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WO2022176954A1 - Complexe métallique radioactif ainsi que procédé de fabrication de celui-ci, et agent de capture de métal radioactif - Google Patents

Complexe métallique radioactif ainsi que procédé de fabrication de celui-ci, et agent de capture de métal radioactif Download PDF

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Publication number
WO2022176954A1
WO2022176954A1 PCT/JP2022/006430 JP2022006430W WO2022176954A1 WO 2022176954 A1 WO2022176954 A1 WO 2022176954A1 JP 2022006430 W JP2022006430 W JP 2022006430W WO 2022176954 A1 WO2022176954 A1 WO 2022176954A1
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Prior art keywords
group
formula
represented
substituent
radioactive metal
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English (en)
Japanese (ja)
Inventor
憲史 小林
伸能 古志野
智之 今井
聡 岸本
彰宏 井澤
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Nihon Medi Physics Co Ltd
Sumitomo Chemical Co Ltd
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Nihon Medi Physics Co Ltd
Sumitomo Chemical Co Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • 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

Definitions

  • the present invention relates to a radioactive metal complex, a method for producing the same, and a radioactive metal scavenger.
  • Linking moieties used in such conjugates include substituent moieties that can be chemically bonded to structures that have affinity for cancer cells, and chelate moieties that can form stable complexes with radionuclides.
  • a multidentate ligand having a structure having moieties is suitable (for example, Patent Document 1, Non-Patent Documents 1 and 2).
  • Alpha-emitting radionuclides or beta-emitting radionuclides can be used in the treatment of cancer, and gamma-emitting radionuclides or positron-emitting radionuclides can be used in cancer diagnosis.
  • 89 Zr and 225 Ac are attracting attention as a combination of radionuclides for achieving radio-theranostics.
  • 89 Zr which has a half-life of 3 days
  • 225 Ac which has a half-life of 10 days, have different valences in an aqueous solution and also have significantly different ionic radii. Even if you try, the complex formation rate of one of them may be low. Therefore, a ligand that coordinates to both 89 Zr and 225 Ac is desired.
  • the present invention provides a novel radioactive metal complex in which a ligand capable of coordinating both 89 Zr and 225 Ac is complexed with a radioactive metal element of 89 Zr or 225 Ac, and a method for producing the same.
  • Another object of the present invention is to provide a radioactive metal scavenger that traps a radioactive metal element such as 89 Zr or 225 Ac.
  • the present inventors have made intensive studies to solve the above problems, and found that a specific compound having a partial structure containing an 8-hydroxyquinoline derivative can coordinate to both 89 Zr and 225 Ac. , have completed the present invention.
  • the radioactive metal complex has a radioactive metal element and a ligand derived from the compound represented by the following formula (1).
  • the radiometal element is 89 Zr or 225 Ac.
  • n represents an integer of 0 to 3.
  • Q 1 , Q 2 , Q 3 , and Q 4 each independently represent a hydrogen atom, a group selected from Group A, a group selected from Group B, a group represented by formula (C1), or a substituent . provided that at least one of Q 1 , Q 2 , Q 3 and Q 4 is a group selected from Group A, and among Q 1 , Q 2 , Q 3 and Q 4 in Group B the formula (B3 ) is 0 to 2 groups.
  • Group A is a group consisting of groups represented by the following formulas (A1), (A2), (A3), (A4), and (A5).
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen represents an atom, a group represented by formula (C1), or a substituent, where * represents a bond.
  • Group B is a group consisting of groups represented by the following formulas (B1), (B2) and (B3).
  • Q B1 represents a group represented by formula (C1) or a divalent heterocyclic group which may have a substituent, and X 1 is a carbon atom or P(OH ), where * represents a bond.
  • Q B2 represents a divalent nitrogen atom-containing monocyclic heterocyclic group that may have a group or substituent represented by formula (C1). Note that * represents a bond.
  • X20 represents a carbon atom or P(OH). * represents a bond.
  • n2 represents an integer of 1 to 5.
  • L 10 represents a single bond or a divalent linking group which may have a substituent.
