WO2022186273A1

WO2022186273A1 - Radioactive compound

Info

Publication number: WO2022186273A1
Application number: PCT/JP2022/008860
Authority: WO
Inventors: 知也上原; 博元鈴木; 祐太貝塚
Original assignee: 国立大学法人千葉大学
Priority date: 2021-03-03
Filing date: 2022-03-02
Publication date: 2022-09-09
Also published as: JPWO2022186273A1

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, R^a, R^b, X, Y, and † are as defined in the specification.]

Description

radioactive compound

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

It is known that cancer cells generally take up many nutrients such as amino acids. Therefore, development of radionuclide-labeled amino acid derivatives would be useful for the diagnosis and treatment of various cancers. In fact, for the purpose of nuclear medicine diagnosis, radioactive fluorine-labeled tyrosine derivatives, phenylalanine derivatives, radioactive iodine-labeled tyrosine derivatives, and the like have been developed, and many clinical studies are being conducted (for example, Non-Patent Document 1). In addition, amino acid derivatives labeled with astatine-211 ( ²¹¹ At), which is an α-emitting nuclide, are expected to enable nuclear medicine treatment using α-rays, enabling 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 (eg, Non-Patent Document 2).

Amino acid derivatives labeled with radioactive fluorine or radioactive iodine that have been developed so far have high in vivo stability and high uptake into tumors, and their usefulness has been recognized. However, while ²¹¹ At-labeled amino acid derivatives exhibit high uptake into tumors, ²¹¹ At is observed to be lost in vivo, and non-specific accumulation in the stomach and thyroid is a problem. This not only leads to increased side effects due to radiation exposure, but also leads to decreased radioactivity in tumor tissue, resulting in insufficient therapeutic effects. Therefore, development of ²¹¹ At-labeled amino acid derivatives with high in vivo stability is desired.
TECHNICAL FIELD The present invention relates to novel radioactive compounds, particularly to radioactive compounds or pharmaceutically acceptable salts 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 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),

(Wherein, * 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 a pharmaceutically acceptable salt thereof according to <1> above, wherein each R ^b independently represents a hydrogen atom or a methyl group.
<3> The radioactive compound or a pharmaceutically acceptable salt thereof according to <1> or <2>, represented by the following formula (Ib-1), (Ib-2) or (Ib-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 <1> to <3> above, comprising the following steps [1] to [4].
[1] providing a compound (i) represented by the following formula (y1), formula (y2) or formula (y3);

(In the formula,
Z ¹ each independently represents a hydrogen atom, an amino group-protecting group or R ^b ,
Z ² represents a hydrogen atom or a carboxy-protecting 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) Substitution of the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) with a group excluding one L ¹ in the compound (ii), and (b) the compound Y of the other L ¹ in (ii) [wherein Y is the same as 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] Step <5> Deprotecting the protecting group of compound (iii) above <5> A radioactive compound comprising the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of <1> to <3> above pharmaceutical composition.
<6> The radiopharmaceutical composition according to <5> above, which is for diagnostic imaging.
<7> The radiopharmaceutical composition according to <5> above, which is for therapeutic use.

A novel radioactive compound or a pharmaceutically acceptable salt thereof is provided by the present invention. The radioactive compounds of the present invention have high biostability.

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. FIG.

[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.

(Wherein, * 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. ]

The "alkyl group having 1 to 6 carbon atoms" for R ^a and R ^b includes, for example, 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 and the like.

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, still more preferably a hydrogen atom is.
Each R ^b independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably represents a hydrogen atom or a methyl group, further preferably is a hydrogen atom.
Two of R ^b are preferably both hydrogen atoms, or one is a hydrogen atom and the other is the above alkyl group, 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 Indicates ¹²⁵ I or ²¹¹ At.

