Radioactive compounds

Abstract

A purpose of the present invention is to provide a novel radioactive compound, in particular a radioactive compound having high biostability.　The present invention relates to a radioactive compound represented by formula (I) or a pharmacologically acceptable salt thereof. [In the formula, Ra, Rb, X, Y, and † are as defined in the specification.]

Description

[Technical Field]

[0001] The present invention relates to a radioactive compound, a method for producing the same, and a radiopharmaceutical composition. [Background technology]

[0002] It is known that cancer cells generally take in a large amount of nutrients such as amino acids. Therefore, if an amino acid derivative labeled with a radionuclide is developed, it is thought that it will be useful for the diagnosis and treatment of various cancers. In fact, radioactive fluorine-labeled tyrosine derivatives, phenylalanine derivatives, and radioactive iodine-labeled tyrosine derivatives have been developed for the purpose of nuclear medicine diagnosis, and many clinical studies are being conducted (for example, Non-Patent Document 1). In addition, astatine-211 ( 211 It is expected that the use of amino acid derivatives labeled with α-rays will enable nuclear medicine therapy, and that diagnosis and treatment can be performed in an integrated manner. 211 As an At-labeled drug 211 At-labeled tyrosine derivatives 211 At-labeled phenylalanine derivatives have been developed (for example, Non-Patent Document 2). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Front. Chem. 2018 Jan 1555(124). [Non-patent document 2] Oncotarget. 2020 Apr 14, 11(15): 1388-1398. Summary of the Invention [Problem to be solved by the invention]

[0004] Amino acid derivatives labeled with radioactive fluorine or radioactive iodine that have been developed so far have been recognized for their usefulness due to their high in vivo stability and high uptake into tumors. 211At-labeled amino acid derivatives show high tumor uptake while 211 The loss of At has been observed, and non-specific accumulation in the stomach and thyroid gland is a problem. This not only leads to increased side effects from radiation exposure, but also to a decrease in radioactivity in tumor tissue, leading to insufficient therapeutic effects. 211 The development of At-labeled amino acid derivatives is desired. The present invention relates to a novel radioactive compound, and more particularly to a radioactive compound or a pharmaceutically acceptable salt thereof having high biostability. [Means for solving the problem]

[0005] The present invention includes the following aspects. <1> A radioactive compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0006] [ka]

[0007] [In the formula, R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R b each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X represents a group represented by the following formula (x1), formula (x2), or formula (x3):

[0008] [ka]

[0009] (In the formula, * indicates the binding site to the α carbon, and ** indicates the binding site on the other side.) Y is 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 132 I, or 211Indicates At, † indicates an asymmetric carbon.] <2> R a represents a hydrogen atom or a methyl group, R b each independently represents a hydrogen atom or a methyl group. <1> 1. A radioactive compound according to claim 1, or a pharmaceutically acceptable salt thereof. <3> The above-mentioned compound represented by the following formula (Ib-1), (Ib-2) or (Ib-3): <1> or <2> 1. A radioactive compound according to claim 1, or a pharmaceutically acceptable salt thereof.

[0010] [ka]

[0011] [In the formula, Y is the same as above.] <4> The above method, which includes the following steps [1] to [4]: <1> ~ <3> 1. A method for producing the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of the above. [1] providing a compound (i) represented by the following formula (y1), formula (y2), or formula (y3);

[0012] [ka]

[0013] (In the formula, Z 1 are each independently a hydrogen atom, a protecting group for an amino group, or R b indicates, Z 2 represents a protecting group for a hydrogen atom or a carboxy group. R a , R b , † is the same as above.) [2] providing a compound (ii) represented by the following formula (II);

[0014] [ka]

[0015] [In the formula, L 1 each independently represents a leaving group. [3] (a) The hydrogen atom of the amino group or hydroxy group in the side chain of the compound (i) is bonded to one of the L groups in the compound (ii). 1 and (b) the other L in the compound (ii) 1 a step of substituting the above with Y (wherein Y is as defined above) to obtain a compound (iii) represented by the following formula (III);

[0016] [ka]

[0017] [In the formula, R a , X, Y, Z 1 , Z 2 is the same as above.] [4] A step of deprotecting the protecting group of the compound (iii) <5> the above <1> ~ <3> 1. A radiopharmaceutical composition comprising the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of the above items. <6> The above is for diagnostic imaging. <5> The radiopharmaceutical composition according to claim 1. <7> The above is for therapeutic use. <5> The radiopharmaceutical composition according to claim 1. [Effects of the Invention]

[0018] The present invention provides a novel radioactive compound or a pharmaceutically acceptable salt thereof. The radioactive compound of the present invention has high biostability. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows the results of HPLC analysis of compound (8) and compound (14) of Synthesis Example 1. [Figure 2] FIG. 2 shows the results of HPLC analysis of compound (12) and compound (16) of Synthesis Example 1. [Figure 3] FIG. 3 shows the results of Evaluation Example 2. [Figure 4]FIG. 4 shows the results of Evaluation Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0020] [Radioactive compound] The radioactive compound of the present invention (hereinafter also referred to as the compound of the present invention) is a radioactive compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0021] [ka]

[0022] [In the formula, R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R b each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X represents a group represented by the following formula (x1), formula (x2), or formula (x3):

[0023] [ka]

[0024] (In the formula, * indicates the binding site to the α carbon, and ** indicates the binding site on the other side.) Y is 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 132 I, or 211 Indicates At, † indicates an asymmetric carbon.]

[0025] R a and R bExamples of the "alkyl group having 1 to 6 carbon atoms" in the above formula include linear or branched alkyl groups having 1 to 6 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.

[0026] R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably a hydrogen atom or a methyl group, and even more preferably a hydrogen atom. R b each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably a hydrogen atom or a methyl group, and even more preferably a hydrogen atom. R b are preferably both hydrogen atoms, or one is a hydrogen atom and the other is the above alkyl group, and more preferably both are hydrogen atoms. Y is a radioactive halogen atom, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 132 I, or 211 At, preferably 18 F, 125 I or 211 At, more preferably 125 I or 211 Indicates At.

