Method for producing radioactive metal complex

Abstract

Provided is a method for producing a radioactive metal complex comprising a complex forming step for causing a radioactive metal nuclide and a ligand compound represented by formula (1) to react with each other in a reaction solution containing water and a buffering agent to form a radioactive metal complex, wherein the buffering agent contains one or more types of water soluble organic compound having a sulfo group or a carboxyl group, and wherein the reaction solution is irradiated with microwave in the complex forming step while cooling the reaction solution. The radioactive metal nuclide is preferably 68Ga, 89Zr, 90Y, 111In, 177Lu, or 225Ac.

Description

Method for producing radioactive metal complexes

[0001] The present invention relates to a method for producing a radioactive metal complex.

[0002] Studies are being conducted to efficiently synthesize radioactive metal complexes in which a ligand compound is coordinated to a radioactive metal nuclide, for use as reagents and diagnostic agents for detecting target molecules or as pharmaceuticals for treating diseases. One such study involves irradiating a radioactive metal nuclide with microwaves during a reaction in which a ligand compound is coordinated to the radioactive metal nuclide (hereinafter also referred to as a "radioactive metal complex formation reaction").

[0003] Patent Document 1 states: ２２５ A method for producing a radioactive metal complex labeled with Ac is described in the literature. ２２５ It is described that when heating is required in carrying out the reaction to form a radioactive metal complex with Ac, it is preferable to heat by microwave irradiation.

[0004] Non-Patent Document 1 states: ６８ The document describes a method for producing a radioactive metal complex consisting of Ga and a ligand compound, DOTATOC. The document also describes that by irradiating microwaves and heating to 90°C during the radioactive metal complex formation reaction, the desired compound can be produced in a shorter time than by heating using a block heater. ６８ It is described that Ga complexes can be obtained.

[0005] Non-Patent Document 2 states: ８９ A method for producing a radioactive metal complex consisting of Zr and TRITA, a ligand compound, is described in the document. The method states that the radioactive metal complex can be produced in a short time and with a high yield by irradiating it with microwaves and heating it to 180°C during the radioactive metal complex formation reaction, compared to when a normal heating method is used. ８９ It is stated that Zr complexes can be obtained.

[0006] US Patent Application Publication No. 2015 / 0157742

[0007] I. Velikyan et al. , Bioconjugate Chem. 2004, 15, 554-560D. N. Pandya et al. , Inorg. Chem. 2020, 59, 17473-17487

[0008] Detailed conditions for microwave irradiation in the radioactive metal complex formation reaction are not examined in Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2. For this reason, the reaction acceleration effect of microwave irradiation is not maximized, and there is still room for improvement in the reaction efficiency of the radioactive metal complex formation reaction.

[0009] Therefore, an object of the present invention is to make the radioactive metal complex formation reaction proceed more efficiently.

[0010] The present invention provides a method for producing a radioactive metal complex, comprising a complex formation step of reacting a radioactive metal nuclide with a ligand compound represented by the following formula (1) in a reaction solution containing water and a buffer to form a radioactive metal complex, wherein the buffer contains one or more water-soluble organic compounds having a sulfo group or a carboxy group, and in the complex formation step, the reaction solution is irradiated with microwaves while being cooled:

[0011] (In formula (1), R １１ , R １２ and R １３ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , or -(CH ２ ) ｐ CONH ２ is a group consisting of 14 or R 15 One of the groups is a hydrogen atom, -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ , or -(CHCOOH)(CH ２ ) ｐ COOH, and the other is -(CH ２ ) pCOOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , or -(CH ２ ) ｐ CONH ２ or a reactive atomic group for linking to a targeting agent or a group linking to a targeting agent, and each p is independently an integer of 0 to 3.

[0012] According to the present invention, there is provided a method for producing a radioactive metal complex, which allows the radioactive metal complex-forming reaction to proceed more efficiently.

[0013] The method for producing a radioactive metal complex of the present invention will be described below based on its preferred embodiments. The production method of the present invention comprises a complex formation step in which a radioactive metal nuclide is reacted with a ligand compound represented by formula (1) described below in a reaction solution to form a radioactive metal complex. This radioactive metal complex is a compound in which a radioactive metal atom is bonded to a ligand compound by a combination of a coordinate bond, a covalent bond, an ionic bond, or the like, and also includes compounds to which a reactive atomic group or a targeting agent described below is further bonded.

[0014] In this specification, forming a complex between a radioactive metal ion and a ligand compound is synonymous with labeling a ligand compound with a radioactive metal ion, and the complex formation efficiency and labeling rate are synonymous.

[0015] From the viewpoint of increasing the labeling rate, the radioactive metal nuclide used in the complex formation step is preferably used in the form of a compound that can be ionized in water, and more preferably in the form of a metal ion (hereinafter, these forms are also collectively referred to as "radioactive metal source"). As the radioactive metal source, for example, a radioactive metal ion-containing liquid in which radioactive metal ions are dissolved or dispersed in a solvent mainly composed of water can be used.

[0016] The radioactive metal nuclide contained in the radioactive complex of the present invention is an α-ray-emitting radionuclide, a β-ray-emitting radionuclide, a positron-emitting radionuclide, or a γ-ray-emitting radionuclide. When the radioactive complex of the present invention is used for cancer treatment, it is preferable to use an α-ray-emitting radionuclide or a β-ray-emitting radionuclide. When the radioactive complex of the present invention is used for cancer diagnosis or detection, it is preferable to use a positron-emitting radionuclide or a γ-ray-emitting radionuclide. As the α-ray-emitting radionuclide, ２１２ Bi, ２１３ Bi, ２２５ Ac, ２２７ Examples of radionuclides that emit β rays include: ６４ Cu, ９０ Y or １７７ Examples of radioactive nuclides that emit positrons include: ６４ Cu, ６８ Ga, ８６ Y. ８９ Zr is an example. In addition, examples of radioactive nuclides that emit gamma rays include: ９９ｍ Tc or １１１ In is an example. The radioactive metal nuclide contained in the radioactive complex of the present invention is ２２５ Ac, ９０ Y. １７７ Lu or ８９ Zr is more preferred.

[0017] The concentration of the radioactive metal nuclide in the reaction solution at the start of the reaction between the radioactive metal nuclide and the ligand compound (hereinafter also referred to as "the start of the complex formation step" or "the start of the reaction") is preferably 1 nmol / L or more and 10,000 nmol / L or less, more preferably 1 nmol / L or more and 5,000 nmol / L or less, even more preferably 1 nmol / L or more and 1,000 nmol / L or less, and even more preferably 1 nmol / L or more and 500 nmol / L or less.

[0018] For example, after production, radioactive metal nuclides can be dissolved in an appropriate solvent and stored in solution, and the required amount can be extracted from this solution when needed and used in the present invention. Hereinafter, the solution for storing radioactive metal nuclides will also be referred to as a "bulk solution." As the radioactive decay of the radioactive nuclide progresses, the amount of bulk solution required to use the desired radioactivity in the complex formation reaction increases. This bulk solution contains non-radioactive metals that were used during the production of the radioactive metal nuclide. Therefore, if the amount of bulk solution used increases, the amount of non-radioactive metals mixed in the complex formation reaction also increases, which reduces the yield of the complex formation reaction. Therefore, it is preferable to use the radioactive nuclide promptly after production.

[0019] The ligand compound used in the complex formation step has a structure represented by the following formula (1).

[0020]

[0021] In formula (1), R １１ , R １２ and R １３ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , or -(CH ２ ) ｐ CONH ２ Each p is independently an integer of 0 or more and 3 or less.

