JP7721166B2 - radioactive compound - Google Patents

Description

The present invention relates to a radioactive compound, a method for producing the same, and a radiopharmaceutical composition.

Cancer cells are known to generally take up large amounts of nutrients, such as amino acids. Therefore, the development of radionuclide-labeled amino acid derivatives would 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 numerous clinical studies are being conducted (e.g., Non-Patent Document 1). Furthermore, amino acid derivatives labeled with the α-particle-emitting nuclide astatine-211 ( ²¹¹ At) enable nuclear medicine therapy using α rays, which is expected to enable integrated diagnosis and treatment. To date, ²¹¹ At-labeled tyrosine derivatives and ²¹¹ At-labeled phenylalanine derivatives have been developed as ²¹¹ At-labeled drugs (e.g., Non-Patent Document 2).

Front. Chem. 2018 Jan 1555(124). Oncotarget. 2020 Apr 14, 11(15): 1388-1398.

Amino acid derivatives labeled with radioactive fluorine or radioactive iodine have been developed to date, demonstrating high in vivo stability and high tumor uptake, and their usefulness has been recognized. However, while ^211At -labeled amino acid derivatives demonstrate high tumor uptake, they suffer from the problem of in vivo shedding of ^211At and nonspecific accumulation in the stomach and thyroid gland. This not only increases the side effects of radiation exposure, but also reduces radioactivity in tumor tissue, leading to insufficient therapeutic efficacy. Therefore, the development of ^211At -labeled amino acid derivatives with high in vivo stability 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.

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

[In the formula,
R ^a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ^b 's each independently represent 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):

(In the formula, * indicates the binding site to the α carbon, and ** indicates the other binding site.)
Y represents 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,
The radioactive compound or pharmaceutically acceptable salt thereof according to the above <1>, wherein R ^b each independently represents a hydrogen atom or a methyl group.
<3> The radioactive compound according to <1> or <2> above, which is represented by the following formula (Ib-1), (Ib-2) or (Ib-3), or a pharmaceutically acceptable salt thereof:

[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 the above <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):

(In the formula,
^Z1 's each independently represent a hydrogen atom, an amino-protecting group, or ^Rb ;
^Z2 represents a hydrogen atom or a protecting group for a carboxy group.
R ^a , R ^b , † are the same as above.)
[2] providing a compound (ii) represented by the following formula (II):

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

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

The present invention provides a novel radioactive compound or a pharmaceutically acceptable salt thereof. The radioactive compound of the present invention has high biostability.

FIG. 1 shows the results of HPLC analysis of compound (8) and compound (14) of Synthesis Example 1. FIG. 2 shows the results of HPLC analysis of compound (12) and compound (16) of Synthesis Example 1. FIG. 3 shows the results of Evaluation Example 2. FIG. 4 shows the results of Evaluation Example 3.

[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:

[In the formula,
R ^a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ^b 's each independently represent 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):

(In the formula, * indicates the binding site to the α carbon, and ** indicates the other binding site.)
Y represents ¹⁸ F, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³² I, or ²¹¹ At;
† indicates an asymmetric carbon.

Examples of the "alkyl group having 1 to 6 carbon atoms" in R ^a and R ^b include a linear or branched alkyl group having 1 to 6 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.

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 's each independently represent 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.
Preferably, two R ^{b s} are both hydrogen atoms, or one is a hydrogen atom and the other is the above-mentioned alkyl group, and more preferably, both are hydrogen atoms.
Y is a radioactive halogen atom, and represents 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 At.

The compounds of the present invention have an asymmetric carbon. The configuration of the asymmetric carbon †C is the L configuration shown below.

Or, the D layout below

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

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.

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.

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

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

[Wherein, Y is the same as above.]

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.