  • R 16 represents a hydrogen atom or a substituted R 16 may be combined with any L 10 to form a ring structure
  • L 10 present in plurality may be the same or different.
  • 30 represents a single bond or a divalent linking group which may have a substituent (* represents a bond).
  • Z 1 , Z 2 , Z 3 and Z 4 each independently represent a single bond or a divalent linking group which may have a substituent. When n is 2 or 3, multiple Z 4 may be the same or different.
  • R represents a divalent linking group which may have a substituent. When n is 2 or 3, multiple R's may be the same or different. ]
  • the compound represented by Formula (1) is preferably a compound represented by Formula (1A) below.
  • [In Formula (1A), Q 1 , Q 2 , Q 3 , Q 4 , Z 1 , Z 2 , Z 3 , Z 4 and R are as defined above. ]
  • Q 2 and Q 3 are preferably groups selected from group B.
  • At least one of Q 1 , Q 2 , Q 3 and Q 4 is preferably a group represented by formula (B1) in group B.
  • the compound represented by Formula (1) is preferably a compound represented by Formula (2) below.
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • R A represents an optionally substituted divalent linking group having 2 to 8 carbon atoms.
  • -Z 2A -Q 2A and -Z 3A -Q 3A are represented by the following formulas (15a), (15b), (15c), (15d), (15e), (15f), and (15g) ) represents a group selected from the group consisting of groups represented by —Z 4A —Q 4A represents a group selected from the group consisting of groups represented by the following formulas (15a), (15b), (15c), (15d), and (15e).
  • the method for producing the radioactive metal complex includes a labeling step of mixing a reactant that provides 89 Zr or 225 Ac with the compound represented by formula (1) to provide reaction conditions.
  • the radioactive metal scavenger is composed of a compound represented by the following formula (1).
  • the capture target of the radioactive metal capture agent is 89 Zr or 225 Ac.
  • n represents an integer of 0 to 3.
  • Q 1 , Q 2 , Q 3 , and Q 4 each independently represent a hydrogen atom, a group selected from Group A, a group selected from Group B, a group represented by formula (C1), or a substituent . provided that at least one of Q 1 , Q 2 , Q 3 and Q 4 is a group selected from Group A, and among Q 1 , Q 2 , Q 3 and Q 4 in Group B the formula (B3 ) is 0 to 2 groups.
  • Group A is a group consisting of groups represented by the following formulas (A1), (A2), (A3), (A4), and (A5).
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen represents an atom, a group represented by formula (C1), or a substituent, where * represents a bond.
  • Group B is a group consisting of groups represented by the following formulas (B1), (B2) and (B3).
  • Q B1 represents a group represented by formula (C1) or a divalent heterocyclic group which may have a substituent, and X 1 is a carbon atom or P(OH ), where * represents a bond.
  • Q B2 represents a divalent nitrogen atom-containing monocyclic heterocyclic group that may have a group or substituent represented by formula (C1). Note that * represents a bond.
  • X20 represents a carbon atom or P(OH). * represents a bond.
  • n2 represents an integer of 1 to 5.
  • L 10 represents a single bond or a divalent linking group which may have a substituent.
  • R 16 represents a hydrogen atom or a substituted R 16 may be combined with any L 10 to form a ring structure
  • L 10 present in plurality may be the same or different.
  • 30 represents a single bond or a divalent linking group which may have a substituent (* represents a bond).
  • Z 1 , Z 2 , Z 3 and Z 4 each independently represent a single bond or a divalent linking group which may have a substituent. When n is 2 or 3, multiple Z 4 may be the same or different.
  • R represents a divalent linking group which may have a substituent. When n is 2 or 3, multiple R's may be the same or different. ]
  • a novel radioactive metal complex in which a ligand having coordinating ability to both 89 Zr and 225 Ac is complexed with a radioactive metal element of 89 Zr or 225 Ac, and a method for producing the same are provided.
  • a radioactive metal scavenger that captures a radioactive metal element such as 89 Zr or 225 Ac.
  • substituteduents are classified into three types, unless otherwise specified.
  • the first is a group having a structure that has affinity with the targeting molecule (hereinafter sometimes referred to as “substituent A”).