[0027] The compound of the present invention has an asymmetric carbon. The configuration of the asymmetric carbon †C carbon is the L configuration shown below.

[0028] [ka]

[0029] Or, the following D arrangement

[0030] [ka]

[0031] [In the formula, R a , R b , X is the same as above.] The L configuration is preferred.

[0032] In formula (I), preferably, R a represents a hydrogen atom or a methyl group, and R b each independently represents a hydrogen atom or a methyl group.

[0033] Preferred embodiments of the compound of the present invention include radioactive compounds represented by the following formula (Ia-1), (Ia-2) or (Ia-3) or pharmaceutically acceptable salts thereof.

[0034] [ka]

[0035] [In the formula, R a , R b , Y, † are the same as above.]

[0036] More preferred embodiments of the compound of the present invention include radioactive compounds represented by the following formula (Ib-1), (Ib-2) or (Ib-3) or pharmaceutically acceptable salts thereof.

[0037] [ka]

[0038] [In the formula, Y is the same as above.]

[0039] The compound of the present invention may be a pharmaceutically acceptable salt of the radioactive compound represented by the above formula (I). Examples of the salt include acid addition salts and base addition salts. The acid addition salt may be either an inorganic acid salt or an organic acid salt. Examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate. Examples of organic acid salts include citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate. The base addition salt may be either an inorganic base salt or an organic base salt. Examples of inorganic base salts include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Examples of organic base salts include triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts. The compound of the present invention may be a solvate such as a hydrate, etc. The solvent is not particularly limited as long as it is a pharmaceutically acceptable solvent.

[0040] The compounds of the present invention can be suitably used as active ingredients in radiopharmaceutical compositions for diagnostic imaging, treatment, etc., as described below.

[0041] [Manufacturing method] The radioactive compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be produced, for example, by a method including the following steps [1] to [4]. [1] providing a compound (i) represented by the following formula (y1), formula (y2), or formula (y3);

[0042] [ka]

[0043] (In the formula, Z 1 are each independently a hydrogen atom, a protecting group for an amino group, or R b indicates, Z 2 represents a protecting group for a hydrogen atom or a carboxy group, R a , R b, † is the same as above.) [2] providing a compound (ii) represented by the following formula (II);

[0044] [ka] [In the formula, L 1 each independently represents a leaving group. [3] (a) The hydrogen atom of the amino group or hydroxy group in the side chain of the compound (i) is bonded to one of the L groups in the compound (ii). 1 and (b) the other L in the compound (ii) 1 a step of substituting the above with Y (wherein Y is as defined above) to obtain a compound (iii) represented by the following formula (III);

[0045] [ka]

[0046] [In the formula, R a , X, Y, Z 1 , Z 2 is the same as above.] [4] A step of deprotecting the protecting group of the compound (iii)

[0047] <Process [1]> In step [1], a compound (i) represented by the above formula (y1), formula (y2) or formula (y3) is provided. The compound represented by formula (y1) is histidine or its α-alkyl and / or N-alkyl derivatives in which the amino and carboxy groups bound to the α-carbon may be protected. The compound represented by formula (y2) is tyrosine or its α-alkyl and / or N-alkyl derivatives in which the amino and carboxy groups bound to the α-carbon may be protected. The compound represented by formula (y3) is α-alkyl and / or N-alkyl tryptophan or its derivatives in which the amino and carboxy groups bound to the α-carbon may be protected. Examples of the protecting group for the amino group include a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz group), and a 9-fluorenylmethyloxycarbonyl group (Fmoc group). Examples of the protective group for the carboxy group include a methyl group, an ethyl group, a benzyl group, and a tert-butyl group. In terms of the reaction efficiency of the production method of the present invention, compound (i) is preferably Z 1 is a protecting group for an amino group, and Z 2 is a protecting group for a carboxy group, and more preferably, Z 1 and Z 2 is a combination of an amino-protecting group and a carboxy-protecting group that can be deprotected under the same conditions, and more preferably a combination of an amino-protecting group and a carboxy-protecting group that can be deprotected using an acid catalyst such as trifluoroacetic acid. 1 is a Boc group, and Z 2 is a tert-butyl group. The introduction of an amino-protecting group and a carboxy-protecting group can be carried out by a conventional method.

[0048] <Process [2]> In step [2], a compound (ii) represented by formula (II) is provided. Compound (ii) can be obtained, for example, by reacting two adjacent hydroxy groups of pentaerythritol with 2,2-dimethoxypropane to form acetal protection, and then reacting the other two hydroxy groups with an activating agent to form leaving groups. L 1 Examples of the leaving group represented by the formula (I) include a trifluoromethanesulfonate (triflate, -OTf) group, a nonafluorobutanesulfonate (nonaflate) group, a p-toluenesulfonate (tosylate) group, a methanesulfonate (mesylate) group, a p-nitrosulfonyloxy (nosylate) group, etc. Among these, from the viewpoint of reactivity, a trifluoromethanesulfonate group and a nonafluorobutanesulfonate group are preferred.

[0049] <Process [3]> In step [3], (a) a hydrogen atom of an amino group or a hydroxy group in a side chain of the compound (i) is substituted with one of L in the compound (ii). 1 and (b) the other L in the compound (ii) 1 is substituted with Y (wherein Y is the same as above) to obtain a compound (iii) represented by the formula (III).

[0050] (Step (a)) In step (a), a hydrogen atom of an amino group or a hydroxy group in a side chain of the compound (i) is substituted with one of L in the compound (ii). 1 Substitution is made to groups other than the above. In the reaction, for example, 0.1 to 10 moles, preferably 0.5 to 2 moles, of compound (ii) can be reacted with 1 mole of compound (i). The reaction can be carried out, if necessary, in the presence of a base in an amount of, for example, 0.1 to an excess mole, preferably 0.5 to 10 moles, per mole of compound (i). Examples of the base include organic bases such as pyridine, triethylamine, diisopropylethylamine (DIPEA), and 2,6-lutidine; and inorganic bases such as alkali metal carbonates such as sodium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate, and alkali metal hydrides such as sodium hydride. From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent. Examples of the solvent include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane, but are not limited thereto. The solvent may be a single solvent or a mixed solvent of two or more solvents.