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

[Manufacturing method]
The radioactive compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be produced, for example, by a method 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):

(In the formula,
^Z1 's each independently represent a hydrogen atom, an amino-protecting group, or ^Rb ;
^Z2 represents a hydrogen atom or a protecting group for a carboxy group,
R ^a , R ^b , † are the same as above.)
[2] providing a compound (ii) represented by the following formula (II):

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

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

<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 derivative in which the amino group and carboxy group bound to the α-carbon may be protected. The compound represented by formula (y2) is tyrosine or its α-alkyl and/or N-alkyl derivative in which the amino group and carboxy group bound to the α-carbon may be protected. The compound represented by formula (y3) is α-alkyl and/or N-alkyl tryptophan or its derivative in which the amino group and carboxy group bound to the α-carbon may be protected.
Examples of the amino-protecting 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 compound (i), from the viewpoint of the reaction efficiency of the production method of the present invention, ^Z1 is preferably an amino-protecting group and ^Z2 is a carboxy-protecting group, more preferably ^Z1 and ^Z2 are a combination of an amino-protecting group and a carboxy-protecting group that can be deprotected under the same conditions, and even more preferably a combination of an amino-protecting group and a carboxy-protecting group that can be deprotected by an acid catalyst such as trifluoroacetic acid. An example of such a combination is a combination where ^Z1 is a Boc group and ^Z2 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.

<Process [2]>
In step [2], 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 protect them as acetals, and then reacting the other two hydroxy groups with an activating agent to form leaving groups.
Examples of the leaving group represented by ^L1 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.

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

(Step (a))
In step (a), the hydrogen atom of the amino group or hydroxy group in the side chain of the compound (i) is substituted with a group obtained by removing one of L ¹ in the compound (ii).
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.

(Step (b))
In step (b), the other ^L1 in the compound (ii) is replaced with a radioactive atom Y (Y is as defined 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 from the viewpoint of their ability to double 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.

The order of steps (a) and (b) is not limited; step (a) may be performed first, followed by step (b), or step (b) may be performed first, followed by step (a). From the perspective of reducing the number of steps involving the handling of radioactive isotopes, it is preferable to perform step (a) first, followed by step (b).

The reaction scheme in the case where step (b) is carried out after step (a) is shown below.

[In the formula, R ^a , X, Y, Z ¹ , Z ² and L ¹ are the same as above.]

The reaction scheme in the case where step (a) is carried out after step (b) is shown below.

[In the formula, R ^a , X, Y, Z ¹ , Z ² and L ¹ are the same as above.]

The compound (iii) represented by formula (III) obtained in this manner can be subjected to isolation steps such as filtration, concentration, extraction, etc., and/or purification steps such as column chromatography and recrystallization, as necessary, before being subjected to the next step [4]. Furthermore, between steps (a) and (b), the target compound can be obtained by isolation steps such as filtration, concentration, extraction, etc., and/or purification steps such as column chromatography and recrystallization, as necessary.

<Process [4]>
In step [4], the protecting group of the compound (iii) is removed. The protecting group of the compound (iii) is when ^Z1 derived from the compound (i) is a protecting group for an amino group, when ^Z2 is a protecting group for a carboxy group, or when Z1 is a protecting group for a neopentyl acetal protecting group derived from the compound (ii).

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.
When Z ¹ is a Boc group and Z ² is a tert-butyl group, deprotection using the above-mentioned acid catalyst is preferred because deprotection can be carried out simultaneously.

In step [4], if necessary, isolation steps such as filtration, concentration, extraction, etc., and/or purification steps such as column chromatography and recrystallization can be carried out to obtain the desired radioactive compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Thus, the radioactive compound of the present invention is produced. Synthesis of the radioactive compound of the present invention can be confirmed by known means such as ¹ H-NMR measurement, ¹³ C-NMR measurement, mass spectrometry, etc.

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 also 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 a group obtained by removing one of ^L1 in the above compound (ii).
An example of the radioactive compound thus obtained is shown below.

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

Radiopharmaceuticals can be prepared as pharmaceutical compositions containing the above-mentioned radioactive compound or its salt as the active ingredient, as well as one or more pharmaceutically acceptable carriers, as needed. 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 that help improve 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.

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/central system diseases, is preferably used for radiological imaging diagnosis of cancer, including solid cancers of the stomach, large intestine, lung, liver, prostate, pancreas, esophagus, bladder, gallbladder/bile duct, breast, uterus, thyroid, ovary, etc.