The compound of the present invention has an asymmetric carbon. The configuration of †C carbon, which is an asymmetric carbon, is the following L configuration

Or, the following D arrangement

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

In formula (I), R ^a preferably 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 compounds of the present invention include radioactive compounds represented by the following formulas (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. ]

A more preferred embodiment of the compound of the present invention includes a radioactive compound 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. ]

The compound of the present invention may be a pharmaceutically acceptable salt of the radioactive compound represented by formula (I) above. Salts 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, and benzenesulfonic acid. salts, p-toluenesulfonate.
The base addition salt may be either an inorganic base salt or an organic base salt. Inorganic base salts include, for example, sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts. Organic base salts include, for example, triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts.
The compounds of the present invention may be solvates such as hydrates. The solvent is not particularly limited as long as it is a pharmaceutically acceptable solvent.

The compound of the present invention can be suitably used as an active ingredient of a radiopharmaceutical composition for diagnostic imaging, treatment, etc., which will be described later.

[Production method]
A 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);

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

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

<Step [1]>
In step [1], compound (i) represented by formula (y1), formula (y2) or formula (y3) is provided.
The compound represented by formula (y1) is histidine or its α-alkyl type and/or N-alkyl type derivative whose amino group and carboxy group bonded to α carbon may be protected. The compound represented by formula (y2) is tyrosine or its α-alkyl type and/or N-alkyl type derivative whose amino group and carboxy group bonded to α carbon may be protected. The compound represented by formula (y3) is α-alkyl and/or N-alkyl tryptophan or a derivative thereof in which the amino group and carboxy group bonded to the α carbon may be protected.
Examples of protective groups for amino groups include tert-butoxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz group), 9-fluorenylmethyloxycarbonyl group (Fmoc group) and the like.
Examples of the carboxy-protecting group include methyl group, ethyl group, benzyl group, tert-butyl group and the like.
In compound (i), from the viewpoint of the reaction efficiency of the production method of the present invention, preferably Z ¹ is an amino group-protecting group and Z ² is a carboxy group-protecting group, more preferably Z ¹ and Z ² are a combination of an amino group-protecting group and a carboxy group-protecting group that can be deprotected under the same conditions, more preferably an amino group-protecting group and a carboxyl group that can be deprotected with an acid catalyst such as trifluoroacetic acid. is a combination of protecting groups of groups. Such combinations include, for example, Z ¹ is a Boc group and Z ² is a tert-butyl group.
Introduction of an amino-protecting group and a carboxy-protecting group can be carried out by a conventional method.

<Step [2]>
In step [2], compound (ii) represented by formula (II) is provided. Compound (ii) is obtained by reacting two adjacent hydroxy groups of pentaerythritol with 2,2-dimethoxypropane to protect the can be obtained by reacting the other two hydroxy groups with an activating agent as leaving groups.
Leaving groups represented by L ¹ include trifluoromethanesulfonate (triflate, —OTf) group, nonafluorobutanesulfonate (nonaflate) group, p-toluenesulfonate (tosylate) group, methanesulfonate (mesylate) group, and p-nitrosulfonyloxy (nosylate) group. Among them, trifluoromethanesulfonate group and nonafluorobutanesulfonate group are preferable from the viewpoint of reactivity.

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

(Step (a))
In the step (a), the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) is substituted with the group excluding one L ¹ in the compound (ii).
In the reaction, 0.1 to 10 mol, preferably 0.5 to 2 mol of compound (ii) can be reacted with 1 mol of compound (i).
The reaction can be carried out in the presence of, for example, 0.1 to excess mol, preferably 0.5 to 10 mol of base per 1 mol of compound (i), if necessary. Examples of the base include organic bases such as pyridine, triethylamine, diisopropylethylamine (DIPEA), and 2,6-lutidine; alkali metal carbonates such as sodium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; Inorganic bases such as alkali metal hydrides are included.
From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent. Examples of solvents include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane, but are limited to these. not to be The solvent may be either a single solvent or a mixture of two or more solvents.