[0051] (Step (b)) In step (b), the other L in the compound (ii) 1 is substituted with a radioactive atom Y (Y is the same as above). In the reaction, 1 mole of compound (ii) or the compound obtained in step (a) can be reacted with, for example, 0.1 to 10 moles, preferably 0.5 to 5 moles of a halogenating agent. Examples of halogenating agents include radioactive halogen molecules corresponding to Y, alkali metal salts of Y such as sodium, oxides of Y, and N-halogen succinimides. The reaction can be carried out, if necessary, in the presence of a base in an amount of, for example, 0.1 to an excess mole, preferably 0.5 to 10 moles, relative to 1 mole of compound (ii) or the compound obtained in step (a). Examples of the base include organic bases such as pyridine, triethylamine, diisopropylethylamine (DIPEA), and 2,6-lutidine; and inorganic bases such as alkali metal carbonates such as sodium carbonate, alkali metal bicarbonates such as sodium bicarbonate, and alkali metal hydrides such as sodium hydride. Among these, organic bases are preferred from the viewpoint of reactivity. Furthermore, organic bases that are liquid at room temperature are more preferred because they can also serve as a solvent. The reaction temperature and reaction time can be appropriately determined by those skilled in the art. The reaction temperature can be, for example, 0 to 40° C. The reaction time can be, for example, 30 minutes to 10 days. From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent. Examples of the solvent include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane, but are not limited thereto. The solvent may be a single solvent or a mixed solvent of two or more solvents.

[0052] The order of steps (a) and (b) is not limited, and step (b) may be performed after step (a), or step (b) may be performed after step (a). From the viewpoint of reducing the number of steps involving handling radioisotopes, it is preferable to perform step (a) before step (b).

[0053] The reaction scheme for carrying out step (b) after step (a) is shown below. [ka] [In the formula, R a , X, Y, Z 1 , Z 2 , L 1 is the same as above.]

[0054] The reaction scheme when step (a) is carried out after step (b) is shown below. [ka] [In the formula, R a , X, Y, Z 1 , Z 2 , L 1 is the same as above.]

[0055] The compound (iii) represented by formula (III) thus obtained can be subjected to the next step [4] after, if necessary, an isolation step such as filtration, concentration, extraction, etc., and / or a purification step such as column chromatography, recrystallization, etc. In addition, between steps (a) and (b), if necessary, an isolation step such as filtration, concentration, extraction, etc., and / or a purification step such as column chromatography, recrystallization, etc. can be performed to obtain the target compound.

[0056] <Process [4]> In step [4], the protecting group of the compound (iii) is deprotected. The protecting group of the compound (iii) is Z derived from the compound (i). 1 is a protecting group for an amino group, and Z 2 is a protecting group for a carboxy group, and is an acetal protecting group of a neopentyl structure derived from compound (ii).

[0057] The protecting group can be deprotected by a conventional method. The acetal protecting group of a neopentyl structure can be deprotected using, for example, 0.1 mole to an excess amount, preferably about 0.5 mole to 10 moles of an acid catalyst relative to 1 mole of compound (iii). Examples of the acid catalyst include organic acids such as trifluoroacetic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid, among which trifluoroacetic acid is preferred. The reaction temperature and reaction time can be appropriately determined by those skilled in the art. The reaction temperature can be, for example, about 10 to 40° C. The reaction time can be, for example, about 30 minutes to 24 hours. From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent, such as an aqueous solvent such as water. Z 1 is a Boc group, and Z 2 is a tert-butyl group, this is preferred because deprotection can be carried out simultaneously with the deprotection using the acid catalyst.

[0058] In step [4], the target radioactive compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be obtained, if necessary, through an isolation step such as filtration, concentration, extraction, etc., and / or a purification step such as column chromatography, recrystallization, etc.

[0059] Thus, the radioactive compound of the present invention is produced. The synthesis of the radioactive compound of the present invention can be confirmed by, for example, 1 H-NMR measurement, 13 This can be confirmed by known means such as C-NMR measurement or mass spectrometry.

[0060] In the above production method, an α-amino acid or an α-alkyl and / or N-alkyl derivative thereof in which the amino group and carboxy group bonded to the α-carbon may be protected, other than compound (i) represented by formula (y1), formula (y2), or formula (y3), can be provided, and a radioactive compound derived from the amino acid or a pharmaceutically acceptable salt thereof can be obtained. Such α-amino acids include lysine, arginine, asparagine, and glutamine, which have an amino group in the side chain; and serine and threonine, which have a hydroxy group in the side chain. Further, such α-amino acids include glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, cysteine, methionine, etc., which do not have an amino group or a hydroxy group in the side chain. In this case, however, in step (a) of the above step [3], the hydrogen atom of the amino group bonded to the α-carbon is substituted with one of the L in the above compound (ii). 1 Substitution is made to groups other than the above. An example of the radioactive compound thus obtained is shown below.

[0061] [ka]

[0062] [ka]

[0063] [Radiopharmaceutical composition] The present invention provides a radiopharmaceutical composition containing the above radioactive compound or a salt thereof as an active ingredient.

[0064] Radiopharmaceuticals can be prepared as pharmaceutical compositions containing the above-mentioned radioactive compound or a salt thereof as an active ingredient, and, if necessary, one or more pharmaceutically acceptable carriers. Examples of carriers include aqueous buffers, pH adjusters such as acids and bases, stabilizers such as ascorbic acid and p-aminobenzoic acid, excipients such as D-mannitol, isotonicity agents, and preservatives. Compounds useful for improving radiochemical purity, such as citric acid, tartaric acid, malonic acid, sodium gluconate, and sodium glucoheptonate, may also be added. Radiopharmaceutical compositions can be provided in the form of an aqueous solution, a frozen solution, or a lyophilized product.