The radiopharmaceutical compositions of the present invention can be used, for example, for therapeutic purposes.
Preferably, it can be used in radiotherapy to suppress cancer. When used as an anticancer agent, the term has the broadest meaning, including both a preventive effect of preventing the onset, metastasis, implantation, and recurrence of cancer, and a therapeutic effect of suppressing the proliferation of cancer cells, preventing the progression of cancer by shrinking the cancer, and improving symptoms, and is not to be interpreted restrictively in any case.
For therapeutic use, Y in the above formula (I) is preferably ²¹¹ At, an alpha-emitting nuclide.

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.

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 patient's age and weight, 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 expected that the diagnostic agent will be used in radiation therapy, and the dosage of the diagnostic agent is not particularly limited, but is, for example, 1.0 MBq/kg to 3.0 MBq/kg in terms of the radioactivity of the radioactive element (e.g., ²¹¹ At).

[Synthesis Example 1]
[Synthesis of N ^α -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 free copper, followed by the addition of dichloromethane ( _CH2Cl2 ) (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 a crude oily product of N,N-Diisopropyl-O-tert-butylisourea (DIC) (6.57 g).
(ii) ^Nα- (tert-butoxycarbonyl)-L-histidine (1) was dissolved in _CH2Cl2 (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, yield 58.4%) was obtained as a pale yellow oil.
¹ H NMR (CDCl ₃ ): δ 1.42-1.44 (18H, overlapped, CH _3, CH ₃ ), 3.07-3.08 (2H, d, CH ₂ ), 4.40 (1H, s, CH), 5.64 (1H, s, NH), 6.83 (1H, s, aromatic), 7.61 (1H, s, aromatic).
^13C -NMR (CDCl ₃ ): 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.

[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 for complete dissolution. 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 solution, and the solvent was removed under reduced pressure. The residue was recovered 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, yield 36.1%).
¹ H-NMR (DMSO-d ₆ ): δ 1.29 (6H, s, CH ₃ ), 3.35-3.36 (4H, d, CH ₂ ), 3.59 (4H, s, CH ₂ ), 4.48-4.51 (2H, t, OH).
^13C -NMR (DMSO- _d6 ): 23.83, 38.88, 60.50, 61.67, 91.12.

[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 CH ₂ Cl ₂ (40 mL), and 2,6-lutidine (4.20 mL, 35.9 mmol) was added. The solution was cooled to -78°C, and trifluoromethanesulfonic anhydride (Tf ₂ O) (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 sequentially with saturated aqueous NaHCO ₃ (20 mL), 5% aqueous citric acid (30 mL x 3), and saturated brine (20 mL). Magnesium sulfate was added to the organic layer and dried, and the solvent was evaporated 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, yield 82.0%) was obtained as a white solid.
¹ H-NMR (CDCl ₃ ): δ 1.44 (6H, s, CH ₃ ), 3.79 (4H, s, CH ₂ ), 4.57 (4H, s, CH ₂ ).
^13C -NMR (CDCl ₃ ): 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.

[N ^α -(tert-butoxycarbonyl)-N ^τ -((2,2-dimethyl-5-(((trifluoromethyl)sulfonyl)oxy)methyl)-1,3-dioxan-5-yl)methyl)-L-histidine tert-butyl Synthesis of ester (6)]
Compound (5) (145 mg, 0.330 mmol) obtained above was dissolved in CH ₂ Cl ₂ (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 CH ₂ Cl ₂ (200 μL) was added dropwise. The reaction solution was stirred overnight at −20°C. The reaction solution was washed sequentially with saturated aqueous NaHCO ₃ (5 mL), 5% aqueous citric acid (10 mL × 3), and saturated brine (10 mL). Sodium sulfate was added to the organic layer for drying, and the solvent was then evaporated under reduced pressure. The residue was dissolved in a small amount of CH ₂ Cl ₂ 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 a developing solvent. Compound (6) (19.9 mg, 0.0331 mmol, yield 20.0%) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ 1.41-1.47 (24H, overlapped, CH ₃ ), 3.03 (2H, broad, CH ₂ ), 3.63-3.74 (4H, multiple, CH ₂ ), 4.11 (2H, s, CH ₂ ), 4.37 (3H, overlapped, CH ₂ , 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.

