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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/002—Heterocyclic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F19/00—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
  • C07F19/005—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00 without metal-C linkages
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• the present invention relates to a method for producing a radioactive metal complex.
• Non-Patent Document 1 describes a method for forming a radioactive metal complex by reacting 89 Zr, which is a radioactive metal, with DOTA, which is a ligand, in a buffer solution.
• Non-Patent Document 2 describes a method of reacting 68 Ga or 44 Sc with DOTATOC, which is a DOTA derivative as a ligand, in a buffer solution to form a radioactive metal complex.
• Non-Patent Document 3 describes a method of reacting 68 Ga or 44 Sc with DOTA in ethanol-containing physiological saline to form a radioactive metal complex.
• an object of the present invention is to provide a method for producing a radioactive metal complex having excellent complex formation efficiency in DOTA, a derivative thereof, or a ligand containing a structure similar to DOTA.
• the present invention comprises a step of reacting a radioactive metal with a ligand represented by the following formula (1) in a reaction solution to form a radioactive metal complex.
• the reaction solution contains water, a buffer and a water-soluble organic solvent. It provides a method for producing a radioactive metal complex in which the radioactive metal is 89 Zr or 225 Ac.
• R 11 , R 12 and R 13 are independently ⁇ (CH 2 ) p COOH, ⁇ (CH 2 ) p C 5 H 5 N, ⁇ (CH 2 ) p PO 3 H 2 , respectively.
• Or-(CH 2 ) p CONH 2 and one of R 14 or R 15 is a hydrogen atom,-(CH 2 ) p COOH,-(CH 2 ) p C 5 H 5 N,-(CH 2) 2) p PO 3 H 2, - (CH 2) p CONH 2, or, - (CHCOOH) (CH 2 ) a consists p COOH group and the other, - (CH 2) p COOH , - (CH 2 ) P C 5 H 5 N,-(CH 2 ) p PO 3 H 2 , or-(CH 2 ) p CONH 2 or a group linked to a peptide, where p is It is an integer of 0 or more and 3 or less.)
• the present invention it is possible to provide a method for producing a radioactive metal complex having excellent complex formation efficiency in DOTA, a derivative thereof, or a ligand containing a structure similar to DOTA.
• the present invention is particularly effective when a poorly water-soluble ligand is used.
• the production method of the present invention comprises a step (complex forming step) of reacting a radioactive metal and a ligand in a reaction solution containing water, a buffer and a water-soluble organic solvent to form a radioactive metal complex. ..
• radioactive metal in this step is preferably used in the form of an ionizable radioactive metal compound, and more preferably in the form of a radioactive metal ion (hereinafter, these aspects are collectively referred to) from the viewpoint of increasing the complex formation efficiency.
• 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. Specific nuclides of radioactive metals will be described later.
• the ligand used in this step has a structure represented by the following formula (1). That is, the ligand used in this step includes 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof, or a structure similar to DOTA. It is a ligand.
• DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
• DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
• R 11 , R 12 and R 13 are independently ⁇ (CH 2 ) p COOH, ⁇ (CH 2 ) p C 5 H 5 N, ⁇ (CH 2 ) p PO 3 H, respectively.
• the above p is an integer of 0 or more and 3 or less independently of each other.
• one of R 14 or R 15 is a hydrogen atom,-(CH 2 ) p COOH,-(CH 2 ) p C 5 H 5 N,-(CH 2 ) p PO 3 H 2 ,-.
• the above p is an integer of 0 or more and 3 or less independently of each other. Details of the peptide will be described later.
• “Slightly water-soluble” means having a property that satisfies at least one of the following (i) or (ii), and preferably has a property that satisfies at least (ii).
• the poor water solubility also includes the meaning of water insolubility in which the ligand is substantially insoluble in water.
• water-insoluble when both (i) and (ii) below are satisfied, it is also referred to as "water-insoluble”.
• the octanol-water partition coefficient (LogP value) of the ligand is a positive value.
• the index (LogS value) indicating the solubility of the ligand in water is a negative value.