(Step (b))
In step (b), the radioactive atom Y[Y of the ^other L1 in compound (ii) is the same as above. ].
In the reaction, 0.1 to 10 mol, preferably 0.5 to 5 mol of a halogenating agent can be reacted with 1 mol of compound (ii) or the compound obtained in step (a). .
Examples of the halogenating agent include radioactive halogen molecules corresponding to Y, alkali metal salts of Y such as sodium, oxides of Y, and N-halogen succinimide.
The reaction is carried out in the presence of, for example, 0.1 to excess mol, preferably 0.5 to 10 mol of a base, relative to 1 mol of compound (ii) or the compound obtained in step (a), if necessary. can be done with Examples of the base include organic bases such as pyridine, triethylamine, diisopropylethylamine (DIPEA), and 2,6-lutidine; alkali metal carbonates such as sodium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; Inorganic bases such as alkali metal hydrides are included. Among them, organic bases are preferable from the viewpoint of reactivity. Further, from the viewpoint that it can also serve as a solvent, an organic base that is liquid at room temperature is more preferable.
A person skilled in the art can appropriately set the reaction temperature and the reaction time. The reaction temperature can be, for example, 0-40°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 solvents include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane, but are limited to these. not to be The solvent may be either a single solvent or a mixture of two or more solvents.

The order of step (a) and step (b) is not limited, and step (b) may be performed after step (a), or step (a) may be performed after step (b). , from the viewpoint of reducing the number of steps for handling radioactive isotopes, step (b) is preferably carried out after step (a).

The reaction scheme for performing step (b) 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 for performing step (a) 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 the formula (III) obtained in this way is subjected to isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization, if necessary. After that, it can be subjected to the next step [4]. In addition, between steps (a) and (b), if necessary, isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization are performed to obtain the target compound. can be done.

<Step [4]>
In step [4], the protecting group of compound (iii) is deprotected. The protecting group of the compound (iii) means that Z ¹ derived from the compound (i) is an amino-protecting group and Z ² is a carboxy-protecting group, and that the compound (ii) is derived from It is an acetal protecting group with a neopentyl structure.

Deprotection of a protecting group can be performed by a conventional method.
The acetal protecting group with a neopentyl structure can be deprotected using an acid catalyst in an amount of, for example, 0.1 mol to excess, preferably about 0.5 mol to 10 mol, per 1 mol of compound (iii). can be done.
Examples of acid catalysts include organic acids such as trifluoroacetic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. Among them, trifluoroacetic acid is preferred.
A person skilled in the art can appropriately set the reaction temperature and the reaction time. 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. Examples of solvents include aqueous solvents such as water.
When Z ¹ is a Boc group and Z ² is a tert-butyl group, deprotection can be performed simultaneously with the above-described deprotection using an acid catalyst, which is preferable.

In step [4], the target radioactive compound represented by the formula (I) or its pharmacological properties is obtained through isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization, as necessary. commercially acceptable salts can be obtained.

Thus, the radioactive compound of the 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 and mass spectrometry.

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

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

A radiopharmaceutical can be prepared as a pharmaceutical composition containing the above-mentioned radioactive compound or a salt thereof as an active ingredient and, if necessary, one or more pharmaceutically acceptable carriers. 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, tonicity agents, and preservatives. I can give an example. Compounds such as citric acid, tartaric acid, malonic acid, sodium gluconate, sodium glucoheptonate, etc. may also be added to help improve radiochemical purity. Radiopharmaceutical compositions can be provided in the form of aqueous solutions, frozen solutions, and lyophilizates.

The radiopharmaceutical composition of the present invention can be used, for example, for diagnostic imaging.
Diagnostic imaging includes, for example, Single Photon Emission Computed Tomography (also simply referred to as "SPECT"), Positron Emission Tomography (also simply referred to as "PET"), and the like.
Diagnosis is not particularly limited, and it is used for various diseases such as tumors, inflammation, infectious diseases, cardiovascular diseases, brain and central system diseases, and radiological image diagnosis of organs or tissues. Used for diagnostic imaging. Types of cancer include solid cancers in the stomach, large intestine, lung, liver, prostate, pancreas, esophagus, bladder, gallbladder/bile duct, breast, uterus, thyroid gland, ovary, and the like.