[0065] The radiopharmaceutical compositions of the present invention can be used, for example, for diagnostic imaging. Examples of imaging diagnosis include Single Photon Emission Computed Tomography (also simply referred to as "SPECT") and Positron Emission Tomography (also simply referred to as "PET"). The diagnostic use is not particularly limited, and the radiological imaging diagnosis of various diseases and organs or tissues, such as tumors, inflammation, infectious diseases, cardiovascular diseases, and brain and central nervous system diseases, is preferred, and the radiological imaging diagnosis of cancer, including solid cancers of the stomach, colon, lung, liver, prostate, pancreas, esophagus, bladder, gallbladder and bile duct, breast, uterus, thyroid, ovary, etc.

[0066] The radiopharmaceutical compositions of the present invention can be used, for example, for therapeutic purposes. Preferably, it can be used in radiation therapy to suppress cancer. When used as an anticancer agent, the term has the broadest meaning, including both preventive effects such as preventing the onset, metastasis, implantation, and recurrence of cancer, and therapeutic effects such as inhibiting the proliferation of cancer cells or shrinking cancer to prevent its progression or ameliorating symptoms, and should not be interpreted in a restrictive manner in any case. For therapeutic use, Y in the above formula (I) is preferably an α-ray emitting nuclide. 211 At.

[0067] The recipient of the radiopharmaceutical composition of the present invention is not particularly limited. For example, mammals including humans are suitable recipients. Humans are not particularly limited in terms of race, sex, or age. Non-human mammals include pet animals such as dogs and cats. The route of administration of the radiopharmaceutical composition of the present invention may be, for example, parenteral administration such as intravenous administration or intraarterial administration, or oral administration, with intravenous administration being preferred. The administration route is not limited to these routes, and any route can be used as long as it allows the action of the radiopharmaceutical composition to be effectively exerted after administration.

[0068] The radioactivity intensity of the radiopharmaceutical composition is not limited as long as the objective can be achieved by administering the radiopharmaceutical composition and the radiation exposure of the subject is as low as possible at the clinical dose. The radioactivity intensity can be determined by reference to the radioactivity intensity used in common diagnostic and therapeutic methods using radiopharmaceutical compositions. The dosage is determined taking into consideration various conditions such as the age and weight of the patient, the radiation imaging device used, and the condition of the target disease. For humans, the radioactivity in the radiopharmaceutical composition is as follows: It is generally assumed that the diagnostic agent will be used in radiation therapy, and the dosage of the diagnostic agent is not particularly limited. For example, the dosage of the diagnostic agent may be, but is not limited to, a radioactive element (e.g., 211 The radioactivity of At is 1.0MBq / kg to 3.0MBq / kg. [Example]

[0069] [Synthesis Example 1] [N α -Synthesis of tert-butoxycarbonyl-L-histidine tert-butyl ester(2)] (i) N,N'-diisopropylcarbodiimide (5.24 g, 41.5 mmol) was dissolved in tert-butanol (tBuOH) (4.6 mL) and heated to 30 °C. After stirring for 10 minutes under a nitrogen atmosphere, CuCl(I) (4.10 mg, 0.0414 mmol) was added and the mixture was stirred at 30 °C for 4 days. Poly(4-vinylpyridine) (0.83 g) was added to adsorb the free copper, followed by the addition of dichloromethane (CHCl) (21 mL) and stirring for 15 minutes. The reaction mixture was filtered to remove the precipitate, and the filtrate was evaporated under reduced pressure to yield 6.57 g of crude N,N-Diisopropyl-O-tert-butylisourea (DIC) as an oil. (ii)N α-(tert-Butoxycarbonyl)-L-histidine (1) was dissolved in CHCl (50 mL) and slowly added to the crude product obtained in (i) under an argon atmosphere. The mixture was stirred at room temperature for 4 days. The by-product diisopropylurea was filtered, and the filtrate was evaporated under reduced pressure. The product was purified from the residue by silica gel chromatography using chloroform:methanol = 10:1 as an eluent. Compound (2) (1.42 g, 4.57 mmol, 58.4% yield) was obtained as a pale yellow oil. 1 H NMR (CDCl3): δ 1.42-1.44 (18H, overlapped, CH 3, CH3), 3.07-3.08 (2H, d, CH2), 4.40 (1H, s, CH), 5.64 (1H, s, NH), 6.83 (1H, s, aromatic), 7.61 (1H, s, aromatic). 13 C-NMR (CDCl3): δ 28.03, 28.40, 29.86, 54.18, 79.85, 81.97, 117.12, 133.42, 135.20, 155.76, 171.40. ESI-MS (M+H) + : m / z 312, found 312.

[0070] [Synthesis of 2,2-Dimethyl-1,3-dioxane-5,5-dimethanol (4)] Pentaerythritol (3) (6.00 g, 44.1 mmol) and (+)-10-camphorsulfonic acid (0.205 g, 0.881 mmol) were added to N,N-dimethylformamide (DMF) (120 mL) and heated to 80 °C to completely dissolve. After gently cooling to 40 °C, 2,2-dimethoxypropane (6.50 mL, 52.8 mmol) was added dropwise. The temperature was then cooled to room temperature and stirred for 2 days. Triethylamine (370 μL, 2.65 mmol) was added to neutralize the reaction mixture, and the solvent was removed under reduced pressure. The residue was collected and subjected to Soxhlet extraction using hexane for 2 days. After the extract was removed under reduced pressure, the product was purified from the residue by recrystallization using ethyl acetate and hexane to obtain compound (4) (633 mg, 3.59 mmol, 36.1% yield). 1 H-NMR (DMSO-d6): δ 1.29 (6H, s, CH3), 3.35-3.36 (4H, d, CH2), 3.59 (4H, s, CH2), 4.48-4.51 (2H, t, OH). 13 C-NMR (DMSO-d6): 23.83, 38.88, 60.50, 61.67, 91.12.