[0022] In formula (1), R14 or R 15 One of the groups is a hydrogen atom, -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ , or -(CHCOOH)(CH ２ ) ｐ In formula (1), R 14 or R 15 The other is -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , or -(CH ２ ) ｐ CONH ２ or a reactive atomic group for linking to a targeting agent or a group linked to the targeting agent. Each p is independently an integer of 0 to 3. Details of the targeting agent and the reactive atomic group for linking to the targeting agent or the group linked to the targeting agent will be described later.

[0023] More specifically, it is more preferable that the ligand compound used in the complex formation step contains one of the compounds shown below or a structure derived from said compound. The ligand compound used in the complex formation step is preferably water-soluble.

[0024] DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid) DOTMA ((1R, 4R, 7R, 10R)-α, α', α'', α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane) DOTA-GA (α-(2-Carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) DOTP (((1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methylene))tetraphosphonic acid) DOTMP (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis (methylenephosphonic acid)) DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis (acetamide methylenephosphonic acid) DO2P (Tetraazacyclododecane dimethanephosphonic acid)

[0025] From the viewpoint of increasing the yield of the desired radioactive metal complex, the concentration of the ligand compound in the reaction solution at the start of the complex formation step is preferably 1 μmol / L or more and 1000 μmol / L or less, more preferably 1 μmol / L or more and 900 μmol / L or less, even more preferably 1 μmol / L or more and 600 μmol / L or less, and even more preferably 1 μmol / L or more and 500 μmol / L or less.

[0026] The reaction solution in the complex formation step is an aqueous reaction solution containing water and a buffer. As the water, any water commonly used in this technical field can be used, such as distilled water or ion-exchanged water.

[0027] The buffer contains a water-soluble organic compound having a predetermined structure. The water-soluble organic compound is an organic compound that dissolves in water and is a compound separate from the above-mentioned ligand compound. Therefore, the water-soluble organic compound in this specification is not included in the ligand compound. In the following description, the water-soluble organic compound having a predetermined structure and not included in the ligand compound or organic solvent is also referred to as a "second organic compound."

[0028] One of the features of the second organic compound contained in the reaction solution is that it has a specific functional group in its structure. In particular, in one embodiment of the second organic compound, it has a sulfo group in its structure. The sulfo group is "-SO ３ H" or "-SO ３ － " is a monovalent functional group represented by the formula: ". In this embodiment, the second organic compound preferably has one or two sulfo groups, i.e., is a monosulfonic acid or disulfonic acid, from the viewpoints of easy availability, reducing production costs, and increasing the yield of the radioactive metal complex. When the second organic compound has a sulfo group in its structure, the total number of carbon atoms in the second organic compound is preferably 4 to 10, more preferably 6 to 8. Furthermore, when the second organic compound has a sulfo group in its structure, it preferably has a heteroatom in its structure, preferably has at least a nitrogen atom in its structure, more preferably has a cyclohexane ring or a heterocycle in its structure, even more preferably has a saturated heterocycle having two nitrogen atoms or a nitrogen atom and an oxygen atom in its structure, and even more preferably has a morpholine ring or a piperazine ring in its structure. Furthermore, when the second organic compound has a sulfo group in its structure, it is also preferable that the second organic compound has an alkane sulfonic acid group in its structure, and it is also preferable that the alkane sulfonic acid group is bonded to a heteroatom, and it is more preferable that the second organic compound has an aminoalkane sulfonic acid in its structure. In any of the above cases, the second organic compound having a sulfo group in its structure is preferably a zwitterionic compound, and more preferably an aminoalkanesulfonic acid derivative.

[0029] Examples of the second organic compound having one sulfo group in its structure include chain amine monosulfonic acids such as N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES); monosulfonic acids having a morpholine ring such as 2-morpholinoethanesulfonic acid (MES) and 3-morpholinopropanesulfonic acid (MOPS); monosulfonic acids having a piperazine ring such as 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid (HEPES); and / or salts thereof. Examples of the second organic compound having two sulfo groups in its structure include disulfonic acids having a piperazine ring in its structure such as 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid (HEPES) and piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES), and / or salts thereof. Examples of counter ions of the second organic compound having a sulfo group in its structure include cations such as alkali metal ions such as sodium and potassium, primary to quaternary ammonium ions such as ammonium and tetramethylammonium salts, and anions such as halogen ions such as chlorine.

[0030] Another embodiment of the second organic compound contained in the reaction solution has a carboxy group in its structure. The carboxy group is represented by "-COOH" or "-COO － " is a monovalent functional group represented by the formula: ". In this embodiment, the second organic compound preferably has one or two carboxy groups and is a monocarboxylic acid or a dicarboxylic acid, from the viewpoints of easy availability, reducing production costs, and increasing the yield of the radioactive metal complex. When the second organic compound has carboxy groups in its structure, the total number of carbon atoms in the second organic compound is preferably 2 or more and 10 or less, more preferably 2 or more and 8 or less. Furthermore, when the second organic compound has carboxy groups in its structure, it is preferable that the second organic compound is a saturated or unsaturated aliphatic carboxylic acid or an aromatic carboxylic acid, and more preferably a saturated aliphatic carboxylic acid.

[0031] Examples of the second organic compound having one carboxy group in its structure include linear aliphatic monocarboxylic acids such as acetic acid and lactic acid; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; and / or salts thereof. Examples of the second organic compound having two carboxy groups in its structure include linear aliphatic dicarboxylic acids such as malonic acid and tartaric acid, and aromatic dicarboxylic acids such as phthalic acid; and / or salts thereof. Examples of counter ions of the second organic compound having a carboxy group in its structure include alkali metal ions such as sodium and potassium, and cations such as primary to quaternary ammonium ions such as ammonium and tetramethylammonium salts.

[0032] Among these, it is more preferable to use one or more compounds selected from acetic acid, phthalic acid, malonic acid, 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, or 2-morpholinoethanesulfonic acid and salts thereof as the second organic compound having a sulfo group or a carboxy group in its structure, and it is even more preferable to use one or more compounds selected from acetic acid or 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid and salts thereof. A reaction liquid containing a suitable second organic compound can be used in the complex formation step in a pre-prepared aqueous solution containing these organic compounds. These compounds may be buffer solutions that exhibit pH buffering action in the complex formation step, or liquids that do not exhibit pH buffering action.

[0033] From the viewpoint of further increasing the labeling efficiency, the concentration of the second organic compound in the reaction solution at the start of the complex formation step is preferably 0.01 mol / L or more and 2.0 mol / L or less, and more preferably 0.1 mol / L or more and 1.0 mol / L or less.

[0034] The reaction solution may contain a stabilizer in addition to water and a buffer. The stabilizer contained in the reaction solution has a structure represented by the following formula (2) or a salt thereof. The stabilizer may be used alone or in combination of two or more types. Depending on the type of radioactive metal nuclide, by adding such a stabilizer to the reaction solution, adsorption of the radioactive metal or the target radioactive metal complex to the inner wall of the reaction vessel can be suppressed even when the radioactivity at the start of the reaction (charged radioactivity) is increased for the purpose of commercial production, etc. As a result, the yield of the target radioactive metal complex can be increased.