The radiopharmaceutical composition of the invention can be used, for example, for therapy.
Preferably, it can be used for radiotherapy to suppress cancer. When used as an anticancer agent, for example, it has a preventive action to prevent the occurrence of cancer, metastasis/implantation, and recurrence, as well as suppressing the growth of cancer cells and shrinking cancer. It has the broadest meaning including both therapeutic actions such as prevention of progression of cancer and amelioration of symptoms, and should not be construed as limited in any case.
For therapeutic use, Y in formula (I) above is preferably ²¹¹ At, an α-emitting nuclide.

The administration target of the radiopharmaceutical composition of the present invention is not particularly limited. For example, mammals, including humans, are suitable administration subjects. Humans are not particularly limited in terms of race, sex, and age. Mammals other than humans include pet animals such as dogs and cats.
The route of administration of the radiopharmaceutical composition of the present invention includes, for example, parenteral administration such as intravenous administration or intraarterial administration, and 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 the radiopharmaceutical composition can effectively express its action after administration.

The radioactivity intensity of the radiopharmaceutical composition is arbitrary as long as it is an intensity that can achieve the purpose by administering the radiopharmaceutical composition and the radiation exposure of the subject is the lowest possible clinical dose. .
The radioactivity intensity can be determined with reference to the radioactivity intensity used in general diagnostic methods and therapeutic methods using radiopharmaceutical compositions. The dose is determined in consideration of various conditions such as the patient's age, body weight, radiographic imaging device to be used, and the state of the target disease.
For humans, the amount of radioactivity in the radiopharmaceutical composition is as follows.
Usually, it is assumed to be used for radiation therapy, and the dosage of the diagnostic agent is not particularly limited, but for example, 1.0 MBq / kg to 3.0 MBq / kg as the radioactivity of a radioactive element (eg ²¹¹ At) is.

[Synthesis Example 1]
[Synthesis of N ^α -tert-butyl-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 nitrogen atmosphere, CuCl(I) (4.10 mg, 0.0414 mmol) was added and stirred at 30° C. for 4 days. Poly(4-vinylpyridine) (0.83 g) was added to adsorb free copper, then dichloromethane (CH ₂ Cl ₂ ) (21 mL) was added and stirred for 15 minutes. After the reaction solution was filtered to remove the precipitate, the filtrate was distilled off under reduced pressure to obtain an oily N,N-Diisopropyl-O-tert-butylisourea (DIC) crude product (6.57 g).
(ii) N ^α -(tert-butoxycarbonyl)-L-histidine (1) was dissolved in CH ₂ Cl ₂ (50 mL), slowly added to the crude product obtained in (i) under an argon atmosphere, and stirred at room temperature. Stirred for 4 days. After diisopropylurea as a by-product was filtered, 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 elution solvent. Compound (2) (1.42 g, 4.57 mmol, 58.4% yield) was obtained as a pale yellow oil.
1H NMR ( _CDCl3 ): δ ^1.42-1.44 (18H, overlapped, CH3 _, _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 (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. and completely dissolved. After gently lowering the temperature to 40° C., 2,2-dimethoxypropane (6.50 mL, 52.8 mmol) was added dropwise. It was 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 distilled off under reduced pressure. The residue was collected and subjected to Soxhlet extraction using hexane for 2 days. After the extract was evaporated 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 _- 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).
^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 was slowly warmed to -20°C and stirred overnight. After the reaction, the reaction solution was washed with saturated NaHCO ₃ aqueous solution (20 mL), 5% citric acid aqueous solution (30 mL×3 times) and saturated brine (20 mL) in that order. After magnesium sulfate was added to the organic layer to dry it, the solvent was distilled off under reduced pressure. The product was purified from the residue by silica gel chromatography using hexane:ethyl acetate=10:1 as the eluent. Compound (5) (1.30 g, 2.94 mmol, 82.0% yield) 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 ( _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.

