阅读说明：本技术 放射性卤素标记化合物的制造方法及放射性医药的制造方法 (Method for producing radioactive halogen-labeled compound and method for producing radiopharmaceutical ) 是由 奥村侑纪 中村大作 桐生真登 市川浩章 殿谷豪太 杉本尚美 于 2018-05-28 设计创作，主要内容包括：本发明提供放射性卤素标记化合物的制造方法,其包含以下的工序：通过对于具备有可利用放射性卤化物离子(X<Sup>-</Sup>)而进行亲核取代的离去基团(L)的放射性卤素标记前体化合物(S-L),实行放射性卤化反应,从而获得包含放射性卤素标记前体化合物(S-L)与放射性卤化反应的反应产物(S-X)的反应混合物RM1的工序；通过将反应混合物RM1与多元酸或其盐进行混合,从而获得反应混合物RM2的工序；以及利用固相萃取法,从反应混合物RM2中将反应产物(S-X)进行纯化的工序。(The present invention provides a method for producing a radioactive halogen-labeled compound, comprising the steps of: by having available radioactive halide ions (X) ‑ ) And a radiohalogen-labeled precursor compound (S-L) of the leaving group (L) undergoing nucleophilic substitution, performing a radiohalogenation reaction to thereby obtain a reaction product (S-X) comprising the reaction product of the radiohalogen-labeled precursor compound (S-L) and the radiohalogenation reactionA step of preparing a mixture RM 1; a step of mixing reaction mixture RM1 with a polybasic acid or a salt thereof to obtain reaction mixture RM 2; and a step of purifying the reaction product (S-X) from the reaction mixture RM2 by a solid-phase extraction method.)

1. A method for producing a radioactive halogen-labeled compound, comprising the steps of:

a step of obtaining a first reaction mixture containing a reaction product of a radioactive halogen-labeled precursor compound and a radioactive halogenation reaction by performing a radioactive halogenation reaction on the radioactive halogen-labeled precursor compound having a leaving group capable of undergoing nucleophilic substitution by a radioactive halide ion;

a step of obtaining a second reaction mixture by mixing the first reaction mixture with a polybasic acid or a salt thereof; and

and purifying the reaction product from the second reaction mixture by a solid phase extraction method.

2. The method for producing a radiohalogen-labeled compound according to claim 1, wherein a solid-phase column having an anion exchange group is used in the solid-phase extraction method.

3. The method for producing a radiohalogen-labeled compound according to claim 1 or 2, wherein the step of obtaining the second reaction mixture comprises: the second reaction mixture is obtained by mixing the first reaction mixture with the polybasic acid or salt thereof and then heating.

4. The method for producing a radiohalogen-labeled compound according to any one of claims 1 to 3, wherein the leaving group is a sulfonyloxy group.

5. The method for producing a radiohalogen-labeled compound according to any one of claims 1 to 4, wherein the radiohalogen is radioactive fluorine.

6. The method for producing a radiohalogen-labeled compound according to any one of claims 1 to 5, wherein the polybasic acid is a polybasic organic acid.

7. The method for producing a radiohalogen-labeled compound according to any one of claims 1 to 6, wherein the salt of the polybasic acid is obtained by salt formation of the polybasic acid with a phase transfer catalyst.

8. A method for producing a radiopharmaceutical containing a radiohalogen-labeled compound as an active ingredient, which comprises carrying out the method for producing a radiohalogen-labeled compound according to any one of claims 1 to 7.

Technical Field

The present invention relates to a method for producing a radioactive halogen-labeled compound and a method for producing a radiopharmaceutical.

Background

In the preparation of a radiohalogenated drug, a compound obtained by binding a leaving group to a halogen-labeled site of a target substrate is often prepared as a labeled precursor compound, and nucleophilic substitution reaction is performed in which a radiohalide ion reacts with the labeled precursor compound. In addition, this reaction is generally carried out by using a small amount of radioactive halide ions for a large amount of labeled precursor compound. Therefore, purification of the obtained radiohalogen-labeled compound is generally performed by separating a large amount of unreacted labeled precursor compound by high performance liquid chromatography (HPLC method). However, the HPLC method is complicated and requires a long time, and is a factor causing a decrease in the yield of the target compound in consideration of the attenuation of the radioactive halogen.

As an alternative strategy that does not require HPLC purification, patent document 1 proposes: a compound obtained by modifying a leaving group moiety of the labeled precursor compound with a compound M (purified moiety) is prepared as a labeled precursor compound, and a nucleophilic agent such as a radioactive halide ion is reacted with the compound, whereby a species containing the purified moiety M can be easily separated from other species not containing the purified moiety M.