[0035]

[0036] In formula (2), R ２１ is -COOH, -CH ２ COOH, -CH ２ OH, -COOR ２８ , -CONH ２ or -CONHR ２８ In formula (2), R ２２ ~R ２６ In formula (2), one to three groups are hydroxy groups (—OH), and the remaining groups are hydrogen atoms. ２１ to R ２８ If it contains, R ２８ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted alkylaryl. ２８ Examples of the substituent that can be substituted on R include a halogen atom, a saturated or unsaturated alkyl group, a hydroxy group, a formyl group, a carboxy group, an acyl group, an amino group, a nitro group, an ester group, an isothiocyanate group, a thioxo group, a cyano group, an amide group, an imide group, a phosphate group, a phenyl group, a benzyl group, and a pyridyl group. One of these substituents may be used alone, or two or more of these substituents may be used in combination. ２８ R may be straight or branched chain, saturated or unsaturated. ２８ The total number of carbon atoms is preferably 1 or more and 10 or less, and more preferably 1 or more and 8 or less.

[0037] When the stabilizer represented by formula (2) is used as a salt, examples of the counter ion include alkali metal ions such as sodium and potassium, and cations such as primary to quaternary ammonium ions such as ammonium and tetramethylammonium salts.

[0038] Examples of the structure of the stabilizer represented by formula (2) include, but are not limited to, structures represented by any of the following formulas (2a) to (2g).

[0039]

[0040] In formula (2g), R ２８ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted alkylaryl. ２８ Examples of the substituent that can be substituted on include a halogen atom, a saturated or unsaturated alkyl group, a hydroxy group, a formyl group, a carboxy group, an acyl group, an amino group, a nitro group, an ester group, an isothiocyanate group, a thioxo group, a cyano group, an amide group, an imide group, a phosphate group, a phenyl group, a benzyl group, a pyridyl group, etc. One of these substituents may be used alone, or two or more of these substituents may be used in combination.

[0041] As an embodiment of the stabilizer represented by formula (2), R ２１ is a carboxy group (—COOH). That is, the stabilizer in this embodiment is a hydroxybenzoic acid. Examples of the hydroxybenzoic acid represented by formula (2) include monohydroxybenzoic acid, dihydroxybenzoic acid, and trihydroxybenzoic acid.

[0042] Examples of monohydroxybenzoic acids include the following: 2-hydroxybenzoic acid (salicylic acid): In formula (2), R ２１ is —COOH, and R ２２ is —OH, and R ２３ ~R ２６ are all hydrogen atoms. This form corresponds to formula (2a). 3-Hydroxybenzoic acid: In formula (2), R ２１ is —COOH, and R ２３ is —OH, and R２２ , R ２４ ~R ２６ are all hydrogen atoms. 4-Hydroxybenzoic acid: In formula (2), R ２１ is —COOH, and R ２４ is —OH, and R ２２ , R ２３ , R ２５ and R ２６ are all hydrogen atoms.

[0043] Dihydroxybenzoic acid includes the following forms: 2,3-dihydroxybenzoic acid (2-pyrocatechuic acid): In formula (2), R ２１ is —COOH, and R ２２ and R ２３ are both —OH, and R ２４ ~R ２６ are all hydrogen atoms. 2,4-Dihydroxybenzoic acid (β-resorcylic acid): In formula (2), R ２１ is —COOH, and R ２２ and R ２４ are both —OH, and R ２３ , R ２５ and R ２６ are all hydrogen atoms. 2,5-Dihydroxybenzoic acid (gentisic acid): In formula (2), R ２１ is —COOH, and R ２２ and R ２５ are both —OH, and R ２３ , R ２４ and R ２６ are all hydrogen atoms. This form corresponds to formula (2b). 2,6-Dihydroxybenzoic acid (γ-resorcylic acid): In formula (2), R ２１ is —COOH, and R ２２ and R ２６ are both —OH, and R ２３ , R ２４ and R ２５ are all hydrogen atoms. 3,4-Dihydroxybenzoic acid (protocatechuic acid): In formula (2), R ２１ is —COOH, and R ２３ and R ２４ are both —OH, and R ２２ , R２５ and R ２６ are all hydrogen atoms. This form corresponds to formula (2c). 3,5-Dihydroxybenzoic acid (α-resorcylic acid): In formula (2), R ２１ is —COOH, and R ２３ and R ２５ are both —OH, and R ２２ , R ２４ and R ２６ are all hydrogen atoms.

[0044] Examples of trihydroxybenzoic acid include, but are not limited to, the following forms: 3,4,5-trihydroxybenzoic acid (gallic acid): In formula (2), R ２１ is —COOH, and R ２３ ~R ２５ are both —OH, and R ２２ and R ２６ are all hydrogen atoms. This form corresponds to formula (2d). 2,4,6-trihydroxybenzoic acid: in formula (2), R ２１ is —COOH, and R ２２ , R ２４ and R ２６ are both —OH, and R ２３ and R ２５ are all hydrogen atoms.

[0045] Another embodiment of the stabilizer represented by formula (2) is R ２１ Ga-CH ２ OH, -COOR ２８ , or -CONHR ２８ Examples of compounds that fall into this category include, but are not limited to, the following: Gentidyl alcohol: In formula (2), R ２１ Ga-CH ２ OH and R ２２ and R ２５ are both —OH, and R ２３ , R ２４ and R ２６ are all hydrogen atoms. This form corresponds to formula (2e). Gentisic acid alkyl ester: In formula (2), R ２１ Ga-COOR ２８and R ２２ and R ２５ are both —OH, and R ２３ , R ２４ and R ２６ are all hydrogen atoms, and R ２８ is a saturated linear alkyl group having 1 to 8 carbon atoms. This embodiment is one embodiment included in formula (2f). Gentisic acid ethanolamide: In formula (2), R ２１ Ga-CONHR ２８ and R ２２ and R ２５ are both —OH, and R ２３ , R ２４ and R ２６ are all hydrogen atoms, and R ２８ Ha-CH ２ -CH ２ This form is one form encompassed by formula (2g).

[0046] Among these, from the viewpoint of further increasing the yield of the radioactive metal complex, it is preferable to use a compound having a structure represented by any one of formulas (2a) to (2g) or a salt thereof as the stabilizer, it is more preferable to use a compound having a structure represented by any one of formulas (2a) to (2d) or a salt thereof, and it is even more preferable to use a compound having a structure represented by formula (2b) or a salt thereof. That is, the stabilizer is more preferably salicylic acid, gentisic acid, protocatechuic acid, or gallic acid or a salt thereof, even more preferably salicylic acid, gentisic acid, or protocatechuic acid or a salt thereof, and most preferably gentisic acid or a salt thereof.

[0047] From the viewpoint of further increasing the yield of the radioactive metal complex, when a stabilizer is used, the concentration of the stabilizer in the reaction solution at the start of the complex formation step is preferably 0.1 mmol / L to 500 mmol / L, more preferably 1 mmol / L to 400 mmol / L, and even more preferably 1 mmol / L to 300 mmol / L. Furthermore, it is preferable that the concentration of the stabilizer in the reaction solution is higher than the concentrations of the radioactive metal ions and the ligand compound in the reaction solution, from the viewpoint of preventing radiolysis and further improving the labeling efficiency.

[0048] In the present invention, the addition of a stabilizer is not essential, but the addition of a stabilizer is not essential. ８９ When Zr is used, it is preferable to add a stabilizer. ８９ This is because when Zr is used, the yield is likely to decrease due to the adsorption described above.

[0049] The reaction solution used in the complex formation step may be free of organic solvents, or an organic solvent may be added depending on the physical properties of the ligand compound and stabilizer. Examples of such organic solvents include protic solvents such as methanol and ethanol, and water-soluble aprotic solvents such as acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and acetone. By including such an organic solvent, even when poorly water-soluble ligand compounds and stabilizers are used, they can be sufficiently dissolved or dispersed in the solvent, thereby achieving a high labeling rate in a stable manner. "Free of organic solvents" means that the reaction solution is not intentionally free of organic solvents, but the inevitable inclusion of organic solvents in the reaction solution is acceptable.