  • the second group is a group having a site capable of cross-linking with a structure having affinity for the targeting molecule (hereinafter sometimes referred to as “substituent B”).
  • the third group is a group that can generally be taken in the field of organic chemistry (organic ligands) (hereinafter sometimes referred to as "substituent C").
  • a structure having affinity with a targeting molecule in Substituent A and Substituent B means a structure that selectively interacts with a specific tissue or surface of a cell. For example, it is a structure that has affinity with an antigen, more preferably a structure that has affinity with an antigen derived from cancer cells.
  • Antigen is a general term for substances that induce an immune response in vivo. "Antigen” is not particularly limited, but includes, for example, antigens derived from cancer cells.
  • Examples of structures that have affinity for targeting molecules include antibodies, antibody fragments, peptide chains, cyclic peptides, enzymes, nucleobase-containing moieties (eg, oligonucleotides, DNA vectors, RNA vectors, aptamers), and the like.
  • Substituent A has a "structure that has affinity with the targeting molecule” and a “site that can be crosslinked with the structure that has affinity with the targeting molecule” in Substituent B (hereinafter simply referred to as "crosslinkable site”). ) is preferably included in the partial structure chemically bonded to.
  • crosslinkable site hereinafter, in the present specification, a preferred embodiment will be described with an example of using an antigen as a targeting molecule, but as described above, this embodiment is not limited to the case where the targeting molecule is an antigen. do not have.
  • the "structure having affinity for the antigen" in Substituent A or Substituent B may be directly connected to the functional group or atom to which it is connected, or to the partial structure chemically bonded to the crosslinkable site. Alternatively, they may be linked via a linker or the like. When linked via a linker, a linker that may contain other atoms such as carbon or nitrogen, oxygen, sulfur, halogen, polyethylene glycol (PEG), or known peptides containing one or more amino acids. A linker can be used. The linker can be introduced not only for the purpose of connecting the "structure having affinity for the antigen" and the ligand, but also for the purpose of controlling the dynamics of the "structure having affinity for the antigen” in vivo. For example, peptide linkers described in WO2017/150549 and WO2019/065774 can be used.
  • the "structure having affinity for the antigen" in Substituent A or Substituent B is an antibody or antibody fragment
  • the binding position to the bound partial structure is randomly selected for some of the amino acid residues constituting the antibody or antibody fragment (e.g., sulfhydryl group of cysteine residue, side chain terminal amino group of lysine residue, etc.) or may be site-specifically bound to an amino acid residue in a specific site such as the Fab region or Fc region.
  • a known amine coupling method a method described in International Publication No. 2019/125982, or the like can be used.
  • the antibody or antibody fragment is treated with a glycosyltransferase (transglutaminase) described in WO 2019/125982 to introduce a "crosslinkable site” described later. and a method of site-specific binding to an amino acid residue having a sugar chain structure that is affected by glycosyltransferase, or a method of using a peptide capable of specifically binding to a lysine residue in the Fc region of an antibody.
  • peptides include IgG-binding peptides described in WO2016/186206 and WO2017/217347.
  • crosslinkable site in the substituent B is a selective covalent bond to a "specific site” (e.g., thiol group, azide group, terminal amino group, etc.) in the structure that has affinity for the antigen. It means a structure that can be formed.
  • a specific site e.g., thiol group, azide group, terminal amino group, etc.
  • crosslinkable sites include groups represented by the following formulas (A-1) to (A-14).
  • a straight line extending from the center of the ring structure represents a bond at any position of the ring structure.
  • * represents a bond, which is a binding site with L2 in formula (25) described later.
  • a substituent or the above linker may be present between these groups or between these groups and the bond.
  • a preferred embodiment of Substituent A a partial structure in which a "structure having affinity with an antigen" and a "crosslinkable site” in Substituent B are chemically bonded (hereinafter sometimes referred to as "crosslinked structure”). ) can be formed, for example, by click chemistry.
  • An example of click chemistry includes a reaction in which an azide group and an alkynyl group represented by the following formula (20) are reacted in the presence of a catalyst to form a 1,2,3-triazole ring. Note that * represents a bond.