Patent documents 2 and 3 propose a radiohalogen labeling precursor compound having a leaving group into which a fat-soluble functional group is introduced, and a radiohalogen labeling method.

Disclosure of Invention

The idea of the method described in patent document 1 is to chemically act an active group fixed to a resin on a purified portion M of a labeled precursor compound after a radioactive halogenation reaction. Thus, there are the following problems: adversely affecting the yield of the product of the radiohalogenation reaction; or the preparation of a resin into which a specific active group or the like is introduced; and so on.

In addition, in the methods described in patent documents 2 and 3, it is necessary to design and change the structure of a conventional labeling precursor compound.

The present invention has been made in view of the above circumstances, and provides the following technologies: the method is used for separating and purifying a reaction product of a radioactive halogenation reaction from an unreacted radioactive halogen labeled precursor compound by a method independent of an HPLC method without changing the structure of the labeled precursor compound.

One embodiment of the present invention provides a method for producing a radioactive halogen-labeled compound, including the steps of:

a step of obtaining a first reaction mixture containing a reaction product of a radioactive halogen-labeled precursor compound and a radioactive halogenation reaction by performing a radioactive halogenation reaction on the radioactive halogen-labeled precursor compound having a leaving group capable of undergoing nucleophilic substitution by a radioactive halide ion;

a step of obtaining a second reaction mixture by mixing the first reaction mixture with a polybasic acid or a salt thereof; and

and purifying the reaction product from the second reaction mixture by a solid phase extraction method.

Another embodiment of the present invention provides a method for producing a radiopharmaceutical containing a radiohalogen-labeled compound as an active ingredient, which comprises carrying out the above-described method for producing a radiohalogen-labeled compound.

According to the present invention, the reaction product of the radiohalogenation reaction can be separated and purified from the unreacted radiohalogen-labeled precursor compound by a method independent of the HPLC method without changing the structure of the labeled precursor compound.

In addition, according to the methods described in patent documents 2 and 3, since the difference in lipid solubility between the radioactive halogen labeled precursor compound and the radioactive halogen labeled compound is large, when analyzing nonradioactive impurities in a radiopharmaceutical containing the radioactive halogen labeled compound as an active ingredient using a reversed-phase system, time is required for the analysis, and as a result, there is a concern that the time required for the quality test of the radiopharmaceutical is prolonged. However, in the method of the present invention, since the radioactive halogen-labeled precursor compound is not designed so as to increase the difference in lipid solubility between the radioactive halogen-labeled precursor compound and the radioactive halogen-labeled compound, the time required for the quality test of the radiopharmaceutical can be shortened without extending the time required for the synthesis of the radiopharmaceutical, and the time required for the production of the radiopharmaceutical as a whole can be shortened.

Detailed Description

The process for producing a radiohalogen-labeled compound of the present invention comprises the following steps [ step 1] to [ step 3] in this order.

[ Process 1]

By having available radioactive halide ions (X)^-) And a step of subjecting the radiohalogen-labeled precursor compound (S-L) having the leaving group (L) which is subjected to nucleophilic substitution to a radiohalogenation reaction to obtain a reaction mixture RM1 (first reaction mixture) containing the radiohalogen-labeled precursor compound (S-L) and a reaction product (S-X) of the radiohalogenation reaction.

[ Process 2]]By reacting the reaction mixture RM1 with a polybasic Acid (AH) or a salt thereof (A)^-B⁺) And a step of mixing the reaction mixture RM2 (second reaction mixture).

[ step 3] the step of purifying the reaction product (S-X) from the reaction mixture RM2 by solid phase extraction.

[ Process 1]]Radiohalogenation procedure

In the radioactive halogenation step, radioactive halide ions (X) are available by the counter ion^-) And the radiohalogen-labeled precursor compound (S-L) of the leaving group (L) which is subjected to nucleophilic substitution, is subjected to a radiohalogenation reaction, thereby obtaining a reaction mixture RM1 comprising the reaction product (S-X) of the radiohalogen-labeled precursor compound (S-L) and the radiohalogenation reaction.