[0071] [Synthesis of (2,2-Dimethyl-1,3-dioxane-5,5-diyl)bis(methylene)bis(trifluoromethanesulfonate)(5)] Compound (4) (633 mg, 3.59 mmol) obtained above was dissolved in CHCl (40 mL) and 2,6-lutidine (4.20 mL, 35.9 mmol) was added. The solution was cooled to -78 °C, and trifluoromethanesulfonic anhydride (TfO) (2.00 mL, 12.2 mmol) was added dropwise and stirred for 1 hour. The reaction solution was gradually warmed to -20 °C and stirred overnight. After the reaction, the reaction solution was washed with saturated aqueous NaHCO (20 mL), 5% aqueous citric acid (30 mL x 3), and saturated brine (20 mL), successively. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The product was purified from the residue by silica gel chromatography using hexane:ethyl acetate = 10:1 as an eluent. Compound (5) (1.30 g, 2.94 mmol, 82.0% yield) was obtained as a white solid. 1 H-NMR (CDCl3): δ 1.44 (6H, s, CH3), 3.79 (4H, s, CH2), 4.57 (4H, s, CH2). 13 C-NMR (CDCl3): 23.39, 39.00, 60.88, 73.54, 99.71, 113.92, 117.11, 120.29, 123.47. ESI-MS (M+H) + : m / z 441, found 441.

[0072] [N α -(tert-butoxycarbonyl)-N τ Synthesis of -((2,2-dimethyl-5-((((trifluoromethyl)sulfonyl)oxy)methyl)-1,3-dioxan-5-yl)methyl)-L-histidine tert-butyl ester(6)] Compound (5) (145 mg, 0.330 mmol) obtained above was dissolved in CHCl (800 μL) and 2,6-lutidine (48.0 μL, 0.413 mmol) was added. The solution was cooled to −20°C, and compound (2) (51.4 mg, 0.165 mmol) dissolved in CHCl (200 μL) was added dropwise. The reaction mixture was stirred overnight at −20°C. The reaction mixture was washed sequentially with saturated aqueous NaHCO (5 mL), 5% aqueous citric acid (10 mL x 3), and saturated brine (10 mL). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of CHCl and applied to a 1 mm-thick preparative thin-layer chromatography (TLC) plate. The product was purified from the residue using chloroform:methanol = 15:1 as the developing solvent. Compound (6) (19.9 mg, 0.0331 mmol, yield 20.0%) was obtained as a colorless oil. 1 H-NMR (CDCl3): δ 1.41-1.47 (24H, overlapped, CH3), 3.03 (2H, broad, CH2), 3.63-3.74 (4H, multiple, CH2), 4.11 (2H, s, CH2), 4.37 (3H, overlapped, CH2, CH), 5.70 (1H, d, NH), 6.74 (1H, s, aromatic), 7.53 (1H, s, aromatic). ESI-MS (M+H) + : m / z 602, found 602.

[0073] [N α -(tert-butoxycarbonyl)-N τ -((5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl)-L-histidine tert-butyl ester (7) synthesis] Compound (6) (37.0 mg, 0.0615 mmol) obtained above was dissolved in acetonitrile (MeCN) (800 μL), and sodium iodide (27.0 mg, 0.184 mmol) was added. The reaction mixture was stirred at room temperature for 5 days. After the reaction, the solvent was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate and washed with MilliQ water (2 mL x 2) and saturated brine (2 mL), successively. Magnesium sulfate was added to the organic layer and dried, after which the solvent was removed by evaporation under reduced pressure. The product was purified from the residue using hexane and ethyl acetate in a purification apparatus (Purif compact, Shoko Scientific Co., Ltd.). Compound (7) (9.9 mg, 0.0171 mmol, 27.8% yield) was obtained as a pale yellow oil. 1 H-NMR (CDCl3): δ 1.41-1.57 (24H, overlapped, CH3), 2.87 (2H, s, CH2), 3.02 (2H, s, CH2), 3.48-3.69 (4H, multiple, CH2), 4.19 (2H, s, CH2), 4.38-4.40 (1H, broad, CH), 5.74-5.76 (1H, d, NH), 6.84 (1H, s, aromatic), 7.56 (1H, s, aromatic). 13 C-NMR (CDCl3): 9.01,19.71, 27.35, 28.02, 28.35, 30.43, 36.74, 47.63, 53.97, 65.26, 79.30, 81.41, 99.00, 117.95, 137.67, 137.88, 155.53, 171.09. ESI-MS (M+H) + : m / z 580, found 580.

[0074] [N τ Synthesis of -(3-hydroxy-2-(hydroxymethyl)-2-(iodomethyl)propyl)-L-histidine(8)〕 Compound (7) (8.2 mg, 0.0142 mmol) was added to a mixture of trifluoroacetic acid (TFA) (800 μL) and MilliQ water (200 μL) and stirred at room temperature for 4 hours. After the reaction, TFA was removed by distillation under reduced pressure, and the solvent was azeotroped with MeCN (1 mL x 2). The residue was dissolved in a 70:30 mixture of MilliQ water and MeCN (2 mL). The product was purified from the residue by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact, 150 x 20 mm) with 0.1% (v / v) TFA / MilliQ water (phase A) and 0.1% (v / v) TFA / MeCN (phase B). The flow rate was 5 mL / min. The gradient was changed from 90% A and 10% B to 50% A and 50% B over the 0-30 min period, and then from 50% A and 50% B to 0% A and 100% B over the 30-50 min period. The trifluoroacetate salt (TFA salt) of compound (8) (3.6 mg, 9.39 nmol, 75.3% yield) was obtained as a pale yellow solid. 1 H-NMR (D2O): δ 3.18 (2H, s, CH2), 3.34 (2H, d, CH2), 3.51-3.53 (2H, d, CH2), 4.05-4.09 (1H, t, CH), 4.30 (2H, s, CH2), 7.47 (1H, s, aromatic), 8.76 (1H, s, aromatic). ESI-MS (M+H) + : m / z 384, found 384.