• Oxyl-water partition coefficient which is one of the indexes of poor water solubility, is an index showing the hydrophobicity of a compound, and the distribution concentration of a substance in each phase of a two-phase solvent system consisting of n-octanol and water. It is defined as the common logarithm of the numerical value of the ratio of. This common logarithm value is a numerical value based on the ratio (C0 / Cw) of the concentration C0 in the n-octanol phase (oil phase) of the test substance to the concentration Cw in the aqueous phase of the test substance to be measured.
• the numerical value indicates whether the ligand as the test substance is more soluble in the oil phase or the aqueous phase. Therefore, the larger the value, the more hydrophobic the ligand is, that is, the less water-soluble it is.
• the calculation of the octanol-water partition coefficient was based on, for example, the method measured by the flask shaking method of JIS Z-7260-107: 2000, the HPLC method of OECD Test Guideline 117, or the partial structure and constituent atoms of the substance. It can be done by a method of computational chemistry estimation.
• the LogP value when the measured LogP value is obtained as the octanol-water partition coefficient of the ligand to be measured, the LogP value is estimated when the measured value is a positive value or by computational chemistry. In the case, when the calculated LogP value is calculated as a positive value, it is assumed that the ligand is poorly water-soluble.
• the "LogS value” which is another index of poor water solubility, is an index showing the solubility of the test substance in water. The lower the LogS value, the less water-soluble the test substance or ligand.
• a value estimated by computational chemistry can be used as the LogS value of the present invention by using commercially available software such as "Chemdraw Professional" manufactured by PerkinElmer.
• the peptide that can be contained in R 14 or R 15 preferably has a molecular weight of 500 Da or more and 10000 Da or less.
• the peptide is, for example, a raw amino acid such as a D-amino acid or an amino acid modified with an N-aliphatic hydrocarbon group such as an N-methyl group. It may be a peptide containing amino acids that do not constitute a protein in the body. Peptides containing amino acids that do not constitute in vivo proteins are generally poorly water-soluble, and the ligand to which the peptide is bound expresses poorly water-soluble as a whole.
• such peptides generally have peptidase resistance and are not easily decomposed in vivo, and as a result, they are highly stable in vivo such as in blood. Therefore, a radioactive metal complex containing this peptide is used in living organisms. When applied to, it can facilitate delivery to the target site.
• such peptides are preferably cyclic peptides. Since the cyclic peptide has a chemically stronger structure than the chain peptide, the stability in the living body can be further enhanced.
• the peptide that can be contained in R 14 or R 15 is not particularly limited as long as it is in the above molecular weight range and exhibits poor water solubility, but for example, a linear peptide such as physalaemin or a cyclic structure such as daptomycin can be used. Examples thereof include peptides having.
• the reaction solution in the complex formation step is an aqueous reaction solution containing water, a buffer, and a water-soluble organic solvent.
• water for example, distilled water or ion-exchanged water can be used.
• the buffer used in this step includes acetic acid and its salt, phosphoric acid and its salt, phosphate, 2-amino-2- (hydroxymethyl) propan-1,3-diol (Tris), 2- [4. -(2-Hydroxyethyl) -1-piperazinyl] -ethanesulfonic acid (HEPES) and one of the basic amino acids are preferably used.
• the counter ion of the buffer include alkali metal ions such as sodium and potassium, cations such as primary to quaternary ammonium such as ammonium and tetramethylammonium salts, and anions such as various halogen ions. Be done. In addition to this, a neutral salt such as sodium chloride may be further added. It is also preferable to select these buffers according to the types and combinations of radioactive metal nuclides and ligands.
• acetic acid and its salt phosphoric acid and its salt, Tris, HEPES, tetramethylammonium acetic acid, and a basic amino acid
• a buffer solution in which a buffer is dissolved in water an acetate-sodium acetate buffer solution (hereinafter, also simply referred to as an acetate buffer solution), an ammonium acetate buffer solution, a phosphate buffer solution, a phosphate buffered physiological saline solution, Tris
• a buffer solution a HEPES buffer solution, a buffer solution such as a tetramethylammonium acetate buffer solution, or the like.
• the reaction solution further contains a water-soluble organic solvent.
• the water-soluble organic solvent in this step is used for the purpose of increasing the solubility of the ligand in the reaction solution and increasing the amount of the ligand subjected to the complex formation reaction, and is particularly poorly water-soluble. It is suitable for increasing the solubility of the ligand of.