  • click chemistry is the reaction between an azide group and cyclooctyne, represented by the following formula (21), or the reaction between a tetrazine group and a terminal alkyne, represented by the following formula (22). be done. Note that * represents a bond.
  • a crosslinker having two or more sites selected from the group consisting of "crosslinkable sites” and “specific sites” can be used.
  • examples of such a cross-linking agent include a cross-linking agent represented by the following formula (23).
  • the cross-linking agent for example, one of the sites selected from the group consisting of "crosslinkable site” and “specific site” is derived from the compound represented by the radioactive metal element and formula (1) in the radioactive metal complex described later.
  • the other one of the sites selected from the group consisting of the "crosslinkable site” and the “specific site” is added to the structure-containing site of the ligand, and the structure-containing site of the "structure having affinity for the antigen” is added, respectively. can be used for conjugation reactions.
  • substituent A examples include groups represented by the following formula (24).
  • L 1 represents a direct bond, a hydrocarbylene group optionally having a substituent C, or a heteroarylene group optionally having a substituent C; When multiple L 1 are present, they may be the same or different.
  • L3 represents the above "crosslinked structure". When multiple L3 are present, they may be the same or different.
  • Sp represents the above-mentioned "structure having affinity with antigen”.
  • n20 represents an integer of 1 to 10
  • n21 represents 1 or 2; Note that * represents a bond.
  • L 1 is a direct bond, a hydrocarbylene group optionally having a substituent C or a heteroarylene group optionally having a substituent C, preferably a direct bond or having a substituent C is a hydrocarbylene group that may be
  • hydrocarbylene group of the hydrocarbylene group optionally having substituent C in L 1 examples include an alkylene group and an arylene group.
  • L 1 is preferably an alkylene group.
  • the alkylene group in the hydrocarbylene group of L 1 is a divalent group in which two hydrogen atoms directly bonded to the carbon atoms constituting the saturated aliphatic hydrocarbon are removed.
  • Alkylene groups include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, and hexylene groups.
  • a portion of —CH 2 — in these alkylene groups may be substituted with —O—.
  • the number of carbon atoms in the alkylene group is not particularly limited, it is preferably 1 to 8.
  • the arylene group in the hydrocarbylene group of L1 is a divalent group in which two hydrogen atoms directly bonded to carbon atoms constituting the aromatic hydrocarbon are removed.
  • Arylene groups include phenylene groups, biphenylene groups, terphenylene groups, naphthylene groups, anthracenylene groups and the like.
  • Arylene groups are preferably phenylene groups.
  • the number of carbon atoms in the arylene group is not particularly limited, it is preferably 6 to 12.
  • Heteroarylene groups optionally having a substituent C of L 1 are, for example, pyridine, pyrazine, pyrimidine, pyrrole, N-alkylpyrrole, furan, thiophene, thiazole, imidazole, oxazole, benzofuran, benzothiophene, isoquinoline, It is a divalent group in which two hydrogen atoms directly bonded to carbon atoms constituting a heterocyclic compound such as quinazoline are removed.
  • a heteroarylene group is preferably a pyridylene group.
  • R e1 , R e2 , R e3 and R e4 each represent a hydrogen atom or a hydrocarbyl group having 1 to 8 carbon atoms. When a plurality of R e1 , R e2 , R e3 and R e4 are present, they may be the same or different.
  • hydrocarbyl groups having 1 to 8 carbon atoms in R e1 , R e2 , R e3 and R e4 include alkyl groups, aryl groups and aralkyl groups having 1 to 8 carbon atoms.
  • Hydrocarbyl groups of 1 to 8 carbon atoms are preferably alkyl groups of 1 to 8 carbon atoms.
  • L3 is the above "crosslinked structure".
  • Examples of L 3 include divalent groups represented by the following formulas (A-20) to (A-28).
  • the divalent groups represented by formulas (A-20) to (A-28) may have a substituent.
  • * represents a bond.
  • n20 is an integer of 1-20, preferably an integer of 1-10, more preferably an integer of 1-6.