[0050] The volume of the reaction solution in the complex formation step is not particularly limited, but from the viewpoint of practicality in the manufacturing process, a volume of 0.01 mL or more and 100 mL or less at the start of the complex formation step is realistic.

[0051] In the complex formation step, the order of addition of the radioactive metal source, the ligand compound, and other components is not important as long as the labeling reaction of the radioactive metal ion with the ligand compound can proceed, specifically, as long as a complex can be formed between the radioactive metal ion and the ligand compound. For example, one of the radioactive metal source and the ligand compound may be added, and then the other may be added, to a reaction vessel previously containing a mixed solvent prepared by mixing water, a stabilizer, and a second organic compound that constitute the reaction solution. Alternatively, one of the radioactive metal source and the ligand compound may be dissolved in a mixed solvent, and the other may be added to the solution, and the reaction may be carried out. Alternatively, the radioactive metal source and the ligand compound may be simultaneously added to a reaction vessel previously containing the mixed solvent, and the reaction may be carried out.

[0052] In the complexation step, the reaction solution is irradiated with microwaves to achieve further improvement in labeling efficiency in a short reaction time. As used herein, microwaves refer to electromagnetic waves with a frequency of 10 MHz to 300 GHz. From the viewpoint of more effectively promoting the complexation reaction, the frequency of the irradiated microwaves is preferably 800 MHz or higher and 3 GHz or lower, and more preferably 2.35 GHz or higher and 2.55 GHz or lower. The microwaves irradiated to the reaction solution are preferably microwaves generated using, for example, a magnetron-type or semiconductor-type microwave generator.

[0053] The output of the microwaves to be irradiated is preferably 10 W or more, and more preferably 30 W or more. By setting the microwave output to 10 W or more, the reaction rate of the complex formation step can be effectively improved.

[0054] The microwaves may be irradiated at a constant output during the complexation step, or may be changed over time within the above-mentioned range. Furthermore, during the complexation step, the microwaves may be irradiated continuously or intermittently. When microwaves are irradiated continuously, the microwave irradiation time may be the same as the reaction time described below. When microwaves are irradiated intermittently, the total microwave irradiation time may be preferably 1 minute or more and 60 minutes or less, more preferably 5 minutes or more and 30 minutes or less.

[0055] From the viewpoint of simultaneously suppressing decomposition of the ligand compound and further improving the labeling efficiency, the temperature of the reaction solution is preferably 10° C. or higher and 90° C. or lower, more preferably 30° C. or higher and 80° C. or lower, and even more preferably 50° C. or higher and 70° C. or lower. The reaction time is preferably 1 minute or higher and 60 minutes or lower, more preferably 5 minutes or higher and 30 minutes or lower, provided that the reaction temperature is as described above.

[0056] In the present invention, microwaves are irradiated onto the reaction solution while cooling it, in order to prevent the temperature of the reaction solution from rising excessively while maintaining a sufficiently high microwave output. As used herein, "cooling the reaction solution" encompasses an embodiment in which the reaction solution is cooled directly, and an embodiment in which the reaction solution is indirectly cooled by exposing the reaction vessel containing the reaction solution to a cooling medium. From the viewpoint of ease of operation, indirect cooling of the reaction solution is preferred. In an embodiment in which the reaction solution is indirectly cooled, the reaction solution is heated by microwave irradiation and cooled by a cooling medium simultaneously, thereby adjusting the temperature of the reaction solution to be maintained within the above-mentioned range.

[0057] The degree of cooling of the reaction solution may be constant throughout the complex formation step, or may be varied over time during the complex formation step. Examples of methods for varying the degree of cooling of the reaction solution over time include changing the temperature of the cooling medium according to a predetermined schedule, or adjusting the temperature of the cooling medium according to the measured temperature of the reaction solution so that the temperature of the reaction solution is maintained within the desired temperature range. Alternatively, cooling may be temporarily stopped.

[0058] Instead of varying the degree of cooling over time, the temperature of the reaction solution may be maintained within the above range by varying the microwave output over time within the above range while keeping the degree of cooling constant, or by varying both the microwave output and the degree of cooling over time.

[0059] Microwave irradiation and cooling of the reaction solution may be carried out continuously during the complex formation reaction, or either one or both may be carried out intermittently. However, from the viewpoint of enhancing the microwave irradiation effect, it is preferable to irradiate microwaves continuously during the complex formation reaction.

[0060] When starting the complex formation reaction, microwave irradiation may be started before cooling the reaction solution, or cooling the reaction solution may be started before microwave irradiation. Alternatively, both may be started simultaneously. From the viewpoint of preventing an excessive rise in the temperature of the reaction solution, it is preferable to start cooling the reaction solution first. However, when the temperature of the cooling medium is below the freezing point of the reaction solvent, it is preferable to start microwave irradiation immediately after starting cooling in order to prevent freezing of the reaction solution.

[0061] Examples of cooling media used when indirectly cooling the reaction solution include gases such as air, liquids such as water and antifreeze, and solids such as aluminum blocks. Of these, from the viewpoints of ease and precision of temperature control and cooling efficiency, it is preferable to use air as the cooling medium, that is, to cool the reaction solution by exposing the reaction vessel to cold air.

[0062] From the viewpoint of facilitating adjustment of the temperature of the reaction liquid, the temperature of the cooling medium is preferably −196° C. or higher and 90° C. or lower, more preferably −35° C. or higher and 25° C. or lower, and even more preferably −10° C. or higher and 0° C. or lower.

[0063] As will be described in the Examples below, in the present invention, by irradiating a reaction solution containing a stabilizer with microwaves, the effect of improving the yield of the radioactive metal complex by microwave irradiation can be further enhanced compared to when a reaction solution not containing a stabilizer is irradiated with microwaves.

[0064] The complex formation step is preferably carried out in a state where the pH of the reaction solution is in the acidic range. That is, in the complex formation step, the reaction is preferably carried out in a state where the acidic pH state is maintained from the start to the end of the reaction. The pH of the reaction solution being in the acidic range means that the pH of the reaction solution is less than 7. By carrying out the reaction in a state where the pH of the reaction solution is in the acidic range, the functional group of the ligand compound that interacts with the radioactive metal and / or the radioactive metal can be appropriately maintained in an ionic state, thereby maintaining a state where they can easily coordinate with each other in the reaction solution. As a result, the productivity of the radioactive metal complex can be further improved. More specifically, the complex formation step is preferably carried out in a state where the pH of the reaction solution is 2.0 or more and 6.0 or less.

[0065] The pH of the reaction solution can be maintained in the acidic range even during the complex formation step by previously adjusting the pH of the reaction solution to be in the acidic range before the start of the reaction, i.e., before the complex formation step is performed. The pH of the reaction solution can be adjusted, for example, by mixing an aqueous solution of the second organic compound and / or stabilizer into the reaction solution. Alternatively, the pH of the reaction solution can be adjusted by previously preparing a radioactive metal ion-containing solution, an aqueous solution of the ligand compound, an aqueous solution of the second organic compound, and an aqueous solution of the stabilizer, and then adjusting the mixing ratio of these aqueous solutions. Alternatively, the pH of the reaction solution can be adjusted by adding an inorganic acid such as hydrochloric acid or a metal hydroxide such as sodium hydroxide to a liquid mixture of the radioactive metal ions, the ligand compound, the second organic compound, and the stabilizer.