• Water-soluble in a water-soluble organic solvent means that when an arbitrary volume of water and an arbitrary volume of an organic solvent are mixed, they are freely mixed without observing the interface between the solvents.
• a protic solvent such as methanol and ethanol
• a polar solvent such as a protic solvent such as acetonitrile, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and acetone are preferably used.
• acetonitrile, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and acetone it is more preferable to use at least one selected from acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and ethanol as the water-soluble organic solvent from the viewpoint of allowing the complex formation reaction to proceed satisfactorily.
• the order of addition of the radioactive metal source and the ligand does not matter, for example, water, a buffer, and a buffer constituting the reaction solution.
• One of the radioactive metal source and the ligand may be added to the reaction vessel containing the mixed solvent containing the water-soluble organic solvent in advance, and then the other may be added and reacted.
• the other may be added to a solution prepared by dissolving one of them in a mixed solvent and reacted. Alternatively, these may be simultaneously added to a reaction vessel containing a mixed solvent in advance for reaction.
• the reaction conditions in the complex formation step can be, for example, the following conditions.
• As the reaction solvent used in this step a mixed solvent containing water, a buffer and a water-soluble organic solvent is used.
• the reaction temperature may be, for example, room temperature (25 ° C.) or heating conditions, but is preferably 30 ° C. from the viewpoint of suppressing the decomposition of the ligand and improving the complex formation efficiency. It is heated to 80 ° C. or higher, more preferably 50 ° C. or higher and 80 ° C. or lower.
• the reaction time is preferably 15 minutes or more and 150 minutes or less, and more preferably 30 minutes or more and 120 minutes or less, provided that the reaction temperature is as described above.
• the amount of the reaction solution in this step is not particularly limited, but from the viewpoint of practicality in the manufacturing process, 0.01 mL or more and 100 mL or less is realistic at the start of this step. Further, the concentrations of the radioactive metal ion and the ligand in the reaction solution are independently set to be 1 ⁇ mol / L or more and 100 ⁇ mol / L or less at the start of this step, which is the desired yield of the radioactive metal complex.
• the reaction solution can be appropriately changed depending on the physical properties of the radioactive metal, ligand and buffer used, but is preferably 4.0 or more and 7.0 or less, and more preferably 4.5 or more and 6.5 or less. , 5.0 or more and 6.0 or less is more preferable.
• the obtained radioactive metal complex may be used as it is, or may be purified by using a filtration filter, a membrane filter, a column filled with various fillers, chromatography or the like.
• the solubility of the ligand in the reaction solution can be enhanced and the complex formation reaction can be sufficiently proceeded.
• a radioactive metal complex having a high complex formation rate can be obtained.
• the reaction system contains a water-soluble organic solvent. Therefore, for example, a part of the structure of the water-soluble ligand is substituted or modified to have a poorly water-soluble property. Even when a poorly water-soluble ligand, such as an expressed ligand or a ligand that is originally poorly water-soluble, has not proceeded with the complex formation reaction in the prior art, it is coordinated with the radioactive metal.
• the complex formation reaction with the ligand proceeds well, and a radioactive metal complex can be obtained in an excellent yield.
• complex formation proceeds well and the yield of the complex is high, so that the radioactive metal It is advantageous in that the complex containing the nuclide can be subjected to the subsequent steps in an unpurified state.
• Examples of the step after complex formation include a formulation step for obtaining a radioactive drug containing the complex containing the radioactive metal nuclide as an active ingredient.
• a pH adjuster such as citrate buffer, phosphate buffer, borate buffer, a solubilizer such as polysolvate, a stabilizer or an antioxidant is added as appropriate, or water or physiological saline is added. It can be carried out by diluting with an isotonic solution such as.
• the formulation step may then include a step of sterilizing and filtering with a membrane filter or the like to prepare an injection.
• the ligand used in the present invention may have any of the structures shown in the following formulas (1-a) to (1-h). preferable. These structures can be appropriately selected depending on the type of radioactive metal or water-soluble organic solvent described later. The effect of the present invention is sufficiently exhibited regardless of the ligand having any structure.