[N ^α -(tert-butoxycarbonyl)-N ^τ -((2,2-dimethyl-5-((((trifluoromethyl)sulfonyl)oxy)methyl)-1,3-dioxan-5-yl)methyl)-L -Synthesis of histidine tert-butyl 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 CH ₂ Cl ₂ (200 μL) in which compound (2) (51.4 mg, 0.165 mmol) was dissolved was added dropwise. The reaction mixture was stirred overnight at -20°C. The reaction solution was washed with saturated NaHCO ₃ aqueous solution (5 mL), 5% citric acid aqueous solution (10 mL×3 times) and saturated brine (10 mL) in that order. After the organic layer was dried by adding sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of CH ₂ Cl ₂ , applied to a 1 mm thick preparative thin layer chromatography (TLC) plate, and the product was isolated from the residue by using chloroform:methanol=15:1 as a developing solvent. Refined. 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, _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.

[N ^α -(tert-butoxycarbonyl)-N ^τ -((5-(iodmethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methyl)-L-histidine tert-butyl ester (7) Synthesis of]
The compound (6) obtained above (37.0 mg, 0.0615 mmol) was dissolved in acetonitrile (MeCN) (800 μL), sodium iodide (27.0 mg, 0.184 mmol) was added thereto, and the reaction solution was allowed to cool at room temperature. Stirred for 5 days. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with MilliQ water (2 mL×2 times) and saturated brine (2 mL) in that order. After magnesium sulfate was added to the organic layer to dry it, the solvent was distilled off under reduced pressure. The product was purified from the residue using hexane and ethyl acetate in a purification apparatus (Purif compact, manufactured by Shoko Scientific Co., Ltd.). Compound (7) (9.9 mg, 0.0171 mmol, yield 27.8%) 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, _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).
^13C -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, 137.155, 137.588
ESI-MS (M+H) ⁺ : m/z 580, found 580.

[Synthesis of N ^τ -(3-hydroxy-2-(hydroxymethyl)-2-(iodethyl)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 distilled off under reduced pressure, and the solvent was azeotroped with MeCN (1 mL x 2 times). The residue was dissolved in a mixture of MilliQ water: MeCN = 70:30 (2 mL), and in high performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., 150 x 20 mm), Using 0.1% (v/v) TFA/MilliQ water for phase A and 0.1% (v/v) TFA/MeCN for phase B with a flow rate of 5 mL/min for 0-30 minutes after initiation. between 90% A phase, 10% B phase, 50% A phase, and 50% B phase. The product was purified from the residue by a linear gradient method changing phases up to 100%. A trifluoroacetic acid salt (TFA salt) of compound (8) (3.6 mg, 9.39 nmol, yield 75.3%) was obtained as a pale yellow solid.
1H ^- 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, 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 ) CH2Cl2
(b) 2,2-Dimethoxypropane, (+)-10-Camphorsulfonic acid, DMF
(c) Tf ₂ O, 2,6-Lutidine, CH ₂ Cl ₂
₍ d) 2,6 _- Lutidine, CH2Cl2
(e) NaI, MeCN
(f) TFA, _H2O

[Synthesis of N ^α -tert-butyl-L-tyrosine tert-butyl ester (9)]
Synthesized as described in the literature 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- Synthesis of tyrosine tert-butyl ester (10)]
NaH (10.8 mg, 0.270 mmol) was suspended in tetrahydrofuran (THF) (0.50 mL). In an argon atmosphere, THF (1.50 mL) in which compound (9) (76.0 mg, 0.226 mmol) obtained above was dissolved was added dropwise under ice cooling, and the mixture was 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 removing the solvent under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated NaHCO ₃ solution (10 mL×3). After magnesium sulfate was added to the organic layer to dry it, the solvent was distilled off. The residue was dissolved in a small amount of CH ₂ Cl ₂ , applied to a preparative TLC plate with a thickness of 1 mm, and hexane:ethyl acetate=2:1 was used as a developing solvent to purify the product from the residue. 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, _CH2 ), 4.96-4.98 (1H, d, NH), 6.80-6.82 (2H, d, aromatic), 7.08-7.10 (2H, d, aromatic).
¹³ C-NMR (CDCL ₃ ): 21.58, 25.62, 28.07, 28.43, 37.90, 38.90, 55.01, 66.22, 75.43, 79.75, 82.16, 99.19, 99.19, 99.19, 99.94 , 155.19, 157.21, 170.93, 171.07.
ESI-MS (M+Na) ⁺ : m/z 650, found 650.