The "radioactive halogen" is selected from each radioisotope of fluorine, chlorine, bromine, iodine and astatine (astatine), and specific examples thereof include¹⁸F、^34mCl、⁷⁶Br、¹²³I、¹²⁴I、¹²⁵I、¹³¹I、²¹¹At. Among them, preferred is radioactive fluorine (A), (B), (C), (D), (¹⁸F)。

With respect to the radioactive halide ion (X)^-) And can be produced by a commonly used method. For example, in the case of radioactive fluoride ion, it can be converted from [ 2], [ using a cyclotron (cyclotron) ]¹⁸O]Water utilization¹⁸O(p，n)¹⁸F is generated by reaction.

In addition, radioactive halide ion (X)^-) The ion-counter may be provided. For example, in the case of radioactive fluoride ions, alkali metal ions and/or tetraalkylammonium ions can be used as counter ions. Examples of the alkali metal ion include lithium ion, sodium ion, potassium ion, rubidium ion, and lithium ion,Cesium ions. In addition, as for the tetraalkylammonium ion, tetramethylammonium ion, tetraethylammonium ion, tetrapropylammonium ion, tetrabutylammonium ion can be exemplified. To produce a radioactive halide ion (X) having a targeted counter ion^-) An anion exchange resin may be used. As an example, the compound can be produced by reacting a solution of [ 2], [ 2] containing a radioactive fluoride ion¹⁸O]The aqueous solution is passed through an anion exchange resin prepared in a carbonic acid form or a hydrogen carbonate form to adsorb radioactive fluoride ions, and the radioactive fluoride ions are eluted with an aqueous potassium carbonate solution or an aqueous tetraethylammonium bicarbonate solution.

With respect to the radioactive halide ion (X)^-) Alternatively, the compound may be a radioactive halide ion (X) activated by using a phase transfer catalyst^-). Examples of the phase transfer catalyst used herein include tetraalkylammonium salts such as tetramethylammonium salt, tetraethylammonium salt, tetrapropylammonium salt, and tetrabutylammonium salt, crown ethers, and cryptands (cryptands). For example, in the case of radioactive fluoride ions, by reaction with 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]Hexacosane (trade name: Kryptofix 222) or tetraalkylammonium salt is mixed and heated as necessary to activate. As for activation of radioactive fluoride ions, there are the following methods: (i) an aqueous solution of radioactive potassium fluoride is prepared using an anion exchange resin and an aqueous solution of potassium carbonate, and then reacted with 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]A method in which hexacosane (trade name: Kryptofix 222) is mixed and water is evaporated while activating radioactive fluoride ions by azeotropy with acetonitrile; or, (ii) a method in which a radioactive tetraethylammonium fluoride aqueous solution prepared by using an anion exchange resin and a tetraethylammonium bicarbonate aqueous solution is azeotroped with acetonitrile, while radioactive fluoride ions are activated, and water is evaporated.

The leaving group (L) is a compound obtained by reacting a radioactive halide ion (X)^-) The group which is attacked and detached as a nucleophilic agent is not limited, and a sulfonyl group is preferableAnd (4) a base. The "sulfonyloxy" is an aromatic sulfonyloxy group, an alkylsulfonyloxy group or a haloalkylsulfonyloxy group, and as the aromatic sulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group and a p-nitrobenzenesulfonyloxy group can be exemplified. In addition, as the alkylsulfonyloxy group, a methylsulfonyloxy group may be exemplified. Further, as the haloalkylsulfonyloxy group, a trifluoromethanesulfonyloxy group can be exemplified.

The radioactive halogen-labeled precursor compound (S-L) is a compound obtained by introducing a leaving group (L) into a substrate (S) containing a biomolecule recognition site or the like (here, the substrate (S) includes a hydroxyl group, an amino group, a carboxyl group or the like, and a radioactive halide ion (X)^-) A substrate having a group which can interact with the substrate protected), the following compounds can be exemplified.

A compound represented by formula (1): fluorodeoxyglucose (f)¹⁸F) Labeled precursor compound of

A compound represented by formula (2): fluciclovine (A)¹⁸F) Labeled precursor compound of

A compound represented by formula (3): [¹⁸F]FLT(3’-[¹⁸F]Fluoro-3' -deoxythymidine) labeled precursor compound

A compound represented by formula (4): [¹⁸F]FET(O-(2-[¹⁸F]Fluoroethyl) -L-tyrosine) labeling precursor compounds

A compound represented by formula (5): [¹⁸F]FES(6α-[¹⁸F]Fluoro-17 β -estradiol) labeled precursor compound

A compound represented by formula (6): [¹⁸F]FMISO([¹⁸F]Labeled precursor compound of fluoromethalone nidazole