• P represents a peptide, preferably a poorly water-soluble peptide having the above-mentioned constitution.
• the ligand represented by each formula has a poorly water-soluble peptide in its structure, so that the ligand as a whole exhibits a poorly water-soluble property.
• R 11 , R 12 and R 13 are all ⁇ (CH 2).
• one of R 14 and R 15 is a carboxyalkyl group represented by-(CH 2 ) p COOH, p is an integer of 1 or more and 3 or less, and the other is a chemical structure containing a poorly water-soluble peptide. It is preferable to have.
• the content of the water-soluble organic solvent contained in the reaction solution should be 2% by volume or more. It is preferably 5% by volume or more and 70% by volume or less, and more preferably 5% by volume or more and 50% by volume or less.
• the content in the reaction solution is preferably 2% by volume or more, more preferably 5% by volume or more and 70% by volume or less, and 5% by volume.
• the content in the reaction solution is preferably 20% by volume or more and 70% by volume or less, and more preferably 30% by volume or more and 60% by volume or less.
• the type of water-soluble organic solvent used is selected in consideration of the solubility of the ligand in the reaction solution, and the content of the water-soluble organic solvent in the reaction solution is selected according to the type of water-soluble organic solvent used.
• the concentration of the buffer in the reaction solution is preferably 0.05 mol / L or more and 5.0 mol / L or less, and is 0. It is more preferably 0.05 mol / L or more and 2.0 mol / L or less.
• the concentration in the reaction solution is preferably 0.05 mol / L or more and 2.0 mol / L or less, and 0.1 mol / L or more and 1 mol / L or less. It is more preferable to have.
• the concentration in the reaction solution is preferably 0.01 mol / L or more and 2.0 mol / L or less, and 0.1 mol / L or more and 1.0 mol / L or less. Is more preferable.
• a metal nuclide that emits ⁇ -rays, ⁇ -rays, ⁇ -rays, or a combination thereof can be used.
• nuclei of such radioactive metals include alkali metals, alkaline earth metals, lanthanoids, actinides, transition metals, and radioisotopes of metals other than these metals.
• 44 Sc, 51 Cr, 57 Co, 58 Co, 60 Co, 59 Fe, 67 Ga, 68 Ga as nuclides of radioactive metals from the viewpoint of being commercially available and improving complex formation.
• radioactive metals can be produced according to a conventional method, and it is preferable to obtain them as a solution containing the radioactive metals in an ionized manner.
• alpha-emitting radionuclide as a radioactive metal or beta - it is preferable to use a line-emitting nuclides.
• the ⁇ -ray emitting nuclide may be any nuclide that emits ⁇ -rays in the process of decay of the radioactive metal. Specifically, 212 Bi, 213 Bi, 227 Th or 225 Ac or the like is preferably used, and more preferably 227 Th or It is 225 Ac, more preferably 225 Ac.
• the ⁇ - ray emitting nuclide may be a nuclide that emits ⁇ - rays in the process of decay of a radioactive metal .
• 60 Co, 59 Fe, 64 Cu, 67 Cu, 89 Sr, 90 Y, 99m Tc, 103 Ru, 153 Sm, 165 Dy, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 203 Hg, 212 Bi, 213 Bi or 212 Pb, etc. are preferably used, more preferably 64 Cu, 67 Cu, etc. 89 Sr or 90 Y is used.
• ⁇ + ray emitting nuclide When the radioactive metal complex is used for the purpose of diagnosing a disease or detecting a lesion, ⁇ + ray emitting nuclide, electron capture decay nuclide, or ⁇ ray emitting nuclide should be used as the radioactive metal from the viewpoint of improving the diagnostic performance. Is preferable.
• the ⁇ + ray emitting nuclide may be any nuclide that emits positrons in the process of decay of the radioactive metal, and 44 Sc, 58 Co, 68 Ga, 64 Cu or 89 Zr or the like is preferably used, and more preferably 64 Cu or 89. Zr.
• the electron-capture decay nuclide may be a nuclide that emits Auger electrons or characteristic X-rays in the process of decay of a radioactive metal, and may be 51 Cr, 57 Co, 58 Co, 67 Ga, 68 Ga, 64 Cu, 89 Zr, 111 In. , 186 Re, 201 Tl or 197 Hg, etc. are preferably used.