[N ^α -(tert-butoxycarbonyl)-N ^τ -((5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl)-L-histidine tert-butyl Synthesis of ester (7)]
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 under reduced pressure, and the mixture was dissolved in ethyl acetate. The mixture was washed with MilliQ water (2 mL x 2) and saturated brine (2 mL), successively. Magnesium sulfate was added to the organic layer, followed by drying, and the solvent was removed 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 (CDCl ₃ ): δ 1.41-1.57 (24H, overlapped, CH ₃ ), 2.87 (2H, s, CH ₂ ), 3.02 (2H, s, CH ₂ ), 3.48-3.69 (4H, multiple, CH ₂ ), 4.19 (2H, s, CH ₂ ), 4.38-4.40 (1H, broad, CH), 5.74-5.76 (1H, d, NH), 6.84 (1H, s, aromatic), 7.56 (1H, s, aromatic).
^13C -NMR (CDCl ₃ ): 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.

[Synthesis of N ^τ -(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 evaporated under reduced pressure, and the solvent was azeotroped with MeCN (1 mL × 2 times). The residue was dissolved in a mixture of MilliQ water and MeCN at a ratio of 70:30 (2 mL). The product was purified from the residue by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact Corporation, 150 x 20 mm). The mobile phases were 0.1% (v/v) TFA/MilliQ water for phase A and 0.1% (v/v) TFA/MeCN for 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 period from 0 to 30 minutes after the start, and then from 50% A and 50% B to 0% A and 100% B over the period from 30 to 50 minutes after the start. The trifluoroacetate salt (TFA salt) of compound (8) (3.6 mg, 9.39 nmol, yield 75.3%) was obtained as a pale yellow solid.
¹ H-NMR (D ₂ O): δ 3.18 (2H, s, CH ₂ ), 3.34 (2H, d, CH ₂ ), 3.51-3.53 (2H, d, CH ₂ ), 4.05-4.09 (1H, t, CH), 4.30 (2H, s, CH ₂ ), 7.47 (1H, s, aromatic), 8.76 (1H, s, aromatic).
ESI-MS (M+H) ⁺ : m/z 384, found 384.

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

The reagents and solvents used in each step are as follows.
(a) (i) DIC, tBuOH, CuCl(I); (ii) CH ₂ Cl ₂
(b) 2,2-Dimethoxypropane, (+)-10-Camphorsulfonic acid, DMF
(c) Tf ₂ O, 2,6-Lutidine, CH ₂ Cl ₂
(d) 2,6-Lutidine, CH ₂ Cl ₂
(e) NaI, MeCN
(f) TFA, _H2O

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

[N ^α -(tert-butoxycarbonyl)-O-((2,2-dimethyl-5-((((trifluoromethyl)sulfonyl)oxy)methyl)-1,3-dioxan-5-yl)methyl)-L-tyrosine Synthesis of 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 dissolved in THF (1.50 mL) was added dropwise under ice cooling and stirred 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 the solvent was removed 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 removed by distillation. The residue was dissolved in a small amount of _CH2Cl2 and applied to a 1 mm-thick preparative TLC plate. The product was purified from the residue by using hexane:ethyl acetate = 2:1 as the developing solvent. Compound (10) (86.2 mg, 0.137 mmol, yield 60.8%) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ 1.41-1.45 (24H, overlapped, CH ₃ ), 2.99-3.01 (2H, t, CH ₂ ), 3.81-3.93 (6H, overlapped, CH ₂ ), 4.39-4.41 (1H, multiple, CH), 4.79 (2H, s, CH ₂ ), 4.96-4.98 (1H, d, NH), 6.80-6.82 (2H, d, aromatic), 7.08-7.10 (2H, d, aromatic).
^13C -NMR (CDCl ₃ ): 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.