  • n21 is 1 or 2, and n21 is preferably 2 when a cross-linking agent such as the cross-linking agent represented by the above formula (23) is used, and preferably 1 when no cross-linking agent is used.
  • Sp is a "structure that has affinity with an antigen".
  • the "structure having an affinity for an antigen” is exemplified by the structures described above.
  • one "antigen-affinity structure” when there are a plurality of structures having a substituent A from an intramolecular and intermolecular point of view, one "antigen-affinity structure" has a plurality of radioactive substances of the present application. It may be bound to a metal complex. In this case, one "antigen-affinity structure" may be shared among a plurality of substituents A.
  • Examples of the substituent B include a group represented by the following formula (25) and a group represented by the following formula (26).
  • L 1 , L 2 and n20 are as defined above.
  • Lk represents the above "crosslinkable site”. Note that * represents a bond.
  • L 1 , L 2 , L 3 , and n20 are as defined above.
  • Lk represents the above "crosslinkable site”. Note that * represents a bond.
  • Substituent C includes, for example, a halogen atom, a hydroxy group, an amino group, a sulfonic acid group, a nitro group, a hydrocarbyl group, a silyl group, a heteroaryl group, an alkyloxy group, an aryloxy group, an aralkyloxy group, and a silyloxy group. be done.
  • Substituent C is preferably a hydroxy group, an amino group, a sulfonic acid group, or an alkyloxy group from the viewpoint of being easily dissolved in a water-soluble liquid and used. A portion of these groups may be substituted with halogen atoms, for example, a hydrogen atom of a methyl group may be substituted with fluorine to form a trifluoromethyl group.
  • the halogen atom represented by the substituent C includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a halogen atom is preferably a fluorine atom.
  • the hydrogen atom on the nitrogen atom may be substituted with a hydrocarbon group.
  • the amino group includes, for example, unsubstituted amino group, dimethylamino group, diethylamino group, di-n-propylamino group, diisopropylamino group and diphenylamino group.
  • the amino group is preferably an unsubstituted amino group.
  • hydrocarbyl groups represented by substituent C include alkyl groups, aryl groups, and aralkyl groups. Hydrocarbyl groups are preferably alkyl groups.
  • alkyl group in the hydrocarbyl group represented by the substituent C examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, norbornyl group, Nonyl group, decyl group, 3,7-dimethyloctyl group, dodecyl group, pentadecyl group, octadecyl group, docosyl group and other saturated aliphatic hydrocarbon groups can be mentioned.
  • a portion of —CH 2 — in these alkyl groups may be substituted with —O—.
  • the number of carbon atoms in the alkyl group is not particularly limited, it is preferably 1 to 8 in terms of availability and cost.
  • Examples of the aryl group in the hydrocarbyl group represented by the substituent C include aromatic hydrocarbon groups such as phenyl group, biphenyl group, terphenyl group, naphthyl group, phenanthryl group and anthracenyl group.
  • Aryl groups are preferably phenyl groups. Although the number of carbon atoms in the aryl group is not particularly limited, it is preferably 6 to 18.
  • Examples of the aralkyl group in the hydrocarbyl group represented by the substituent C include a benzyl group, (2-methylphenyl)methyl group, (3-methylphenyl)methyl group, (4-methylphenyl)methyl group, (2, 4-dimethylphenyl)methyl group, (ethylphenyl)methyl group and naphthylmethyl group.
  • Aralkyl groups are preferably benzyl groups. Although the number of carbon atoms in the aralkyl group is not particularly limited, it is preferably 7 to 18.
  • the hydrogen atom on the silicon atom may be substituted with a hydrocarbon group.