• the ⁇ -ray emitting nuclide may be any nuclide that emits ⁇ -rays by ⁇ -decay, and 99 m Tc, 68 Ga or 201 Tl is preferably used as the nuclide that emits ⁇ -rays by ⁇ -decay.
• the radioactive metal having an ionic radius of about 70 to 130 pm is 67 Ga, 68 Ga, 64 Cu, 67 Cu, 89 Zr, 90 Y, 99m Tc, 103 Ru, 111 In, 153 Sm, 165 Dy, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 201 Tl, 197 Hg, 203 Hg, 212 Bi, 213 Bi , 212 Pb, 225 Ac, etc.
• the radioactive metal-labeled antibody when used for the purpose of diagnosing a disease or detecting a lesion, the above formula (1-b) or (1-d) to (1-h) It is preferable to use any of the ligands having the structure represented by the above formula (1-b), (1-d) or (1-e). More preferred.
• the radioactive metal complex produced for the treatment of a disease and the diagnosis of a disease and the detection of a lesion are used. It is more preferable that the ligands constituting these complex have the same structure as the radioactive metal complex produced for the purpose of. That is, in this case, it is more preferable to produce a radioactive metal complex using ligands having the same structure.
• Suitable combinations of the radioactive metal, the buffer and the water-soluble organic solvent include, for example, the following combinations, but the combination is not limited to this.
• 89 Zr is more preferably used as the ⁇ + ray emitting nuclide
• the ligand has a structure represented by the above formulas (1-b), (1-d) or (1-e). Is more preferably used.
• tetramethylammonium acetic acid having a concentration of 0.1 mol / L or more and 2.0 mol / L or less as a buffer in the reaction solution and 2 volumes as a water-soluble organic solvent are used. Includes% or more and 30% by volume or less of ethanol or acetonitrile.
• 225 Ac is more preferably used as the ⁇ -ray emitting nuclide, and any of the ligands having the structures represented by the above formulas (1-a) to (1-h) is more preferably used as the ligand. Be done.
• the radioactive metal complex When 225 Ac is used as the radioactive metal and ethanol is used as the water-soluble organic solvent under the condition (b-1) above, according to this production method, even when the concentration of ethanol is relatively low, the radioactive metal complex The formation efficiency can be increased. In addition to this, it is advantageous in that the amount of the water-soluble organic solvent used can be reduced and the manufacturing cost can be reduced.
• the content of ethanol in the reaction solution is preferably 2% by volume or more and 30% by volume or less, more preferably 2% by volume or more and 20% by volume. % Or less.
• a radioactive metal as an ⁇ -ray emitting nuclei
• sodium acetate or ammonium acetate having a concentration of 0.05 mol / L or more and 2.0 mol / L or less as a buffer in the reaction solution and 2 as a water-soluble organic solvent in the reaction solution.
• 225 Ac is more preferably used as the ⁇ -ray emitting nuclide
• any of the ligands having the structures represented by the above formulas (1-a) to (1-h) is more preferably used as the ligand. Be done.
• a radioactive metal as an ⁇ -ray emitting nuclide
• sodium acetate or ammonium acetate having a concentration of 0.05 mol / L or more and 2.0 mol / L or less as a buffer is used as a buffer in the reaction solution, and 10 as a water-soluble organic solvent. Includes dimethyl sulfoxide in an amount of at least 50% by volume.
• 225 Ac is more preferably used as the ⁇ -ray emitting nuclide
• any of the ligands having the structures represented by the above formulas (1-a) to (1-h) is more preferably used as the ligand. Be done.
• the radioactive metal complex is used even when the ligand concentration is increased. Formation efficiency can be increased. This is advantageous in that a high efficiency of forming the radioactive metal complex can be achieved while maintaining the solubility in the reaction solution even when a large amount of ligand is used in the commercial production of the radioactive metal complex.
• Peptides that can be used in the present invention include, for example, liquid phase synthesis method, solid phase synthesis method, automatic peptide synthesis method, gene recombination method, phage display method, and genetic code reprogramming, RaPID (Random non-standard Peptide Integrated Discovery). It can be synthesized by a method such as a method. In the synthesis of the peptide, the functional groups of the amino acids used may be protected, if necessary.