[N ^α -(tert-butoxycarbonyl)-O-((5-(iodomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl)-L-tyrosine tert-butyl Synthesis of ester (11)]
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 thereto. 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 sequentially with 5% _aqueous NaHCO3 solution (5 mL), MilliQ water (5 mL x 2), and saturated saline (5 mL). Magnesium sulfate was added to the organic layer, followed by drying, and the solvent was removed under reduced pressure. The residue was dissolved in _a small amount of _CH2Cl2 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 (CDCl ₃ ): δ 1.42-1.44 (24H, overlapped, CH ₃ ), 2.99-3.01(2H, t, CH ₂ ), 3.41 (2H, s, CH ₂ ), 3.78-3.91 (4H, multiple, CH ₂ ), 3.98 (2H, s, CH ₂ ), 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).
^13C -NMR (CDCl ₃ ): 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.

[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 evaporated under reduced pressure, and the solvent was azeotroped with MeCN (1 mL × 2 times). The residue was dissolved in a mixture of MilliQ water and MeCN at a ratio of 70:30 (2 mL). The product was purified from the residue by high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, Intact Corporation, 150 x 20 mm). The mobile phases were 0.1% (v/v) TFA/MilliQ water for phase A and 0.1% (v/v) TFA/MeCN for 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 period from 0 to 30 minutes after the start, and then from 50% A and 50% B to 0% A and 100% B over the period from 30 to 50 minutes after the start. The TFA salt of compound (12) (5.45 mg, 10.8 nmol, yield 64.1%) was obtained as a white solid.
¹ H-NMR (D ₂ O): δ 2.95-3.14 (2H, multiple, CH ₂ ), 3.20 (2H, s, CH ₂ ), 3.51 (4H. s, CH ₂ ), 3.79 (2H, s, CH ₂ ), 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.

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

The reagents and solvents used in each step are as follows.
(g) NaH, THF
(h) NaI, MeCN
(i) TFA, _H2O

[Synthesis of [ ¹²⁵ I]N ^τ -(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). An aqueous solution of [ ¹²⁵ I]NaI (1.0 μL, 57.1 μCi) was added to the solution, and the mixture was allowed to react 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 x 20 mm). The mobile phases were MilliQ water for phase A and MeCN for phase B, with a flow rate of 1 mL/min. The gradient was changed from 40% A and 60% B to 30% A and 70% B over the period from 0 to 20 minutes, and then from 30% A and 70% B to 0% A and 100% B over the period from 20 to 30 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 saturated aqueous NaHCO ₃ solution was added to neutralize the remaining TFA. 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 as phase A and MeCN as 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 0-20 minutes, and then from 80% A and 20% B to 0% A and 100% B over the first 20-30 minutes. Compound (14) was obtained in radiochemical yield >99% and radiochemical purity >99%.

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

The reagents and solvents used in each step are as follows.
(j) [ ¹²⁵ I]NaI aq. , DIPEA, MeCN
(k) TFA, _H2O

[Synthesis of [ ¹²⁵ 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). An aqueous solution of [ ¹²⁵ I]NaI (1.0 μL, 82.0 μCi) was added to the solution, and the mixture was allowed to react 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 x 20 mm). The mobile phases were MilliQ water for phase A and MeCN for phase B, with a flow rate of 1 mL/min. The gradient was changed from 30% A and 70% B to 20% A and 80% B over the period from 0 to 20 minutes, and then from 20% A and 80% B to 0% A and 100% B over the period from 20 to 30 minutes. Compound (15) was obtained in a radiochemical yield of 89.6%.
The collected solution was concentrated to 50 μL using a rotary evaporator, and TFA (450 μL) was added to the concentrated solution, followed by a reaction 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 NaHCO ₃ solution. 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 as phase A and MeCN as phase B, with a flow rate of 1 mL/min. The gradient was changed from 90% A and 10% B to 50% A and 50% B over the first 0-20 minutes, and then from 50% A and 50% B to 0% A and 100% B over the first 20-30 minutes. Compound (16) was obtained in radiochemical yield >99% and radiochemical purity >99%.

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

The reagents and solvents used in each step are as follows.
(l) [ ¹²⁵ I]NaI aq. , DIPEA, MeCN
(m) TFA, _H2O

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.