[N ^α -(tert-butyl)-O-((5-(iodmethyl)-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), sodium iodide (46.0 mg, 0.309 mmol) was added thereto, and the reaction solution was allowed to stand at room temperature. Stir overnight. After the reaction, the solvent was distilled off under reduced pressure, and after dissolving in ethyl acetate, the residue was washed with 5% NaHCO ₃ aqueous solution (5 mL), MilliQ water (5 mL×2 times), and saturated brine (5 mL) in that order. After magnesium sulfate was added to the organic layer to dry it, the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of CH ₂ Cl ₂ , applied to a 1 mm thick preparative TLC plate, and hexane:ethyl acetate=2:1 was used as a developing solvent to purify the product. 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, _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 (CDCL ₃ ): 10.42, 27.58, 24.74, 28.11, 28.45, 36.63, 37.63, 55.02, 68.81, 68.81, 79.73, 82.11, 98.63
ESI-MS (M+Na) ⁺ : m/z 628, found 628.

[Synthesis of O-(3-hydroxy-2-(hydroxymethyl)-2-(iodethyl)propyl)-L-tyrosine (12)]
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 the mixture was stirred at room temperature for 5 hours. After the reaction, TFA was distilled off under reduced pressure, and the solvent was azeotroped with MeCN (1 mL x 2 times). The residue was dissolved in a mixture of MilliQ water: MeCN = 70:30 (2 mL), and in high performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., 150 x 20 mm), Using 0.1% (v/v) TFA/MilliQ water for phase A and 0.1% (v/v) TFA/MeCN for phase B with a flow rate of 5 mL/min for 0-30 minutes after initiation. between 90% A phase, 10% B phase, 50% A phase, and 50% B phase. The product was purified from the residue by a linear gradient method changing phases up to 100%. The TFA salt of compound (12) (5.45 mg, 10.8 nmol, yield 64.1%) was obtained as a white solid.
1H ^- 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 ). 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-(iodmethyl)propyl)-L-histidine (14)]
Compound (6) obtained above (600 μg, 1.0 nmol) was dissolved in 1% N,N-diisopropylethylamine (DIPEA)/MeCN (100 μL). An aqueous [ ¹²⁵ I]NaI solution (1.0 μL, 57.1 μCi) was added to the solution and reacted at 37° C. for 1 hour. After the reaction, high performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm) was performed using MilliQ water as the mobile phase for phase A and MeCN for phase B, and the flow rate was At 1 mL/min, 40% A phase, 60% B phase, 30% A phase, 70% B phase for 0-20 minutes after initiation, and 30% A phase 20-30 minutes after initiation , the product was purified by a linear gradient method varying from 70% B phase to 0% A phase to 100% B phase. Compound (13) was obtained with a radiochemical yield of 84.6%.
The separated solution was concentrated to 50 μL with a rotary evaporator, TFA (450 μL) was added to the concentrated solution, and reacted at 37° C. for 1 hour. After the reaction, the TFA in the solution was removed under a stream of nitrogen, and saturated _NaHCO3 aqueous solution was added to neutralize the remaining TFA. In high performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm), the mobile phase was MilliQ water for phase A and MeCN for phase B, and the flow rate was 1 mL/min. As, 0-20 minutes after the start, change from 100% A phase, 0% B phase to 80% A phase, 20% B phase, and 20-30 minutes after the start A phase 80%, B phase The product was purified by a linear gradient method varying from 20% to 0% phase A to 100% phase B. 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-(iodethyl)propyl)-L-tyrosine (16)]
Compound (10) obtained above (627 μg, 1.0 nmol) was dissolved in 1% DIPEA/MeCN (100 μL). An aqueous [ ¹²⁵ I]NaI solution (1.0 μL, 82.0 μCi) was added to the solution and reacted at 37° C. for 1 hour. After the reaction, high performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm) was performed using MilliQ water as the mobile phase for phase A and MeCN for phase B, and the flow rate was As 1 mL / min, from 0 to 20 minutes after the start, change from 30% A phase, 70% B phase to 20% A phase, 80% B phase, and 20 to 30 minutes after the start 20% A phase , B phase 80% to A phase 0%, B phase 100%. Compound (15) was obtained with a radiochemical yield of 89.6%.
The separated solution was concentrated to 50 μL with a rotary evaporator, TFA (450 μL) was added to the concentrated solution, and reacted at 37° C. for 1 hour. After the reaction, the TFA in the solution was removed under a stream of nitrogen, and saturated _NaHCO3 aqueous solution was added to neutralize the remaining TFA. In high performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm), the mobile phase was MilliQ water for phase A and MeCN for phase B, and the flow rate was 1 mL/min. As, 0-20 minutes after the start, change from 90% A phase, 10% B phase to 50% A phase, 50% B phase, and 20-30 minutes after the start 50% A phase, B phase The product was purified by a linear gradient method varying from 50% to 0% phase A to 100% phase B. 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).
The absorbance of compound (8) was measured and analyzed at 220 nm, and the absorbance of compound (12) was measured and analyzed at 254 nm. Compounds (14) and (16) were analyzed by connecting a gamma ray detector (Gabistar, manufactured by Raytest) online.