• the poorly water-soluble peptide and the ligand precursor are linked to each other by an amide bond or a thiourea bond. It is preferable to form a poorly water-soluble ligand.
• the amide bond can be formed, for example, by reacting an amino group derived from the side chain of an amino acid constituting the peptide with a carboxy group contained in a ligand precursor. Examples of such a ligand include a ligand having a structure represented by the above formula (1-a) or (1-c).
• the thiourea bond is formed by, for example, reacting an amino group derived from the side chain of an amino acid constituting the peptide with an isothiocyanate group having a ligand precursor, or a side chain of an amino acid constituting the peptide. It can be formed by reacting the thiol group derived from the above with the maleimide group of the ligand precursor.
• a ligand include a ligand having a structure represented by the above formula (1-b) or (1-d) to (1-h).
• Example 1-1 [Examples 1-1 to 1-4: 89 Zr labeling study (type of organic solvent)] [Example 1-1] 89 Zr was used as the radioactive metal element.
• DOTA in the above formula (1), R 11 , R 12 , R 13 and R 14 are all "-CH 2 COOH" groups, and R 15 is a hydrogen atom
• R 11 , R 12 , R 13 and R 14 are all "-CH 2 COOH" groups, and R 15 is a hydrogen atom
• the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent to prepare a solution containing 200 ⁇ mol / L of the ligand. 0.029 mL of this solution, 0.02 mL of a solution containing 89 Zr ions as a radioactive metal source (solvent: 0.1 mol / L hydrochloric acid aqueous solution, radioactivity concentration 33.4 MBq / mL), and 1.5 mol / L acetate buffer (1.5 mol / L acetate buffer)
• the reaction solution mixed with pH 5.5) 0.01 mL was reacted under heating conditions to obtain an 89 Zr complex solution.
• the heating temperature of the reaction solution was 70 ° C., and the heating time was 60 minutes.
• Example 1-2 DOTA was used as a ligand, and the ligand was dissolved in water containing 90% by volume of acetonitrile as an organic solvent, but the conditions were the same as in Example 1-1.
• the labeling rate of the 89 Zr complex was 59%.
• Example 1-3 DOTA was used as a ligand, and the ligand was dissolved in water containing 90% by volume of ethanol as an organic solvent under the same conditions as in Example 1-1.
• the labeling rate of the 89 Zr complex was 55%.
• Example 1-4 The procedure was carried out under the same conditions as in Example 1-1 except that DOTA was used as a ligand and the ligand was dissolved in water containing 90% by volume of N, N-dimethylformaldehyde as an organic solvent. The labeling rate of the 89 Zr complex was 54%.
• Example 2-1 DOTA is used as a ligand, the ligand is dissolved in 1.5 mol / L acetate buffer (pH 5.5) containing 90% by volume of dimethyl sulfoxide as an organic solvent, and the ligand is 200 ⁇ mol / L. The solution contained.
• Example 2-2 Example 2-1 except that DOTA was used as a ligand and the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent to prepare a solution containing 200 ⁇ mol / L of the ligand.
• the conditions were the same as above.
• the final concentration of the buffer in the reaction solution was 0.25 mol / L.
• the labeling rate of the 89 Zr complex at this time was 55%.
• Example 2-3 DOTA was used as a ligand, and the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent to prepare a solution containing 200 ⁇ mol / L of the ligand. 0.029 mL of this solution, 0.02 mL of 89 Zr ion-containing solution as a radioactive metal source (solvent: 0.1 mol / L hydrochloric acid aqueous solution, radioactivity concentration 25.2 MBq / mL) and 0.75 mol / L acetate buffer (pH 5) .5) The reaction was carried out under the same conditions as in Example 2-1 except that the reaction solution mixed with 0.01 mL was reacted under heating conditions. The final concentration of the buffer in the reaction solution was 0.13 mol / L. The labeling rate of the 89 Zr complex was 66%.
• Example 2-4 With DOTA as a ligand, the ligand is dissolved in water, except that the solution containing the ligand 200 [mu] mol / L is performed in the same conditions as in Example 2-1, the 89 Zr complex solution Obtained. The final concentration of the buffer in the reaction solution was 0.25 mol / L. The labeling rate of the 89 Zr complex was 50%.