  • substituted silyl groups include monosubstituted silyl groups substituted with one hydrocarbon group having 1 to 18 carbon atoms such as methylsilyl group, ethylsilyl group and phenylsilyl group; Silyl group, disubstituted silyl group substituted with two hydrocarbon groups having 1 to 18 carbon atoms such as diphenylsilyl group; trimethylsilyl group, triisopropylsilyl group, tri-n-butylsilyl group, tri-tert- a trisubstituted silyl group substituted with three hydrocarbon groups having 1 to 18 carbon atoms such as a butylsilyl group, a tri-isobutylsilyl group, a tert-butyl-dimethylsilyl group, a tri-n-pentylsilyl
  • heteroaryl group represented by the substituent C examples include pyridyl group, pyrazyl group, pyrimidyl group, pyrrolyl group, N-alkylpyrrolyl group, furyl group, thiophenyl group, thiazolyl group, imidazolyl group, oxazolyl group, A benzofuranyl group, a benzothiophenyl group, and an isoquinolinyl group can be mentioned.
  • a heteroaryl group is preferably a pyridyl or pyrimidinyl group.
  • alkyloxy group represented by the substituent C examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group and n-pentyloxy group. , n-octyloxy group and the like. A portion of —CH 2 — in these alkyloxy groups may be substituted with —O—.
  • Alkyloxy groups are preferably methoxy groups. Although the number of carbon atoms in the alkyloxy group is not particularly limited, it is preferably 1 to 8.
  • aryloxy group represented by the substituent C examples include phenoxy group, 2-methylphenoxy group, 3-methylphenoxy group, 4-methylphenoxy group, 2,4-dimethylphenoxy group and naphthoxy group.
  • Aryloxy groups are preferably phenoxy groups. Although the number of carbon atoms in the aryloxy group is not particularly limited, it is preferably 6 to 18.
  • Examples of the aralkyloxy group represented by the substituent C include a benzyloxy group, (2-methylphenyl)methoxy group, (3-methylphenyl)methoxy group, (4-methylphenyl)methoxy group, (2,4 -dimethylphenyl)methoxy group and naphthylmethoxy group.
  • An aralkyloxy group is preferably a benzyloxy group.
  • the number of carbon atoms in the aralkyloxy group is not particularly limited, it is preferably 7 to 18.
  • the hydrogen atom on the silicon atom may be substituted with a hydrocarbon group.
  • substituted silyloxy groups include trimethylsilyloxy, triethylsilyloxy, tri-n-butylsilyloxy, triphenylsilyloxy, triisopropylsilyloxy, and tert-butyldimethylsilyloxy groups. be done.
  • a substituted silyloxy group is preferably a trimethylsilyloxy group or a tert-butyldimethylsilyloxy group.
  • the substituent is preferably the substituent A or the substituent C, more preferably the substituent C, unless otherwise specified.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Bn represents a benzyl group.
  • alkyl groups such as propyl, butyl, pentyl, hexyl and octyl groups
  • alkylene groups such as propylene, butylene, pentylene, hexylene and octylene groups. If a chain structure or branched structure is not specified, these may be a straight chain structure or a branched structure. These groups preferably have a linear structure.
  • the number of carbon atoms means the number of carbon atoms excluding the number of carbon atoms of the substituent.
  • a radioactive metal complex of one embodiment has a radioactive metal element and a ligand derived from a compound represented by the following formula (1).
  • the radiometal element is 89 Zr or 225 Ac.
  • n represents an integer of 0 to 3.
  • Q 1 , Q 2 , Q 3 , and Q 4 each independently represent a hydrogen atom, a group selected from Group A, a group selected from Group B, a group represented by formula (C1), or a substituent . provided that at least one of Q 1 , Q 2 , Q 3 and Q 4 is a group selected from Group A, and among Q 1 , Q 2 , Q 3 and Q 4 in Group B the formula (B3 ) is 0 to 2 groups.
  • n is 2 or 3
  • multiple Q4 's may be the same or different.
  • Q2 and Q3 may be bonded to each other or form a ring structure via a divalent linking group.
  • Group A is a group consisting of groups represented by the following formulas (A1), (A2), (A3), (A4), and (A5).
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen represents an atom, a group represented by formula (C1), or a substituent, where * represents a bond.
  • Group B is a group consisting of groups represented by the following formulas (B1), (B2) and (B3).
  • Q B1 represents a group represented by formula (C1) or a divalent heterocyclic group which may have a substituent, and X 1 is a carbon atom or P(OH ), where * represents a bond.