A compound represented by formula (7): [¹⁸F]FRP-170(1-(2-[¹⁸F]Labelled precursor compounds of fluoro-1- (hydroxymethyl) ethoxy) methyl-2-nitroimidazole)

A compound represented by formula (8): [¹⁸F]FAZA([¹⁸F]Labeled precursor compound of fluazinamycin cytarabine (fluoroazomycin nabinoside))

Is of the formula(9) A compound represented by: 1- (2, 2-dihydroxymethyl-3-)¹⁸F]Label precursor compounds for fluoropropyl) -2-nitroimidazole (Compound 1 of WO 2013/042668)

A compound represented by formula (10): flubetepin (florbetapir) ((florbetapir))¹⁸F) Labeled precursor compound of

A compound represented by formula (11): flurbipetaban (florbetaben) ((R))¹⁸F) Labeled precursor compound of

A compound represented by formula (12): [¹⁸F]Labeled precursor compounds of FP-CIT

A compound represented by formula (13): [¹⁸F]FDDNP(2-(1-{6-[(2-[¹⁸F]Fluoroethyl) (methyl) amino]-2-naphthyl } -ethylidene) malononitrile (malono nitrile)) as a labeling precursor compound

A compound represented by formula (14): labeled precursor compounds of compounds having CYP11B2 selective inhibitory activity described in WO2015/199205

(in the formula (14), R₁Represents a hydrogen atom or CO₂Ra，R₂Represents a hydrogen atom, a halogen atom or CO₂R_a，R₃Represents a hydrogen atom or a hydroxyalkyl group having 1 to 10 carbon atoms, R₄Represents a hydrogen atom, a hydroxyl group or an alkoxy group having 1 to 10 carbon atoms, n represents an integer of 1 to 5, A represents CH or a nitrogen atom, X₁、X₃Each independently represents a hydrogen atom or a halogen atom, X₂Represents a hydrogen atom, a halogen atom or a nitrile group, X₁、X₂、X₃At least 1 of (A) is a halogen atom, R_aEach independently represents an alkyl group having 1 to 10 carbon atoms. )

[ chemical formula 1]

[ chemical formula 2]

Wherein the formula (I) is1) In (1) to (14), L is a leaving group, P₁Is a protecting group for hydroxy, P₂Is a protecting group for amino, P₃Is a protecting group for a carboxyl group. L can be selected for each of the compounds represented by the formulae (1) to (14) from among the aforementioned leaving groups. In addition, regarding P₁、P₂、P₃From Greene's Protective Groups in organic Synthesis (protecting Groups in Green's organic Synthesis) (John Wiley&Sons Inc, 5 th edition, published 10/27/2014), for each of the compounds represented by the formulae (1) to (14).

The radioactive halogenation reaction is carried out so long as the reaction is carried out with a radioactive halide ion (X)^-) The conditions under which the nucleophilic substitution reaction of the radioactive halogen-labeled precursor compound (S-L) as a nucleophile proceeds are not particularly limited, and known methods can be suitably used. Preferably, this is carried out using an aprotic solvent in the presence of a base. The reaction may be carried out under heating to increase the reaction rate.

As the aprotic solvent, acetone, diethyl ether, dimethylformamide, dimethyl sulfoxide, acetonitrile, or the like can be exemplified.

As the base, a non-nucleophilic base such as potassium carbonate, triethylamine, N-diisopropylethylamine or diazabicycloundecene is preferably used.

Using radioactive fluoride ion as radioactive halide ion (X)^-) In the case of the radiofluorination reaction of (3), a method carried out in the presence of a phase transfer catalyst and a base is exemplified. Representative examples include: using 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]Hexacosane (trade name: Kryptofix 222) and potassium carbonate; examples of the quaternary ammonium bicarbonate include tetramethylammonium bicarbonate, tetraethylammonium bicarbonate, tetrapropylammonium bicarbonate, tetrabutylammonium bicarbonate and the like. In addition, in the radioactive fluorination reaction, preferably in 20 ~ 180 ℃ temperature conditions for implementation.

In the case of the radiohalogenation reaction, the amount of the substance of the radiohalogen-labeled precursor compound (S-L) is used in excess with respect to the amount of the substance of the radiohalide ion. Thus, the reaction mixture RM1 obtained by carrying out the radiohalogenation reaction contains at least the radiohalogen-labeled precursor compound (S-L) and the reaction product (S-X).