• Example 2-5 Example 2-Except that DOTA was used as a ligand and the ligand was dissolved in 1.5 mol / L acetate buffer (pH 5.5) to prepare a solution containing 200 ⁇ mol / L of the ligand. The same conditions as in 1 were carried out to obtain an 89 Zr complex solution. The final concentration of the buffer in the reaction solution was 1.00 mol / L. The labeling rate of the 89 Zr complex was 28%.
• Example 2-6 Example 2 except that DOTA was used as a ligand and the ligand was dissolved in 3.0 mol / L acetate buffer (pH 5.5) to prepare a solution containing 200 ⁇ mol / L of the ligand. The procedure was carried out under the same conditions as in -1, and an 89 Zr complex solution was obtained. The labeling rate of the 89 Zr complex was 10%.
• Example 3-1 DOTA was used as a ligand, and the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent to prepare a solution containing 200 ⁇ mol / L of the ligand.
• Example 3-2 DOTA was used as the ligand, and the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent so that the final concentration of the ligand in the reaction solution was 50 ⁇ mol / L. The reaction was carried out under the same conditions as in Example 3-1 to obtain an 89 Zr complex solution. The labeling rate of the 89 Zr complex was 50%.
• Example 3-3 DOTA was used as the ligand, and the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent so that the final concentration of the ligand in the reaction solution was 10 ⁇ mol / L. The reaction was carried out under the same conditions as in Example 3-1 to obtain an 89 Zr complex solution. The labeling rate of the 89 Zr complex was 12%.
• Example 3-4 DOTA was used as the ligand, and the ligand was dissolved in water containing 90% by volume of dimethyl sulfoxide as an organic solvent so that the final concentration of the ligand in the reaction solution was 1 ⁇ mol / L. The reaction was carried out under the same conditions as in Example 3-1 to obtain an 89 Zr complex solution. The labeling rate of the 89 Zr complex was 9%.
• Example 4-1 DOTA was used as a ligand, and the ligand was dissolved in water containing 10% by volume of ethanol as an organic solvent to prepare a solution containing 100 ⁇ mol / L of the ligand.
• Example 4-2 DOTA was used as a ligand, and the ligand was reacted under the same conditions as in Example 4-1 except that the ligand was dissolved in water containing 10% by volume of acetonitrile as an organic solvent to obtain a 225 Ac complex solution. .. The labeling rate of the 225 Ac complex was 86%.
• Examples 4-3-4-4 Examples except that DOTA was used as a ligand and the ligand was dissolved in water containing 90% by volume or 50% by volume of ethanol as an organic solvent to prepare a solution containing 100 ⁇ mol / L of the ligand. The reaction was carried out under the same conditions as in 4-1 to obtain a 225 Ac complex solution. The labeling rate of the 225 Ac complex was 25% or 67%, respectively.
• Examples 4-5 to 4-6 Under the same conditions as in Example 4-1 except that the ligand was dissolved in water containing 90% by volume or 50% by volume of acetonitrile as an organic solvent to prepare a solution containing 100 ⁇ mol / L of the ligand. The reaction was carried out to obtain a 225 Ac complex solution. The labeling rate of the 225 Ac complex at this time was 27% or 69%, respectively.
• Example 1 Example 1 except that DOTA was used as a ligand and the ligand was dissolved in 0.5 mol / L phosphate buffer (pH 5.5) to prepare a solution containing 2 mmol / L of the ligand. The conditions were the same as in -1. In this comparative example, the reaction solution did not contain a water-soluble organic solvent. The labeling rate of the 89 Zr complex was 0%, and the complex formation reaction did not proceed at all.
• Examples 5-1 and 5-2 Except for the use of a ligand having DOTA in the structure and a peptide having a computationally-estimated calculated LogS value of negative value and having a calculated calculated LogS value of negative value as a whole ligand.
• the reaction is carried out under the same reaction conditions as in Example 1. In this case, the complex formation reaction proceeds to obtain an 89 Zr complex solution.