  • Q B2 represents a divalent nitrogen atom-containing monocyclic heterocyclic group that may have a group or substituent represented by formula (C1). Note that * represents a bond.
  • X20 represents a carbon atom or P(OH). * represents a bond.
  • n2 represents an integer of 1 to 5.
  • L 10 represents a single bond or a divalent linking group which may have a substituent.
  • R 16 represents a hydrogen atom or a substituted R 16 may be combined with any L 10 to form a ring structure
  • L 10 present in plurality may be the same or different.
  • 30 represents a single bond or a divalent linking group which may have a substituent (* represents a bond).
  • Z 1 , Z 2 , Z 3 and Z 4 each independently represent a single bond or a divalent linking group which may have a substituent. When n is 2 or 3, multiple Z 4 may be the same or different.
  • R represents a divalent linking group which may have a substituent. When n is 2 or 3, multiple R's may be the same or different. ]
  • R 1 , R 2 , R 3 , R 4 and R 5 each independently represents a hydrogen atom, a group represented by formula (C1), or a substituent.
  • R 1 , R 2 , R 3 , R 4 and R 5 the total number of hydrogen atoms, groups represented by formula (C1) and substituents is four.
  • the number of groups and substituents represented by formula (C1) is preferably 0 to 2, more preferably is 0 or 1.
  • the number of hydrogen atoms is preferably 3 or 4.
  • the group selected from group A is preferably a group represented by formula (A1).
  • Groups selected from Group A include, for example, groups represented by the following formulas (AA-1) to (AA-20).
  • the groups represented by formulas (AA-1) to (AA-20) may have a substituent. Note that * represents a bond.
  • Groups selected from Group A are preferably groups represented by formula (AA-1) or formulas (AA-4) to (AA-20).
  • X1 is a carbon atom or P(OH), preferably a carbon atom.
  • Q B1 is a divalent heterocyclic group optionally having a substituent.
  • bivalent heterocyclic groups for Q B1 include heterocyclic groups such as pyridine, pyrazine, pyrimidine, pyrrole, N-alkylpyrrole, furan, thiophene, thiazole, imidazole, oxazole, benzofuran, benzothiophene, isoquinoline, and quinazoline.
  • Examples include divalent groups in which two hydrogen atoms directly bonded to carbon atoms constituting the heterocyclic compound of the compound are removed.
  • the heterocyclic compound is preferably pyridine, pyrimidine, thiazole or imidazole.
  • the group represented by formula (B1) in group B is preferably a compound represented by the following formula (10a), formula (10b), formula (10c), or formula (11), and the carbon atoms constituting the ring It is a group excluding one hydrogen atom directly bonded to an atom.
  • R 7a , R 8a , R 9a , R 7b , R 8b , R 9b , R 7c , R 8c , and R 9c each independently represent a hydrogen atom, ) represents a group or a substituent. However, at least one of R 7a , R 8a and R 9a is a hydrogen atom. At least one of R 7b , R 8b and R 9b is a hydrogen atom. At least one of R 7c , R 8c and R 9c is a hydrogen atom.
  • X2 represents a nitrogen atom or CR10a .
  • R 10a represents a hydrogen atom, a group represented by formula (C1), or a substituent.
  • R 11 represents a hydrogen atom, a group represented by formula (C1), or a substituent.
  • X 3 and X 4 each independently represent CR 12 , N, NR 13 , S or O;
  • R 12 and R 13 each independently represent a hydrogen atom, a group represented by formula (C1), or a substituent.
  • R 12 and R 13 may be the same or different.
  • each bond indicated by a double line consisting of a solid line and a broken line is arbitrarily selected from the group consisting of a single bond and a double bond.
  • X2 is a nitrogen atom or CR10a .
  • X2 is preferably CR10a .
  • R 7a , R 8a , R 9a and R 10a are each independently a hydrogen atom, a group represented by formula (C1), or a substituent. At least one of R 7a , R 8a and R 9a is a hydrogen atom. When R 7a , R 8a , R 9a and R 10a are substituents, the substituents are preferably substituents A or C. Among R 7a , R 8a , R 9a and R 10a , the number of groups and substituents represented by formula (C1) is preferably 0 or 1.
