 3; q represents an integer between 1 and 3; n represents an integer between 0 and 3.

2. L １ and L ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both are single bonds.

3. L １ ga-CO-(CH ２ ) ｍ１ -CO- (wherein m1 is the same as in claim 1), and L ２ - is -NH- (CH ２ ) ｍ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is -CH(COOH)-NH- (wherein m2 is the same as in claim 1).

4. p1 unit -CO-A １ A compound according to any one of claims 1 to 3, wherein at least one of the -NH- groups is a glutamic acid residue, or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein p1 is an integer from 0 to 2.

6. p2 units of -CO-A ２ A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein at least one of the -NH- groups is a glycinic acid residue.

7. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein p2 is 0 or 1.

8. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl group.

9. R １ and R ２ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a hydrogen atom.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A therapeutic agent for tumors or cancers expressing prostate-specific membrane antigen (PSMA), comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

12. The therapeutic agent according to claim 11, wherein the tumor or cancer expressing PSMA is prostate cancer.

13. A diagnostic agent for tumors or cancers expressing prostate-specific membrane antigen (PSMA), comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

14. The diagnostic agent according to claim 13, wherein the tumor or cancer expressing PSMA is prostate cancer.

15. A compound represented by formula (II) or a salt thereof. 【Chemistry 2】 [In the formula, p1 unit -CO-A １ -NH- independently represents an amino acid residue; p2 units of -CO-A ２ -NH- independently represents an amino acid residue; L １ This is a single bond, or -CO-(CH ２ ) ｍ１ -CO- (where m1 represents an integer from 1 to 6) is shown; L ２ This is a single bond, or -NH-(CH ２ ) ｍ２ -CH(COOH)-NH- (where m² represents an integer from 1 to 6) is shown; Ar is C ６－１４ Showing an aryl group; q R １ These are, independently, hydrogen atoms and C １－６ Exhibiting an alkyl group or amino group; q R ２ These are, independently, hydrogen atoms or C １－６ The alkyl group was shown; n R ３ These are, independently, C １－６ Representing an alkyl group or hydroxyl group; Y is a boryl group (-B(OH) ２ ) or the ester group thereof, and the ester group is 【Transformation 3】 [In the formula, R4 represents a C1-6 alkyl group.] Selected from; p1 represents an integer between 0 and 3; p2 represents an integer between 0 and 3; q represents an integer between 1 and 3; n represents an integer between 0 and 3.

16. Y is a boryl group (-B(OH) ２ The compound or salt thereof according to claim 15, wherein the compound is a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group.

17. A method for producing a radiolabeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: 【Chemistry 4】 [In the formula, p1 unit -CO-A １ -NH- independently represents an amino acid residue; p2 units of -CO-A ２ -NH- independently represents an amino acid residue; L １ This is a single bond, or -CO-(CH ２ ) ｍ１ -CO- (where m1 represents an integer from 1 to 6) is shown; L ２ This is a single bond, or -NH-(CH ２ ) ｍ２ -CH(COOH)-NH- (where m² represents an integer from 1 to 6) is shown; Ar is C ６－１４ Showing an aryl group; q R １ These are, independently, hydrogen atoms and C １－６ Exhibiting an alkyl group or amino group; q R ２ These are, independently, hydrogen atoms or C １－６ The alkyl group was shown; n R ３ These are, independently, C １－６ Representing an alkyl group or hydroxyl group; X is, ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ The radioactive nuclides selected from Br are shown; Y is a boryl group (-B(OH) ２ ) or the ester group thereof, and the ester group is 【Transformation 5】 [In the formula, R4 represents a C1-6 alkyl group.] Selected from; p1 represents an integer between 0 and 3; p2 represents an integer between 0 and 3; q represents an integer between 1 and 3; n represents an integer between 0 and 3. Step 1: The compound represented by formula (II) or a salt thereof is heated in water in the presence of a reagent selected from alkali metal iodide, alkali metal bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and hydrogen peroxide. ２１１ At, ２１０ At, １３１ I, １２５ I, １２４ I, １２３ I, ７７ Br and ７６ A step of reacting a radionuclide selected from Br with a radioactively labeled compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

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