[Evaluation Example 1: Evaluation of biodistribution in tumor-bearing mice (1)]
[Generation of tumor-bearing mice]
Tumor-bearing mice were prepared by transplanting C6 cells (5×10 ⁶ cells/mouse) into the left leg of 4-week-old BALB/c Slc-nu/nu strain male mice.
It should be noted that experiments using mice in the present specification were performed with approval from the Animal Ethics Committee of Chiba University.
[Biodistribution test in tumor-bearing mice]
One week after transplantation of C6 cells to mice, compound (14), compound (16) or control compound (0.3 μCi/100 μL/mouse) was administered through the tail vein of each mouse. Mice were sacrificed 1 hour and 2 hours after administration, and organs of interest and tumors were harvested. After measuring the mass, the radioactivity was measured with an Autowell gamma system (WIZARD3, manufactured by PerkinElmer).
As a control compound, the following compounds were used

The results are shown in Table 1. The unit in the table is the radioactivity accumulation rate (%) [% ID/g] with respect to 100% of the radioactivity injected dose per 1 g of organ or tissue, except for the stomach, intestine and neck. For the stomach, intestines and neck, it is the radioactivity accumulation rate (%) [% ID] with respect to 100% of the injected dose per organ or tissue.

As shown in the table, in tumor-bearing mice administered compound (14) or compound (16), high radioactivity accumulation was observed in the tumor. In tumor-bearing mice administered with compound (14) or compound (16), less radioactivity was accumulated in the neck where free iodine tends to accumulate in the thyroid gland. Therefore, it was found that compound (14) and compound (16) are efficiently taken up by tumors and have high stability 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) in which [ ²¹¹ At] was dissolved was added to the solution, and the mixture was allowed to react at 37° C. for 30 minutes. Then, TFA (100 μL) was added and reacted at 37° C. for 1 hour. After the reaction, TFA in the solution was removed under a nitrogen stream, and a 1N NaOH aqueous solution was added to neutralize the remaining TFA.
In high-performance liquid chromatography (HPLC) using an ODS column (Unison US-C18, manufactured by Intact Co., Ltd., 150 x 4.6 mm), phase A contained 0.1% TFA/MilliQ water and phase B contained 0.1% TFA/MilliQ water. Using 1% TFA / MeCN, the flow rate is 1 mL / min, and from 0 to 20 minutes after the start, the phase A is changed from 90%, the B phase 10% to the A phase 50%, the B phase 50%. The product was purified by a linear gradient method varying from 50% phase A, 50% phase B to 0% phase A, 100% phase B during 20-30 minutes. Compound (17) was obtained with a radiochemical yield of 48.3% and 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 through the tail vein of 6-week-old ISR strain mice. Mice were sacrificed 1 hour and 3 hours after administration, and organs of interest were harvested. After measuring the mass, the radioactivity was measured with an Autowell gamma system (WIZARD3, manufactured by PerkinElmer).
The results are shown in FIG. The unit in the figure is the radioactivity accumulation rate (%) [% ID/g] with respect to 100% of the radioactivity dose (injected dose) per gram of organ or tissue for blood, liver, and pancreas. For the stomach, it is the radioactivity accumulation rate (%) [% ID] with respect to 100% of the radioactivity dose (injected dose) per organ.