[0075] The reaction scheme leading to the synthesis of compound (8) is shown below.

[0076] [ka]

[0077] The reagents and solvents used in each step are as follows. (a)(i)DIC,tBuOH,CuCl(I);(ii)CH2Cl2 (b)2,2-Dimethoxypropane,(+)-10-Camphorsulfonic acid,DMF (c) Tf2O, 2,6-Lutidine, CH2Cl2 (d) 2,6-Lutidine, CH2Cl2 (e) NaI,MeCN (f) TFA, HO

[0078] [N α -Synthesis of tert-butoxycarbonyl-L-tyrosine tert-butyl ester (9)] It was synthesized according to the description in Bioconjug. Chem. 2013: 24, 2, 291-299.

[0079] [N α Synthesis of -(tert-butoxycarbonyl)-O-((2,2-dimethyl-5-((((trifluoromethyl)sulfonyl)oxy)methyl)-1,3-dioxan-5-yl)methyl)-L-tyrosine tert-butyl ester(10)] NaH (10.8 mg, 0.270 mmol) was suspended in tetrahydrofuran (THF) (0.50 mL). Under an argon atmosphere, compound (9) (76.0 mg, 0.226 mmol) obtained above was dissolved in THF (1.50 mL) and added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Next, compound (5) (100 mg, 0.226 mmol) obtained above was added at room temperature and stirred for 40 minutes. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution (10 mL x 3). The organic layer was dried over magnesium sulfate, and the solvent was then distilled off. The residue was dissolved in a small amount of CHCl2 and applied to a 1 mm-thick preparative TLC plate. The product was purified from the residue using a 2:1 hexane:ethyl acetate mixture as the developing solvent. Compound (10) (86.2 mg, 0.137 mmol, yield 60.8%) was obtained as a colorless oil. 11H-NMR (CDCl3): δ 1.41 - 1.45 (24H, overlapped, CH3), 2.99 - 3.01 (2H, t, CH2), 3.81 - 3.93 (6H, overlapped, CH2), 4.39 - 4.41 (1H, multiple, CH), 4.79 (2H, s, CH2), 4.96 - 4.98 (1H, d, NH), 6.80 - 6.82 (2H, d, aromatic), 7.08 - 7.10 (2H, d, aromatic). 13 13C-NMR (CDCl3): 21.58, 25.62, 28.07, 28.43, 37.71, 38.90, 55.01, 61.85, 66.22, 75.43, 79.75, 82.16, 99.19, 113.94, 114.43, 117.12, 120.30, 123.48, 129.57, 130.61, 130.75, 155.19, 157.21, 170.93, 171.07. ESI-MS (M+Na) + : m / z 650, found 650.

[0080] 〔N α -(tert-butoxycarbonyl)-O-((5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl)-L-tyrosine tert-butyl ester (11) Synthesis〕 Compound (10) (64.6 mg, 0.103 mmol) obtained above was dissolved in MeCN (1.0 mL), and sodium iodide (46.0 mg, 0.309 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction, the solvent was removed under reduced pressure. The mixture was dissolved in ethyl acetate and washed with 5% aqueous NaHCO3 (5 mL), MilliQ water (5 mL x 2), and saturated brine (5 mL), successively. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of CHCl2 and applied to a 1 mm-thick preparative TLC plate. The product was purified using a 2:1 hexane:ethyl acetate mixture as the developing solvent. Compound (11) (51.4 mg, 0.0849 mmol, 82.4% yield) was obtained as a colorless oil. 1 H-NMR (CDCl3): δ 1.42-1.44 (24H, overlapped, CH3), 2.99-3.01(2H, t, CH2), 3.41 (2H, s, CH2), 3.78-3.91 (4H, multiple, CH2), 3.98 (2H, s, CH2), 4.40-4.41 (1H, multiple, CH), 4.95-4.97 (1H, d, NH), 6.83-6.85 (2H, d, aromatic), 7.07-7.09 (2H, d, aromatic). 13 C-NMR (CDCl3): 10.42, 27.58, 24.74, 28.11, 28.45, 36.84, 37.63, 55.02, 64.84, 68.81, 79.73, 82.11, 98.85, 114.63, 129.00, 130.65, 155.21, 157.76, 171.11. ESI-MS (M+Na) + : m / z 628, found 628.

[0081] [Synthesis of O-(3-hydroxy-2-(hydroxymethyl)-2-(iodomethyl)propyl)-L-tyrosine(12)] The compound (11) (10.2 mg, 16.8 nmol) obtained above was added to a mixture of TFA (800 μL) and MilliQ water (200 μL) and stirred at room temperature for 5 hours. After the reaction, TFA was removed by evaporation under reduced pressure, and the solvent was azeotroped with MeCN (1 mL x 2). The residue was dissolved in a 70:30 mixture of MilliQ water and MeCN (2 mL). The product was purified from the residue by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact, 150 x 20 mm) with 0.1% (v / v) TFA / MilliQ water (phase A) and 0.1% (v / v) TFA / MeCN (phase B). The flow rate was 5 mL / min. The gradient was changed from 90% A and 10% B to 50% A and 50% B over the 0-30 min period, and then from 50% A and 50% B to 0% A and 100% B over the 30-50 min period. The TFA salt of compound 12 (5.45 mg, 10.8 nmol, 64.1% yield) was obtained as a white solid. 1 H-NMR (D2O): δ 2.95-3.14 (2H, multiple, CH2), 3.20 (2H, s, CH2), 3.51 (4H. s, CH2), 3.79 (2H, s, CH2), 4.04-4.07 (1H, q, CH), 6.86-6.88 (2H, d, aromatic), 7.07-7.09 (2H, d, aromatic). ESI-MS (M+H) + : m / z 410, found 410.

[0082] The reaction scheme leading to the synthesis of compound (12) is shown below.