[ Process 2]]Decomposition step of radioactive halogen-labeled precursor Compound

In the step of decomposing the radioactive halogen-labeled precursor compound (S-L), the reaction mixture RM1 is reacted with a polybasic Acid (AH) or a salt thereof (A)^-B⁺) Mixing to effect the leaving group (L) of the radioactive halogen-labeled precursor compound (S-L) and the polybasic acid ion (A)^-) Thereby obtaining A decomposed product (S-A) of the radioactive halogen-labeled precursor compound. Thus, A reaction mixture RM2 containing the reaction product (S-X) of the radiofluorination reaction and the decomposition product (S-A) of the radiohalogen-labeled precursor compound can be obtained.

The polybasic Acid (AH) is an acid having a valence of 2 or more, and a polybasic acid which is substituted with the leaving group (L) of the radioactive halogen-labeled precursor compound (S-L) but does not react with the reaction product (S-X) can be suitably used. The polybasic acid may be a polybasic organic acid or a polybasic inorganic acid. The polybasic organic acid is a polybasic organic acid having a plurality of acidic groups selected from one of a carboxyl group, a sulfonic acid group and a phenol group, or a polybasic organic acid having a combination of these acidic groups, and examples of the polybasic organic acid having a plurality of carboxyl groups include citric acid, oxalic acid, phthalic acid, malic acid, tartaric acid, diethylenetriamine pentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA). Further, as the polyvalent organic acid having a carboxyl group and a phenol group in combination, gentisic acid is exemplified. Further, as the polybasic inorganic acid, phosphoric acid may be exemplified.

The polybasic acid may form a salt (A) to improve the reactivity with the radioactive halogen-labeled precursor compound (S-L)^-B⁺). Salts of polybasic acids (A)^-B⁺) Is a polybasic acid radical ion (A)^-) With a cation (B)⁺) Salts, preferably by salifying a polyacid with a phase transfer catalystThe salt obtained is more preferably a salt obtained by salifying a polybasic organic acid with a phase transfer catalyst. In a preferred embodiment, the salt (A) of a polybasic acid^-B⁺) They can be prepared by mixing a polybasic acid with a phase transfer catalyst. Examples of the phase transfer catalyst used herein include tetraalkylammonium salts such as tetramethylammonium salt, tetraethylammonium salt, tetrapropylammonium salt and tetrabutylammonium salt, and alkali metal complexes of crown ether and cryptate (for example, 4, 7, 13, 16, 21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]Potassium ion (K) of hexacosane (trade name: Kryptofix 222)⁺) A complex). In order to salt the polybasic acid and the phase transfer catalyst, it is preferable to prepare the salt by mixing under conditions such that the amount of the substance of the polybasic acid multiplied by the valence number is equivalent to the amount of the substance of the phase transfer catalyst. In the preparation of the salt of the polybasic acid, the polybasic acid and the phase transfer catalyst may be mixed in an arbitrary solvent. As the solvent, a solvent which dissolves the polybasic acid and the phase transfer catalyst and is easily evaporated can be appropriately selected, and examples thereof include: water; alcohols such as methanol and ethanol; acetone; tetrahydrofuran; ethyl acetate; and so on.

The amount of the polybasic acid or salt thereof used in step 2 may be theoretically equivalent to the amount of the substance of the radiohalogen-labeled precursor compound (S-L) remaining in the radiofluorination reaction in step 1, but may be equivalent to the amount of the substance of the radiohalogen-labeled precursor compound (S-L) used in step 1. From the viewpoint of rapidly decomposing the radiohalogen-labeled precursor compound (S-L), the amount of the substance of the polybasic acid or the salt thereof is preferably used in excess of the amount of the substance of the radiohalogen-labeled precursor compound (S-L) used in step 1. For example, the amount of the substance of the polybasic acid or the salt thereof is 1 to 100 molar equivalents, preferably 1.5 to 50 molar equivalents, and more preferably 2 to 20 molar equivalents, relative to the amount of the substance of the radioactive halogen-labeled precursor compound (S-L) used in step 1.