As shown in FIG. 3, normal mice to which compound (16) or compound (17) was administered showed less accumulation of radioactivity in the stomach. In general, compounds that are stable in vivo have a radioactivity accumulation 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)]
[Generation of tumor-bearing mice]
Tumor-bearing mice were prepared by transplanting C6 cells (5×10 ⁶ cells/mouse) into the left leg of 5-week-old BALB/c Slc-nu/nu strain male mice.
One week after transplantation of C6 cells to mice, Compound (17) [n=2] (0.3 μCi/100 μL/mouse) was administered through the tail vein of each mouse. Mice were sacrificed 1 hour after administration, and organs of interest and tumors were harvested. After measuring the mass, the radioactivity was measured with an Autowell gamma system (WIZARD3, manufactured by PerkinElmer).
The results and the corresponding results for compound (16) obtained in Evaluation Example 1 are shown in FIG. The unit in the figure is the radioactivity accumulation rate (%) [% ID/g] with respect to 100% of the radioactivity dose (injected dose) per 1 g of tissue for blood and tumor. For the stomach, it is the radioactivity accumulation rate (%) [% ID] with respect to 100% of the radioactivity dose (injected dose) per organ.
As shown in FIG. 4, in tumor-bearing mice to which compound (17) was administered, high accumulation of radioactivity was observed in tumors. Therefore, compound (17) was found to be efficiently taken up by tumors. In addition, similar to the results of compound (16) in tumor-bearing mice and compound (17) in normal mice, compound (17) showed less accumulation of radioactivity in the stomach of tumor-bearing mice and was highly stable in vivo. found to have sex.

The radioactive compound of the present invention or a pharmaceutically acceptable salt thereof is efficiently taken up by tumors and the like, and has high stability in vivo. A radiopharmaceutical composition is provided.

Claims

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 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),

(Wherein, * 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 or a pharmaceutically acceptable salt thereof according to claim 1, represented by the following formula (Ib-1), (Ib-2) or (Ib-3).

[In the formula, Y is the same as above. ]
A method for producing a 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] providing a compound (i) represented by the following formula (y1), formula (y2) or formula (y3);

(In the formula,
Z 1 each independently represents a hydrogen atom, an amino group-protecting group or R b ,
Z 2 represents a hydrogen atom or a carboxy-protecting 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) Substitution of the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) with a group excluding one L 1 in the compound (ii), and (b) the compound Y of the other L 1 in (ii) [wherein Y is the same as 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] Step of deprotecting the protecting group of compound (iii)
A radiopharmaceutical composition comprising the radioactive compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
The radiopharmaceutical composition according to claim 5, which is for diagnostic imaging.
The radiopharmaceutical composition according to claim 5, which is for therapeutic use.