• ligands have a structure represented by the above formula (1-b), and have a structure derived from DOTA and a peptide in the structure. Details of the chemical structure are shown in the following formulas (E1) and (E2). These ligands are poorly water-soluble because the calculated LogS value is negative.
• each ligand was dissolved in 1.5 mol / L acetate buffer (pH 5.5) containing 45% by volume of dimethyl sulfoxide (DMSO) as a water-soluble organic solvent to prepare a solution.
• DMSO dimethyl sulfoxide
• 89 Zr ion-containing solution solvent: 0.1 mol / L hydrochloric acid aqueous solution, radioactivity concentration 33.4 MBq / mL
• 1.5 mol / L acetate buffer pH 5.5
• 59 ⁇ L of the mixed reaction solution was reacted under heating conditions at 70 ° C. for 2 hours to obtain an 89 Zr complex solution.
• the ligand concentration and the amount of radioactivity in the reaction solution at the start of the reaction were as shown in Table 1 below.
• the obtained 89 Zr complex was subjected to thin layer chromatography (Agient, iTLC-SG, developing solvent: water / acetonitrile (1: 1)) to count the total 89 Zr radioactivity including unreacted 89 Zr.
• the percentage of the radioactivity count of the 89 Zr complex was defined as the labeling rate (%).
• the results of the labeling rate of the 89 Zr complex are shown in Table 1 below.
• Examples 6-1 and 6-2 Using the ligands represented by the above formulas (E1) and (E2), the ligand was dissolved in water containing ethanol as an organic solvent to prepare a solution. This solution and a 225 Ac ion-containing solution (solvent: 0.2 mol / L hydrochloric acid aqueous solution, radioactivity concentration 5 MBq / mL) and 0.5 mol / L tetramethylammonium acetate buffer (pH 7.8) were used as a radioactive metal source. 79 ⁇ L of the mixed reaction solution was reacted under heating conditions of 70 ° C. for 1 hour to obtain a 225 Ac complex solution.
• solvent 0.2 mol / L hydrochloric acid aqueous solution, radioactivity concentration 5 MBq / mL
• 0.5 mol / L tetramethylammonium acetate buffer pH 7.8
• the ligand concentration and the amount of radioactivity in the reaction solution at the start of the reaction were as shown in Table 2 below.
• the concentration of the water-soluble organic solvent (ethanol) in the reaction solution was 10% by volume.
• Thin layer chromatography was performed under the same conditions as in Example 5-1.
• the results of the labeling rate (%) of the 225 Ac complex are shown in Table 2 below.
• Examples 7-1 to 7-4 the ligand represented by the above formula (E2) was used.
• the ligand concentration and 225 Ac radioactivity in the reaction solution at the start of the reaction were as shown in Table 3 below.
• the types and concentrations of the water-soluble organic solvent in the reaction solution were changed as shown in Table 3 below.
• the reaction was carried out under the same reaction conditions as in Example 6-1 to obtain a 225 Ac complex solution.
• the results of the labeling rate (%) of the 225 Ac complex are shown in Table 3 below.
• Examples 7-5 to 7-11 the ligand represented by the above formula (E2) was used.
• the ligand concentration and 225 Ac radioactivity in the reaction solution at the start of the reaction were as shown in Table 3 below.
• the type of buffer in the reaction solution and the type and concentration of the water-soluble organic solvent were changed as shown in Table 3 below.
• the reaction was carried out under the same reaction conditions as in Example 6-1 to obtain a 225 Ac complex solution.
• the results of the labeling rate (%) of the 225 Ac complex are shown in Table 3 below.
• the complex formation reaction proceeds satisfactorily when a water-soluble organic solvent is used in the reaction solution. Further, it can be seen that the complex formation reaction proceeds satisfactorily by adjusting the concentration thereof or the concentration of the ligand to an appropriate concentration range according to the type of the water-soluble organic solvent or the buffer. Under the production conditions using 89 Zr and a poorly water-soluble ligand, the complex formation rate (labeling rate) can be further improved by adopting a combination of DMSO and acetate buffer having a predetermined concentration. I understand.
• the production method of the present invention is excellent in complex formation efficiency, and its effect is particularly remarkable when a poorly water-soluble ligand is used.

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