[Evaluation Example 1: Evaluation of biodistribution in tumor-bearing mice (1)]
[Creation of tumor-bearing mice]
C6 cells (5×10 ⁶ cells/mouse) were transplanted into the left leg of 4-week-old BALB/c Slc-nu/nu male mice to prepare tumor-bearing mice.
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 into mice, compound (14), compound (16), or a control compound (0.3 μCi/100 μL/mouse) was administered via the tail vein of each mouse. 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:

The results are shown in Table 1. Note that 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.

As shown in the table, high levels of radioactivity were observed in tumors in tumor-bearing mice administered compound (14) or compound (16). Furthermore, in tumor-bearing mice administered 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 are highly stable in vivo.

[Synthesis Example 2]
[Synthesis of [ ²¹¹ 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). A MeCN solution (10 μL, 135 μCi) of [ ²¹¹ At] was added to the solution, and the mixture was allowed to react at 37°C for 30 minutes. Next, TFA (100 μL) was added, and the mixture was 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 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 a mobile phase of 0.1% TFA/MilliQ water for phase A and 0.1% TFA/MeCN for phase B at a flow rate of 1 mL/min. The gradient was changed from 90% A and 10% B to 50% A and 50% B over the period from 0 to 20 minutes, and then from 50% A and 50% B to 0% A and 100% B over the period from 20 to 30 minutes. Compound (17) was obtained in a radiochemical yield of 48.3% and with a radiochemical purity of >98%.

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

The reagents and solvents used in each step are as follows.
(n) [ ²¹¹ At]/MeCN, DIPEA, MeCN
(o) TFA, _H2O

[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 hour 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 per gram of organ or tissue (injected dose) for the blood, liver, and pancreas, and the radioactivity accumulation rate (%) [%ID] relative to 100% of the radioactivity administered per organ (injected dose) for the stomach.
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.

[Evaluation Example 3: Evaluation of biodistribution in tumor-bearing mice (2)]
[Creation of tumor-bearing mice]
C6 cells (5×10 ⁶ cells/mouse) were transplanted into the left leg of 5-week-old male BALB/c Slc-nu/nu mice to prepare tumor-bearing mice.
One week after C6 cell transplantation into the mice, 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).
The results and the corresponding results for compound (16) obtained in Evaluation Example 1 are shown in Figure 4. 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 radioactivity accumulation was observed in tumors in tumor-bearing mice administered compound (17). Therefore, compound (17) was found to be efficiently taken up by tumors. Furthermore, similar to the results of compound (16) in tumor-bearing mice and compound (17) in normal mice, compound (17) showed low radioactivity accumulation in the stomach of tumor-bearing mice, demonstrating high stability in vivo.

The radioactive compounds of the present invention or their pharmaceutically acceptable salts are efficiently taken up by tumors and other organs and are highly stable in vivo, allowing radiopharmaceutical compositions containing these compounds as active ingredients for use in diagnostic imaging, treatment, etc. to be provided.

Claims (7)

A radioactive compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[In the formula,
R ^a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ^b 's each independently represent 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):

(In the formula, * indicates the binding site to the α carbon, and ** indicates the other binding site.)
Y represents ¹⁸ F, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³² I, or ²¹¹ At;
† indicates an asymmetric carbon. R ^a represents a hydrogen atom or a methyl group;
2. The radioactive compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R ^b independently represents a hydrogen atom or a methyl group. 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:

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

(In the formula,
^Z1 's each independently represent a hydrogen atom, an amino-protecting group, or ^Rb ;
^Z2 represents a hydrogen atom or a protecting group for a carboxy group.
R ^a , R ^b , † are the same as above.)
[2] providing a compound (ii) represented by the following formula (II):

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

[In the formula, R ^a , X, Y, Z ¹ and Z ² are the same as above.]
[4] A step of deprotecting the protecting group of the compound (iii) A radiopharmaceutical composition comprising the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3. The radiopharmaceutical composition described in claim 5, which is for use in diagnostic imaging. The radiopharmaceutical composition of claim 5, for therapeutic use.