[0066] In the complex formation step, it is preferable to set the radioactivity of the radioactive metal nuclide in the reaction solution at the start of the reaction as follows, from the viewpoint of improving the production efficiency of the radioactive metal complex. ８９ In an embodiment using Zr, the amount of radioactivity in the reaction solution at the start of the complex formation step is: ８９ The radioactivity of Zr is set to 5 MBq or more, preferably 15 MBq or more, and more preferably 50 MBq or more. ２２５ In an embodiment using Ac, the amount of radioactivity in the reaction solution at the start of the complex formation step is: ２２５ The radioactivity of Ac is set to 1 MBq or more, preferably 2 MBq or more, and more preferably 4 MBq or more. In any embodiment, the upper limit of the radioactivity in the reaction solution at the start of the reaction is not particularly limited as long as it is a radioactivity amount that can be realized on a commercial production scale, but can be set to, for example, 1000 GBq or less.

[0067] In the complex formation reaction, it is preferable to set the ratio of the radioactivity of the radioactive metal nuclide to the amount of the ligand compound in the reaction solution at the start of the reaction to a value not less than the value described below, in order to reduce the amount of the ligand compound used and to suppress the production cost of the radioactive metal complex. ８９In an embodiment using Zr, the ratio of the ligand compound to the radioactivity in the reaction solution at the start of the reaction is preferably 10 MBq or more, more preferably 20 MBq or more, and even more preferably 60 MBq or more, per 1 nmol of the ligand compound. There is no particular upper limit, but it is, for example, 10,000 MBq or less. ２２５ In an embodiment using Ac, the ratio of the radioactivity of the radioactive metal nuclide per 1 nmol of the ligand compound in the reaction solution at the start of the reaction is preferably 0.3 MBq or more, more preferably 1 MBq or more, and even more preferably 2 MBq or more. There is no particular upper limit, but it is, for example, 10,000 MBq or less. Generally, the yield of the complex formation reaction tends to decrease as the radioactivity of the radioactive metal nuclide per 1 nmol of the ligand compound increases. However, in the present invention, the complex formation reaction is effectively promoted by microwave irradiation, so the complex formation reaction proceeds with a high yield even when the radioactivity of the radioactive metal nuclide per 1 nmol of the ligand compound is increased to the above-mentioned range.

[0068] The reaction pressure in the complexation step can be atmospheric pressure.

[0069] The production method of the present invention, which includes the complex formation step described above, performs the complex formation reaction while irradiating microwaves with sufficiently high power, thereby increasing the rate of the complex formation reaction compared to conventional techniques that involve heating without microwave irradiation or conventional techniques in which microwave irradiation conditions are not optimized. This makes it possible to produce a radioactive metal complex with a high yield even in a short reaction time. Furthermore, the production method of the present invention irradiates the reaction solution with microwaves while cooling it, thereby preventing an excessive rise in the temperature of the reaction solution while increasing the microwave output. This makes it possible to suppress the progression of side reactions caused by an excessive rise in the temperature of the reaction solution. The production method of the present invention is also advantageous in that the yield of the obtained radioactive metal complex is high, allowing the complex to be subjected to subsequent steps without separating and purifying unreacted radioactive metal nuclides.

[0070] Improved handling of the ligand compound used and the resulting ８９From the viewpoint of improving the stability of the Zr complex, particularly the formation stability of the complex, in formula (1), R 11 , R 12 and R 13 are both -(CH ２ ) ｐ It is preferably a carboxyalkyl group represented by a group consisting of COOH, where p is an integer of 1 or more and 3 or less. 14 and R 15 is a hydrogen atom or -(CH ２ ) ｐ It is also preferable that the carboxyalkyl group is represented by a group consisting of COOH, where p is an integer of 1 or more and 3 or less. 14 and R 15 The other is -(CH ２ ) ｐ It is also preferred that R is a carboxyalkyl group represented by a group consisting of COOH, where p is an integer of 1 to 3, or a reactive atomic group or a linking group for linking to a targeting agent. 11 , R 12 , R 13、 R 14 and R 15 When R has the suitable groups described above, 14 and R 15 When one of R is a hydrogen atom, 14 and R 15 The other is preferably a reactive group for linking to a targeting agent or a group linking to a targeting agent. 14 is a reactive group for linking to a targeting agent or a group linking to a targeting agent, R 15 is a hydrogen atom, and R 15 is a reactive group for linking to a targeting agent or a group linking to a targeting agent, R 14 is preferably a hydrogen atom.

[0071] When a ligand compound containing a group linked to a targeting agent is used in formula (1), the targeting agent is preferably one or more atomic groups selected from a low molecular weight compound, a polypeptide, a peptide aptamer, a growth factor, an affibody, a unibody, a nanobody, a monosaccharide, a polysaccharide, a vitamin, a nucleic acid, a liposome, a micelle, a carbon nanotube, or a nanoparticle. From the perspective of pharmaceutical applications, the targeting agent is preferably a low molecular weight compound, a polypeptide, or a nucleic acid. The low molecular weight compound is, for example, a compound having a target-directing structure or an atomic group capable of click reaction. As used herein, "targeting agent" refers to a chemical structure that exhibits targeting properties toward a target organ or tissue in the body or specificity for a target molecule. As used herein, target organs or tissues or target molecules are collectively referred to as "target sites." These targeting agents may be directly bound to the ligand compound or indirectly bound via other known linker structures such as PEG.

[0072] Furthermore, these targeting agents may be modified with a reactive atomic group capable of bonding to other structures, so that they can be linked to a ligand compound. To link to a ligand compound, known reactions such as a click reaction can be used. When a click reaction is used for linking, for example, the reactive atomic group possessed by the targeting agent and the reactive atomic group possessed by the ligand compound for linking to the targeting agent can both be groups containing a click-reactive atomic group. By using a ligand compound having such a chemical structure, it is possible to easily link to a targeting agent having specificity or directionality for a target site, and a radioactive metal complex having specificity or directionality for a target site can be obtained in high yield while fully maintaining the specificity or directionality of the targeting agent for the target site.

[0073] When the targeting agent includes a polypeptide, the targeting agent is preferably a linear peptide, a cyclic peptide, or a combination thereof, or a protein that specifically binds to a specific molecule. Examples of such atomic groups include peptides consisting of three or more amino acid residues. From the viewpoint of chemically controlling synthesis, the molecular weight of the peptide is preferably 500 to 20,000, more preferably 1,000 to 6,000. The polypeptide may also be an antibody or a fragment thereof. Examples of such antibodies include antibodies (immunoglobulins) of the IgG, IgA, IgM, IgD, and IgE classes, Fab fragments, and F(ab') ２ Examples of the targeting agent include antibody fragments such as antibody fragments, peptide aptamers, etc. The amino acids constituting the targeting agent described above may be natural or synthetic.

[0074] Various polypeptides that can be used as targeting agents can be synthesized by conventionally known methods, such as liquid phase synthesis, solid phase synthesis, automated peptide synthesis, genetic recombination, phage display, genetic code reprogramming, RaPID (Random Non-Standard Peptide Integrated Discovery), etc. When synthesizing various polypeptides, the functional groups of the amino acids used may be protected as necessary.

[0075] When the targeting agent is an atomic group containing a nucleic acid, the atomic group is preferably an atomic group containing an antisense nucleic acid, siRNA, miRNA, nucleic acid aptamer, decoy nucleic acid, cPG oligonucleic acid, or peptide nucleic acid that specifically binds to a specific molecule. Furthermore, the nucleic acid base constituting such a targeting agent may be a natural one such as deoxyribonucleic acid or ribonucleic acid, or may be a synthetic one.