[0083] [ka]

[0084] The reagents and solvents used in each step are as follows. (g) NaH, THF (h) NaI,MeCN (i) TFA, HO

[0085] [[ 125 I]N τ Synthesis of -(3-hydroxy-2-(hydroxymethyl)-2-(iodomethyl)propyl)-L-histidine(14)] The compound (6) (600 μg, 1.0 nmol) obtained above was dissolved in 1% N,N-diisopropylethylamine (DIPEA) / MeCN (100 μL). 125 An aqueous solution of [I]NaI (1.0 μL, 57.1 μCi) was added and reacted at 37°C for 1 hour. After the reaction, the product was purified by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact Corporation, 150 × 20 mm) with MilliQ water as the mobile phase (phase A) and MeCN as the mobile phase (phase B). The flow rate was 1 mL / min. The gradient was changed from 40% A and 60% B to 30% A and 70% B over the first 20 minutes, and then from 30% A and 70% B to 0% A and 100% B over the first 20 minutes. Compound (13) was obtained in a radiochemical yield of 84.6%. The collected solution was concentrated to 50 μL using a rotary evaporator. TFA (450 μL) was added to the concentrated solution and allowed to react at 37°C for 1 hour. After the reaction, the TFA in the solution was removed under a nitrogen stream, and the remaining TFA was neutralized by adding saturated aqueous NaHCO3. The product was purified by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact Corporation, 150 x 20 mm). The mobile phases were MilliQ water (phase A) and MeCN (phase B). The flow rate was 1 mL / min. The gradient was changed from 100% A and 0% B to 80% A and 20% B over the first 20 minutes, and then from 80% A and 20% B to 0% A and 100% B over the first 20 minutes. Compound (14) was obtained in a radiochemical yield of >99% and a radiochemical purity of >99%.

[0086] The reaction scheme leading to the synthesis of compound (14) is shown below.

[0087] [ka]

[0088] The reagents and solvents used in each step are as follows. (j) 125 I]NaI aq., DIPEA, MeCN (k) TFA, HO

[0089] [[ 125 Synthesis of I]O-(3-hydroxy-2-(hydroxymethyl)-2-(iodomethyl)propyl)-L-tyrosine (16) The compound (10) (627 μg, 1.0 nmol) obtained above was dissolved in 1% DIPEA / MeCN (100 μL). 125 An aqueous solution of [I]NaI (1.0 μL, 82.0 μCi) was added and reacted at 37°C for 1 hour. After the reaction, the product was purified by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact, 150 × 20 mm) with MilliQ water as the mobile phase (phase A) and MeCN as the mobile phase (phase B). The flow rate was 1 mL / min. The gradient was changed from 30% A and 70% B to 20% A and 80% B over the first 20 minutes, and then from 20% A and 80% B to 0% A and 100% B over the first 20 minutes. Compound 15 was obtained in a radiochemical yield of 89.6%. The collected solution was concentrated to 50 μL using a rotary evaporator. TFA (450 μL) was added to the concentrated solution and allowed to react at 37°C for 1 hour. After the reaction, the TFA in the solution was removed under a nitrogen stream, and the remaining TFA was neutralized by adding saturated aqueous NaHCO3. The product was purified by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact Corporation, 150 x 20 mm). The mobile phases were MilliQ water (phase A) and MeCN (phase B). The flow rate was 1 mL / min. The gradient was changed from 90% phase A and 10% phase B to 50% phase A and 50% phase B over the first 0-20 minutes, and then from 50% phase A and 50% phase B to 0% phase A and 100% phase B over the first 20-30 minutes. Compound (16) was obtained in a radiochemical yield of >99% and a radiochemical purity of >99%.

[0090] The reaction scheme leading to the synthesis of compound (16) is shown below.

[0091] [ka]

[0092] The reagents and solvents used in each step are as follows. (l)[ 125 I]NaI aq., DIPEA, MeCN (m) TFA, HO

[0093] FIG. 1 shows the results of HPLC analysis of compound (8) and compound (14). FIG. 2 shows the results of HPLC analysis of compound (12) and compound (16). Compound (8) was analyzed by measuring absorbance at 220 nm, and compound (12) was analyzed by measuring absorbance at 254 nm. Compounds (14) and (16) were analyzed by connecting a gamma-ray detector (Gabi star, manufactured by Raytest) online.

[0094] [Evaluation Example 1: Evaluation of biodistribution in tumor-bearing mice (1)] [Creation of tumor-bearing mice] Four-week-old BALB / c Slc-nu / nu male mice were inoculated with C6 cells (5 × 10 6 The tumor-bearing mice were then transplanted with 1000 cells / mouse into the left leg. The experiments using mice in this specification were carried out with the approval of the Animal Ethics Committee of Chiba University. [Biodistribution test in tumor-bearing mice] One week after C6 cell transplantation, mice were administered compound 14, compound 16, or a control compound (0.3 μCi / 100 μL / mouse) via the tail vein. One and two hours after administration, the mice were sacrificed, and the organs of interest and tumors were collected. After measuring the mass, radioactivity was measured using an Autowell Gamma System (WIZARD3, PerkinElmer). The following compounds were used as control compounds:

[0095] [ka]

[0096] The results are shown in Table 1. The units in the table are the radioactivity accumulation rate (%) [%ID / g] relative to 100% of the radioactivity administered (injected dose) per 1g of organ or tissue, except for the stomach, intestines, and neck. For the stomach, intestines, and neck, the units are the radioactivity accumulation rate (%) [%ID] relative to 100% of the radioactivity administered (injected dose) per organ or tissue.

[0097] [Table 1]

[0098] As shown in the table, high levels of radioactivity were observed in tumor-bearing mice administered with compound (14) or compound (16). Furthermore, in tumor-bearing mice administered with compound (14) or compound (16), low levels of radioactivity were observed in the neck, where the thyroid gland is located and where free iodine tends to accumulate. Therefore, it was found that compound (14) and compound (16) are efficiently taken up by tumors and have high stability in vivo.