With regard to the mixture of polybasic acid or salt thereof with reaction mixture RM1, in order to promote the dissociation of the polybasic acidSub (A)^-) The reaction rate with the radioactive halogen-labeled precursor compound (S-L) may be optionally heated. When the mixture of the reaction mixture RM1 and the polybasic acid or salt thereof is heated, it is preferable to heat the mixture in a solvent. The type of solvent and the temperature condition are selected so as to increase the amount of the polybasic acid group ion (A)^-) And the kind of solvent and temperature conditions that do not cause reaction or decomposition of the reaction product (S-X). In the case where the radiohalogenation reaction is carried out in the aprotic solvent in step 1, the reaction mixture RM1 may be mixed with the polybasic acid or a salt thereof in a state where the reaction mixture contains the aprotic solvent. Further, a solvent may be added to the reaction mixture RM1, or a solvent different from the solvent used in the radiohalogenation reaction may be used by evaporating the aprotic solvent used in the radiohalogenation reaction. As the solvent used herein, acetonitrile, dimethyl sulfoxide, or dimethylformamide is preferably used. In addition, the temperature condition is preferably 60 to 180 ℃.

The polybasic acid ion (A) is increased^-) From the viewpoint of reactivity of the radioactive halogen-labeled precursor compound (S-L), the reaction mixture RM1 preferably contains a phase transfer catalyst used in the radioactive halogenation reaction.

By doing so, A reaction mixture RM2 containing the reaction product (S-X) and the decomposition product (S-A) of the radioactive halogen-labeled precursor compound can be obtained.

[ step 3] purification step

In the purification step, the reaction product (S — X) of the radiohalogenation reaction is purified from the reaction mixture RM2 by a solid phase extraction method.

The solid phase extraction method used in step 3 is not particularly limited as long as it is A condition under which the reaction product (S-X) of the radioactive halogenation reaction and the decomposed product (S-A) of the radioactive halogen-labeled precursor compound can be separated from each other, but it is preferable to use A solid phase column (solid phase cartridge) having an anion exchange group. By doing so, among the plurality of acidic groups of the polybasic acid, an acidic group other than the one that is bound to S (substrate) by substitution with the leaving group (L) is ionically bonded to the anion exchange group of the solid phase column, and thus the decomposed product (S-A) can be retained in the solid phase column. On the other hand, the reaction product (S-X) of the radiohalogenation reaction is not ion-bonded to the anion exchange group of the solid phase column, and thus the adsorption capacity to the solid phase column is relatively weak with respect to the decomposed product (S-A) of the radiohalogen-labeled precursor compound. Therefore, the reaction product (S-X) of the radiohalogenation reaction can be separated from the decomposition product (S-A) of the radiohalogen-labeled precursor compound.

In addition, as the solid phase extraction method used in step 3, it is more preferable to use a solid phase column having both reverse phase partition ability and anion exchange ability (mixed mode solid phase column). Specifically, a solid phase column obtained by binding anion exchange groups to a porous polymer containing a copolymer of divinylbenzene and vinylpyrrolidone, or a solid phase column having octadecyl groups and anion exchange groups is preferably used. By doing so, the nonradioactive impurities contained in the reaction mixture RM2 can be separated from the reaction product (S-X) of the radiohalogenation reaction, further improving the purity of the reaction product (S-X) of the radiohalogenation reaction.

As an example of the operation of the solid phase extraction method, the following method can be mentioned: the reaction mixture RM2 was diluted with water, passed through A mixed-mode solid phase column, and then the reaction product (S-X) of the radiohalogenation reaction and the decomposition product (S-A) of the radiohalogen-labeled precursor compound were adsorbed on the solid phase column, and the reaction product (S-X) was eluted in A state where the decomposition product (S-A) of the radiohalogen-labeled precursor compound was adsorbed on the solid phase column with ethanol. However, the type of the diluent and the eluent is not limited to this example, and various diluents and eluents can be used depending on the type of the reaction product (S — X) of the radioactive halogenation reaction.

When the reaction product (S — X) of the radiohalogenation reaction is the target radiohalogen-labeled compound, the target radiohalide can be obtained by performing the solid-phase extraction in step 3.In step 1, the compound having a protecting group (P) represented by the formulae (1) to (11) is used₁、P₂、P₃) When the compound (2) is used as the radioactive halogen-labeled precursor compound (S-L), the target radioactive halogen-labeled compound can be obtained by subjecting the reaction product (S-X) of the radioactive halogenation reaction to a deprotection reaction after the step 3.

After the step 3, the following purification may be further performed in order to purify the radiohalogen-labeled compound: purification using alumina for the removal of radioactive halide ions; purification using a reversed-phase solid-phase column for the purpose of separating non-radioactive impurities; and so on.

The radiopharmaceutical can be prepared by adding a pH adjuster, a solubilizer, a stabilizer, or an antioxidant to the obtained radiohalogen-labeled compound as appropriate, and diluting the mixture with an isotonic solution such as water or a physiological salt solution.