[0076] The atomic group containing the nucleic acid that can be used in the present invention can be produced by a conventionally known method. For example, in the case of a nucleic acid aptamer, a nucleic acid aptamer that specifically binds to a specific target substance such as a protein can be produced using the SELEX method (Systematic Evolution of Ligands by Exponential Enrichment).

[0077] When a ligand compound containing a click-reactive atomic group is used as the ligand compound containing a reactive atomic group for linking to a targeting agent used in the present invention, the click-reactive atomic group can be derived from a known reagent that can be used in a click reaction. As used herein, the term "reactive atomic group" refers to a chemical structure that directly reacts to bond one compound to another. Examples of such reactive atomic groups include, but are not limited to, click-reactive atomic groups.

[0078] Examples of the click-reactive atomic group include an alkynyl group or an azide group, or a diene or dienophile such as a 1,2,4,5-tetrazine or an alkenyl group. From the viewpoint of simplifying the click reaction step, the click-reactive atomic group as the reactive atomic group is preferably an atomic group that can be used in a metal catalyst-free click reaction.

[0079] A click reaction is a reaction that occurs, for example, between an alkyne and an azide, or between a diene and a dienophile, such as 1,2,4,5-tetrazine and an alkene. Specific examples of click reactions involving the combination of such atomic groups include the Huisgen cycloaddition reaction and the Diels-Alder reaction.

[0080] Typically, the chemical structure produced by the click reaction of a combination of an alkyne and an azide contains a triazole skeleton, and the chemical structure produced by the click reaction of a combination of a diene and a dienophile, 1,2,4,5-tetrazine and an alkene, contains a pyridazine skeleton. Therefore, if the click-reactive atomic group that can be contained in the reactive atomic group for linking to a targeting agent contains an atomic group containing an alkyne or an azide, a triazole skeleton can be formed by the click reaction. Also, if the click-reactive atomic group that can be contained in the reactive atomic group for linking to a targeting agent contains an atomic group containing a diene or a dienophile, 1,2,4,5-tetrazine or an alkene, a pyridazine skeleton can be formed by the click reaction.

[0081] Specific examples of the atomic group capable of a click reaction include, as shown in the following formulas, an atomic group containing dibenzylcyclooctyne (DBCO) as an alkyne (formula (5a)), an atomic group containing an azide group as an azide (formula (5b)), an atomic group containing 1,2,4,5-tetrazine (formula (5c)), or an atomic group containing trans-cyclooctene (TCO) as an alkene (formula (5d)).

[0082]

[0083]

[0084] In formula (5a), R １ represents a binding site with an atomic group including a ligand compound or a targeting agent. ２ represents a binding site with an atomic group including a ligand compound or a targeting agent. ３ and R ４ In formula (5d), one of R represents a binding site with an atomic group containing a ligand compound or a targeting agent, and the other represents a hydrogen atom, a methyl group, a phenyl group, or a pyridyl group. ５ indicates the site of attachment to the atomic group comprising the ligand compound or targeting agent.

[0085] When a click-reactive atomic group is introduced into a ligand compound, it can be introduced using various commercially available reagents. Specifically, when an atomic group containing dibenzylcyclooctyne (DBCO) is introduced as a click-reactive atomic group, for example, DBCO-C6-Acid, DBCO-Amine, DBCOMaleimide, DBCO-PEG acid, DBCO-PEG-NHS, etc. DBCO reagents such as ester, DBCO-PEG-Alcohol, DBCO-PEG-amine, DBCO-PEG-NH-Boc, Carboxyrhodamine-PEG-DBCO, Sulforhodamine-PEG-DBCO, TAMRA-PEG-DBCO, DBCO-PEG-Biotin, DBCO-PEG-DBCO, DBCO-PEG-Maleimide, TCO-PEG-DBCO, and DBCO-mPEG can be used.

[0086] Suitable ligand compounds for use in the present invention include, but are not limited to, those having the structures shown in the following formulas (1-a) to (1-e). Ligand compounds having any of these structures can sufficiently achieve the effect of stably improving the labeling rate. In each of the following formulas, P represents an atomic group containing a reactive atomic group or an atomic group containing a targeting agent. From the viewpoint of stably improving the labeling rate, ligand compounds having the structure shown in the above formula (1-c) are more preferably used.

[0087]

[0088]

[0089] In formula (1), when a ligand compound containing a click-reactive atomic group is used, it is also preferable that the ligand compound and the click-reactive atomic group are indirectly bonded via a linker structure shown in formula (P) below. This structure is derived from ethylene glycol, and in formula (P), n is preferably an integer of 2 or more and 10 or less, more preferably an integer of 2 or more and 8 or less.

[0090]

[0091] The structure of the ligand compound containing a click-reactive atomic group is not particularly limited as long as the effects of the present invention are achieved, but it is more preferable that the ligand compound has the structure shown below. That is, it is more preferable that the ligand compound has at least one of DO3A-DBCO, DOTA-DBCO, DO3A-PEG4-DBCO, DO4A-PEG7-Tz, and DOTAGA-DBCO shown below.

[0092]

[0093]

[0094] When a ligand compound containing a click-reactive atomic group is used as the reactive atomic group, for example, the ligand compound can be coordinated to a radioactive metal nuclide by the above-described method, and then the click-reactive atomic group of the ligand compound can be reacted with the click-reactive atomic group in the targeting agent via a click reaction or the like to produce a radioactive metal complex. In this case, the targeting agent can be a compound modified with a click-reactive atomic group that specifically binds to the reactive atomic group in the ligand compound. The click-reactive atomic group modifying the targeting agent can be the same as those described above. By using such a compound, a radioactive metal complex with specificity or directionality toward a target site can be produced.

[0095] The radioactive metal complex produced through the above-mentioned steps exists in a dissolved state in the reaction solution. That is, the radioactive metal complex can be obtained as an aqueous solution. The aqueous solution containing the radioactive metal complex may be used as is, or may be purified using a filtration filter, a membrane filter, a column filled with various packing materials, chromatography, or the like.

[0096] Steps that can be carried out after the radioactive metal complex is obtained include, for example, a formulation step for obtaining a radiopharmaceutical containing the radioactive metal complex as an active ingredient. The formulation step can be carried out by appropriately adding various stabilizers, such as a pH adjuster such as a citrate buffer, a phosphate buffer, or a borate buffer, a solubilizer such as polysorbate, a stabilizer, or an antioxidant, or by adjusting the radioactivity concentration by diluting with an isotonic solution such as water or physiological saline. The formulation step may also include a step of preparing an injection by sterilizing filtration using a membrane filter or the like after adding various stabilizers or adjusting the concentration.

[0097] The above-described embodiments of the present invention encompass the following technical concepts: [1] A method for producing a radioactive metal complex, comprising a complex formation step of reacting a radioactive metal nuclide with a ligand compound represented by the above formula (1) in a reaction solution containing water and a buffer to form a radioactive metal complex, wherein the buffer contains one or more water-soluble organic compounds having a sulfo group or a carboxy group, and in the complex formation step, the reaction solution is irradiated with microwaves while being cooled. [2] A method for producing a radioactive metal complex, comprising: ６８ Ga, ８９ Zr, ９０ Y. １１１ In, １７７ Lu or ２２５ [3] The manufacturing method according to [1], wherein the radioactive metal nuclide is Ac. ８９ [4] The method according to any one of [1] to [3], wherein the reaction solution contains a stabilizer. [5] The method according to [4], wherein the stabilizer is one or more selected from gentisic acid, salicylic acid, protocatechuic acid, and salts thereof. [6] The method according to any one of [3] to [5], wherein at the start of the complex formation step, 10 MBq or more of the radioactive metal nuclide is used per 1 nmol of the ligand compound. [7] The method according to any one of [3] to [5], wherein the radioactive metal nuclide is ２２５[8] The manufacturing method according to [7], wherein 0.3 MBq or more of the radioactive metal nuclide is used per 1 nmol of the ligand compound at the start of the complex formation step. [9] The manufacturing method according to any one of [1] to [8], wherein the targeting agent is a low molecular weight compound, a polypeptide, or a nucleic acid.