[0099] [Synthesis Example 2] [[ 211 Synthesis of At]O-(3-hydroxy-2-(hydroxymethyl)-2-(astatomethyl)propyl)-L-tyrosine (17) Compound (10) (300 μg, 0.48 μmol) obtained in the same manner as in Synthesis Example (1) was dissolved in 1% N,N-diisopropylethylamine (DIPEA) / MeCN (50 μL). 211 A solution of At in MeCN (10 μL, 135 μCi) was added and the mixture was allowed to react for 30 minutes at 37°C. Then, TFA (100 μL) was added and the mixture was allowed to react for 1 hour at 37°C. After the reaction, the TFA in the solution was removed under a nitrogen stream, and the remaining TFA was neutralized by adding 1N aqueous NaOH solution. The product was purified by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact, 150 x 4.6 mm) with 0.1% TFA / MilliQ water as the mobile phase (phase A) and 0.1% TFA / MeCN as the mobile phase (phase B). The flow rate was 1 mL / min. The gradient was changed from 90% A and 10% B to 50% A and 50% B over the 0-20 min period, and then from 50% A and 50% B to 0% A and 100% B over the 20-30 min period. Compound 17 was obtained in a radiochemical yield of 48.3% and with a radiochemical purity of >98%.

[0100] The reaction scheme leading to the synthesis of compound (17) is shown below.

[0101] [ka]

[0102] The reagents and solvents used in each step are as follows. (n)[ 211 At] / MeCN,DIPEA,MeCN (o) TFA, HO

[0103] [Evaluation Example 2: Evaluation of biodistribution in normal mice] Compound 16 [n = 4-5] and compound 17 [n = 4] (0.3 μCi / 100 μL / mouse) were administered via the tail vein of 6-week-old ISR mice. One and three hours after administration, the mice were sacrificed, and organs of interest were collected. After measuring the mass, radioactivity was measured using an Autowell Gamma System (WIZARD3, PerkinElmer). The results are shown in Figure 3. The units in the figure are the radioactivity accumulation rate (%) [%ID / g] relative to 100% of the radioactivity administered (injected dose) per 1 g of organ or tissue for the blood, liver, and pancreas. For the stomach, the units are the radioactivity accumulation rate (%) [%ID] relative to 100% of the radioactivity administered (injected dose) per organ. As shown in Figure 3, normal mice administered compound (16) or compound (17) showed low accumulation of radioactivity in the stomach. Generally, compounds that are stable in vivo have an accumulation of radioactivity in the stomach of 2% ID or less. Therefore, compound (16) and compound (17) were found to have high stability in vivo.

[0104] [Evaluation Example 3: Evaluation of biodistribution in tumor-bearing mice (2)] [Creation of tumor-bearing mice] Five-week-old BALB / c Slc-nu / nu male mice were inoculated with C6 cells (5 × 10 6 The tumor-bearing mice were then transplanted with 1000 cells / mouse into the left leg. One week after C6 cell transplantation, compound (17) [n = 2] (0.3 μCi / 100 μL / mouse) was administered via the tail vein of each mouse. One hour after administration, the mice were sacrificed, and the organs of interest and tumors were collected. After measuring the mass, radioactivity was measured using an Autowell Gamma System (WIZARD3, PerkinElmer). Figure 4 shows the results and the corresponding results for compound (16) obtained in Evaluation Example 1. The units in the figure are the radioactivity accumulation rate (%) [%ID / g] relative to 100% of the radioactivity administered per gram of tissue (injected dose) for blood and tumor, and the radioactivity accumulation rate (%) [%ID] relative to 100% of the radioactivity administered per organ (injected dose) for the stomach. As shown in Figure 4, high levels of radioactivity were observed in tumor-bearing mice administered compound (17). This indicates that compound (17) is efficiently taken up by tumors. Furthermore, similar to the results for compound (16) in tumor-bearing mice and compound (17) in normal mice, compound (17) showed low levels of radioactivity in the stomach of tumor-bearing mice, demonstrating its high in vivo stability. [Industrial Applicability]

[0105] The radioactive compound of the present invention or a pharmaceutically acceptable salt thereof is efficiently taken up by tumors and has high stability in vivo, and therefore radiopharmaceutical compositions containing the compound as an active ingredient for diagnostic imaging, treatment, etc. can be provided.

Claims

1. A radioactive compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 [In the formula, R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R b each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X represents a group represented by the following formula (x1), formula (x2), or formula (x3): 【Chemistry 2】 (In the formula, * indicates the binding site to the α carbon, and ** indicates the other binding site.) Y is, 18 F. 76 Br, 77 Br, 123 I, 124 I, 125 I, 132 I, or 211 At, † indicates an asymmetric carbon.

2. R a represents a hydrogen atom or a methyl group, R b and each independently represent a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof.

3. 3. The radioactive compound according to claim 1 or 2, which is represented by the following formula (Ib-1), (Ib-2) or (Ib-3), or a pharmaceutically acceptable salt thereof: 【Chemistry 3】 [In the formula, Y is the same as above.]

4. A method for producing the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, comprising the following steps [1] to [4]: [1] a step of providing a compound (i) represented by the following formula (y1), formula (y2), or formula (y3): 【Chemistry 4】 (In the formula, Z 1 are each independently a hydrogen atom, a protecting group for an amino group, or R b indicates, Z 2 represents a protecting group for a hydrogen atom or a carboxy group. R a , R b , † is the same as above.) [2] providing a compound (ii) represented by the following formula (II): 【Chemistry 5】 [In the formula, L １ each independently represents a leaving group. [3] (a) The hydrogen atom of the amino group or hydroxy group in the side chain of the compound (i) is bonded to one of the L groups in the compound (ii). 1 and (b) the other L in the compound (ii) 1 a step of substituting the above with Y (wherein Y is the same as above) to obtain a compound (iii) represented by the following formula (III); 【Chemistry 6】 [In the formula, R a , X, Y, Z 1 , Z 2 is the same as above.] [4] A step of deprotecting the protecting group of the compound (iii)

5. A radiopharmaceutical composition comprising the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

6. The radiopharmaceutical composition of claim 5, which is for use in diagnostic imaging.

7. The radiopharmaceutical composition of claim 5, which is for therapeutic use.

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