[10] The manufacturing method according to any one of [1] to [9], wherein the reaction solution contains an organic solvent.

[11] The manufacturing method according to

[10] , wherein the organic solvent is one or more selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and ethanol.

[12] The manufacturing method according to any one of [1] to

[11] , wherein the pH of the reaction solution is in the acidic range.

[13] The method according to any one of [1] to

[12] , wherein the water-soluble organic compound is one or more selected from acetic acid, phthalic acid, malonic acid, 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, 3-morpholinopropanesulfonic acid, and salts thereof.

[14] The method according to any one of [1] to

[13] , wherein the temperature of the reaction solution is 10°C or higher and 90°C or lower.

[15] The method according to any one of [1] to

[14] , wherein the reaction solution is irradiated with microwaves at an output of 10 W or higher in the complex formation step.

[16] The method according to any one of [1] to

[15] , wherein the reaction solution is irradiated with microwaves generated using a magnetron or semiconductor microwave generator in the complex formation step.

[17] The method according to any one of [1] to

[16] , wherein in the complex formation step, a container containing the reaction solution is cooled by exposing it to cold air.

[0098] The present invention will be described in more detail below with reference to examples. However, the scope of the present invention is not limited to these examples. All of the following examples and comparative examples were carried out at atmospheric pressure, and the reaction temperature for the complex formation reaction was 70°C. In addition, the pH of the reaction solution at the start of the reaction was 4.0 to 5.5 in all examples and comparative examples.

[0099] In the following examples and comparative examples, the radioactive Zr element, the ligand compound, and the stabilizer are ８９Zr, DOTAGA-DBCO, and gentisic acid were used, and acetic acid and sodium acetate were used as the second organic compound. ８９ Zr is ８９ The Zr ions were used after being extracted from a bulk solution. ８９ The bulk solutions of Zr ions were prepared from the following lots A to D: Lot A: 3.9 GBq ８９ Zr bulk solution 4 days after production. Lot B: 11.8 GBq ８９ Bulk solution of Zr one day after production. Lot C: 8.8 GBq ８９ Zr bulk solution 4 days after production. Lot D: 8.8 GBq ８９ Bulk solution of Zr 6 days after production. The reaction results of the complexation reaction (labeling rate, adsorption rate, theoretical yield, etc., described below) are affected by the lot of the bulk solution, so comparison of the reaction results of each Example and Comparative Example must be made between Examples and Comparative Examples using the same lot.

[0100] [Example 1] (Preparation of reaction solution) ８９ 0.1 mL of Zr ion bulk solution (Lot A, solvent: 1.0 mol / L hydrochloric acid) was dispensed, and its radioactivity was measured using a radioisotope dose calibrator (manufactured by CAPINTEC). The measured radioactivity was 1,491 MBq. Next, the vial was heated at 110°C for 40 minutes under an argon stream, and the solvent was distilled off. 100 μL of 0.1 mol / L hydrochloric acid was added to the resulting residue, and the radioactivity concentration was measured. ８９ A Zr ion-containing solution (radioactivity concentration: 14910 MBq / mL) was prepared. ８９A portion of the Zr ion-containing solution (the amount necessary to bring the charged radioactivity to 7.20 MBq) was added to a 10 mL glass tube, and 0.1 mol / L hydrochloric acid was further added to make a 200 μL solution (hereinafter also referred to as "Solution 1"). Next, 200 μL of a 0.156 mol / L acetic acid-sodium acetate buffer solution containing gentisic acid at a concentration of 150 mmol / L (hereinafter also referred to as "Solution 2") and 200 μL of a 0.156 mol / L acetic acid-sodium acetate buffer solution containing DOTAGA-DBCO at a concentration of 0.01 mmol / L (hereinafter also referred to as "Solution 3") were added in this order, and the glass tube was stirred. The ８９ The radioactivity of Zr (hereinafter also referred to as "specific radioactivity") was 3.6 MBq / nmol, and the reaction solution volume was 600 μL.

[0101] (Complexation step) Next, a complexation reaction was carried out using a semiconductor microwave generator (MR-2G-100-CA50T15AC, manufactured by Ryowa Electronics Co., Ltd.). First, cold air was blown into the glass tube to start cooling the reaction solution in the glass tube, and immediately thereafter, microwave irradiation of the reaction solution was started. The microwave output was set to a maximum output of 100 W, and during the complexation reaction, the microwave output was varied and continuous irradiation was performed so that the temperature of the reaction solution was constant at 70°C. The temperature of the cold air was set to -5°C to -10°C, and cold air within this temperature range was continuously blown onto the glass tube during the complexation reaction. 10 minutes after the start of microwave irradiation, the supply of cold air and microwave irradiation were stopped.

[0102] (Analysis of reaction products) 2 μL of the reaction solution was extracted and used for thin layer chromatography (TLC) analysis. TLC conditions: iTLC-SG (Agilent), developing solvent: water / acetonitrile mixture (volume ratio 1:1). The developed thin layer chromatogram was introduced into a TLC analyzer (GITAStar, Raytest) to analyze the unreacted fraction in the reaction solution. ８９ All containing Zr ８９ Zr radioactivity count and ８９ The radioactivity counts of the Zr complexes were measured. ８９ For Zr radioactivity counts ８９The percentage of radioactive counts of the Zr complex was calculated as the labeling rate (%). The labeling rate indicates the degree of progress of the labeling reaction. The higher the labeling rate, the more likely it is to be of the intended use. ８９ A large amount of Zr complex was produced, which means that the labeling reaction was progressing well. The labeling rate of this sample was 91%. ８９ The adsorption rate (%) of the Zr complex was calculated based on the amount of adsorption confirmed by measuring the amount of radioactivity in the reaction vessel from which the reaction solution was taken using a radioisotope dose calibrator (manufactured by CAPINTEC). The adsorption rate is the ratio of the amount of radioactivity adsorbed on the inner wall of the reaction vessel to the amount of radioactivity charged. ８９ The adsorption rate of this sample was 19%. ８９ The theoretical yield (%) of the Zr complex was calculated by the following formula: Theoretical yield (%) = Labeling rate (%) × (100 - Adsorption rate (%)) / 100 The theoretical yield calculated by the above formula is ８９ The amount of Zr that can be taken out of the reaction vessel and used relative to the amount of Zr charged ８９ The theoretical yield of this sample was 74%.

[0103] [Examples 2 to 6, Comparative Examples 1 to 7] ８９ Examples 2 to 6 and Comparative Examples 1 to 7 were prepared in the same manner as in Example 1, except that the lot of the Zr ion bulk solution, the charged radioactivity, the amount of solutions 1 to 3 added, the concentration of the ligand compound DOTAGA-DBCO contained in solution 3, the reaction time, and the heating method were as shown in Table 1. ８９ Zr complexes were produced. The labeling rates, adsorption rates, and theoretical yields are shown in Table 1. In Comparative Examples 1 to 7, the reaction solution was heated using a block heater without irradiating it with microwaves. This also applies to Comparative Examples 8 to 10 described below. In Table 1 and Tables 2 and 4 described below, the semiconductor microwave generator is referred to as "semiconductor MW."

[0104]

[0105] As shown in Table 1, when Examples 1 to 4 are compared, the lower the specific radioactivity, the more the target ８９The theoretical yield of the Zr complex was high. In Examples 5 and 6, the lot contained a small amount of non-radioactive metal nuclides as impurities. ８９ A bulk solution of Zr ions was used. In this case, despite the high specific activity of 81-100 MBq / nmol, the Zr ions were obtained in a high theoretical yield. ８９ In Comparative Examples 1 to 7, in which the reaction solution was heated by a block heater without microwave irradiation, the specific radioactivity and ８９ Compared with examples using the same lot of Zr ion bulk solution, the theoretical yield was lower in both cases. This comparison shows that microwave irradiation has the effect of effectively promoting the complex formation reaction. It also shows that microwave irradiation can produce a radioactive metal complex in high yield even when the specific radioactivity is increased. Furthermore, a comparison of Example 1, in which the reaction was carried out for 10 minutes under microwave irradiation, and Comparative Example 2, in which the reaction was carried out for 60 minutes using a block heater, shows that the labeling rate and theoretical yield were similar, indicating that microwave irradiation could shorten the reaction time to about 1 / 6.

[0106] [Examples 7 to 10, Comparative Example 8] ８９ The same procedures as in Example 1 were carried out except that the lot of the Zr ion bulk solution, the charged radioactivity, the amount of solutions 1 to 3 added, the concentration of the ligand compound DOTAGA-DBCO contained in solution 3, and the heating method were as shown in Table 2. ８９ Zr complexes were produced. The labeling rates, adsorption rates, and theoretical yields are shown in Table 2. The magnetron microwave generator is referred to as "magnetron MW" in Table 2 and Table 3 described below. The magnetron microwave generator used was a Discover manufactured by CEM.

[0107]

[0108] As shown in Table 2, when either the semiconductor microwave generator (Examples 7 and 8) or the magnetron microwave generator (Examples 9 and 10) was used, the desired compound was obtained in a significantly higher theoretical yield than in Comparative Example 8, in which the complex formation reaction was carried out using a block heater without irradiating microwaves. ８９A Zr complex was obtained. Furthermore, since there was no significant difference between the semiconductor microwave generator and the magnetron microwave generator, it can be seen that the reaction acceleration effect is the same regardless of which one is used.

[0109] [Examples 11 to 14, Comparative Examples 9 to 10] ８９ Examples 11 to 14 and Comparative Examples 9 to 10 were prepared in the same manner as in Example 1, except that the lot of the Zr ion bulk solution, the charged radioactivity, the amount of Solutions 1 to 3 added, the reaction time, the heating method, and the maximum microwave output were as shown in Table 3. ８９ The labeling rate, adsorption rate and theoretical yield of Zr complexes were prepared as shown in Table 3.

[0110]

[0111] In Examples 11 to 14, in which the reaction was carried out with a maximum microwave output of 20 to 100 W, the desired reaction product was obtained, compared to Comparative Example 9, in which the reaction was carried out with heating by a block heater without irradiating with microwaves. ８９ The Zr complex was obtained in a high theoretical yield. Microwaves, especially at a maximum output of 60 W, ８９ The theoretical yield of the Zr complex was the highest. Furthermore, Examples 11 to 13, in which the reaction was carried out for 10 minutes with a maximum microwave output of 40 to 100 W, gave a higher theoretical yield than Comparative Example 10, in which the reaction was carried out for 60 minutes without microwave irradiation. This shows that under these reaction conditions, the reaction time could be reduced to 1 / 6 or less compared to when microwave irradiation was not performed.

[0112] Examples 15 and 16 ８９ The lot of the Zr ion bulk solution, the charged radioactivity, the amounts of solutions 1 to 3 added, the heating method, and the maximum microwave output were as shown in Table 4, and the same procedure as in Example 1 was repeated except that the microwave irradiation was switched on and off every 10 seconds. ８９ In Example 16, a Zr complex was produced in the same manner as in Example 15, except that Solution 2, which did not contain gentisic acid as a stabilizer, was used. ８９ The labeling rate, adsorption rate and theoretical yield of Zr complexes were prepared as shown in Table 4.

[0113]

[0114] As shown in Table 4, Example 16, which did not use gentisic acid, had a higher adsorption rate and a lower theoretical yield than Example 15, which did use gentisic acid. That is, in the present invention, the combination of the effect of accelerating the complex formation reaction by microwave irradiation and the effect of suppressing adsorption of the radioactive metal complex by the stabilizer makes it possible to produce the radioactive metal complex more efficiently.

Claims

1. A method for producing a radioactive metal complex, comprising a complex formation step of reacting a radioactive metal nuclide with a ligand compound represented by the following formula (1) in a reaction solution containing water and a buffer to form a radioactive metal complex, wherein the buffer contains one or more water-soluble organic compounds having a sulfo group or a carboxy group, and in the complex formation step, the reaction solution is irradiated with microwaves while being cooled: (In formula (1), R １１ , R １２ and R １３ are each independently -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , or -(CH ２ ) ｐ CONH ２ is a group consisting of 14 or R 15 One of the groups is a hydrogen atom, -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , -(CH ２ ) ｐ CONH ２ , or -(CHCOOH)(CH ２ ) ｐ COOH, and the other is -(CH ２ ) ｐ COOH, -(CH ２ ) ｐ C ５ H ４ N, -(CH ２ ) ｐ P.O. ３ H ２ , or -(CH ２ ) ｐ CONH ２ or a reactive atomic group for linking to a targeting agent or a group linking to a targeting agent, and each p is independently an integer of 0 to 3.

2. The radioactive metal nuclide ６８ Ga, ８９ Zr, ９０ Y. １１１ In, １７７ Lu or ２２５ The method according to claim 1, wherein the compound is Ac.

3. The radioactive metal nuclide ８９ The method according to claim 2, wherein the metal is Zr.

4. The method of claim 3, wherein the reaction solution contains a stabilizer.

5. The method according to claim 4, wherein the stabilizer is one or more selected from the group consisting of gentisic acid, salicylic acid, protocatechuic acid, and salts thereof.

6. The method of claim 3 or 4, wherein at the start of the complex formation step, 10 MBq or more of the radioactive metal nuclide is used per 1 nmol of the ligand compound.

7. The radioactive metal nuclide ２２５ The method according to claim 2, wherein the compound is Ac.

8. The method of claim 7, wherein at the start of the complex formation step, 0.3 MBq or more of the radioactive metal nuclide is used per 1 nmol of the ligand compound.

9. The method of claim 1 or 2, wherein the targeting agent is a low molecular weight compound, a polypeptide, or a nucleic acid.

10. The method of claim 1 or 2, wherein the reaction solution contains an organic solvent.

11. The method according to claim 10, wherein the organic solvent is one or more selected from the group consisting of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and ethanol.

12. The method of claim 1 or 2, wherein the pH of the reaction solution is in the acidic range.

13. The production method according to claim 1 or 2, wherein the water-soluble organic compound is one or more selected from the group consisting of acetic acid, phthalic acid, malonic acid, 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, 3-morpholinopropanesulfonic acid, and salts thereof.

14. The method of claim 1 or 2, wherein the temperature of the reaction solution is 10°C or higher and 90°C or lower.

15. The method of claim 1 or 2, wherein in the complex formation step, the reaction solution is irradiated with microwaves at an output of 10 W or more.

16. The manufacturing method according to claim 1 or 2, wherein in the complex formation step, microwaves generated by a magnetron type or semiconductor type microwave generator are irradiated.

17. The manufacturing method according to claim 1 or 2, wherein in the complex formation step, the container containing the reaction solution is cooled by exposing it to cold air.

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