  • the number of hydrogen atoms in R 7a , R 8a , R 9a and R 10a is preferably 2 to 4.
  • the group represented by formula (B1) in group B is preferably a group obtained by removing one hydrogen atom from R 9a of the compound represented by formula (10a), from the viewpoint of improving metal retention.
  • R 7b , R 8b and R 9b are each independently a hydrogen atom, a group represented by formula (C1), or a substituent. At least one of R 7b , R 8b and R 9b is a hydrogen atom. When R 7b , R 8b and R 9b are substituents, the substituents are preferably substituents A or C. Among R 7b , R 8b and R 9b , the number of groups and substituents represented by formula (C1) is preferably 0 or 1.
  • the number of hydrogen atoms in R 7b , R 8b and R 9b is preferably 2 or 3.
  • the group represented by formula (B1) in group B is preferably a group obtained by removing one hydrogen atom from R 9b of the compound represented by formula (10b), from the viewpoint of improving metal retention.
  • R 7c , R 8c and R 9c are each independently a hydrogen atom, a group represented by formula (C1), or a substituent. At least one of R 7c , R 8c and R 9c is a hydrogen atom. When R 7c , R 8c and R 9c are substituents, the substituents are preferably substituents A or C. Among R 7c , R 8c and R 9c , the number of groups and substituents represented by formula (C1) is preferably 0 or 1.
  • the number of hydrogen atoms in R 7c , R 8c and R 9c is preferably 2 or 3.
  • the group represented by formula (B1) in group B is preferably a group obtained by removing one hydrogen atom from R 9c of the compound represented by formula (10c), from the viewpoint of improving metal retention.
  • X 3 and X 4 are each independently CR 12 , N, NR 13 , S, or O.
  • X3 is preferably CR12 .
  • the combination of X3 and X4 is preferably a combination in which X3 is O and X4 is CR12 , or a combination in which X3 is CR12 and X4 is NR13 .
  • a compound in which X 3 is O and X 4 is CR 12 is a compound represented by the following formula (11a), and a compound in which X 3 is CR 12 and X 4 is NR 13 is a compound represented by the following formula (11b).
  • R 11 is a hydrogen atom, a group represented by formula (C1), or a substituent.
  • the substituent is substituent A or substituent C, preferably substituent C.
  • R 12 is a hydrogen atom, a group represented by formula (C1), or a substituent.
  • the substituent is substituent A or substituent C, preferably substituent C.
  • R13 is a hydrogen atom or a substituent.
  • the substituent includes, for example, a hydrocarbyl group, a hydroxy group, a heteroaryl group, etc. in the substituent C.
  • Substituents are preferably hydrocarbyl groups.
  • the group represented by formula (B1) in group B is preferably hydrogen directly bonded to a carbon atom constituting the ring from the compound represented by formula (10a), formula (10b) or formula (10c) A group in which one atom is removed, more preferably a group in which one hydrogen atom directly bonded to a carbon atom constituting a ring is removed from the compound represented by formula (10a).
  • Examples of the group represented by formula (B1) in group B include groups represented by formulas (B1-1) to (B1-57) below.
  • a group obtained by removing one hydrogen atom directly bonded to a carbon atom constituting a ring from a compound represented by formula (10a), formula (10b), or formula (10c) is represented by formula (B1- 1) ⁇ formula (B1-9), formula (B1-27) ⁇ formula (B1-29), formula (B1-32) ⁇ formula (B1-41), formula (B1-42) ⁇ formula (B1-44 ), and groups represented by (B1-47) to (B1-57), wherein one hydrogen atom directly bonded to a carbon atom constituting the ring is removed from the compound represented by formula (11)
  • the group is represented by formulas (B1-16) to (B1-22), formula (B1-24), formula (B1-30), formula (B1-31), formula (B1-45), and formula (B1- 46).
  • * represents a bond
  • Sp represents "a structure having affinity with an antigen
  • the group represented by formula (B2) is preferably a group obtained by removing one hydrogen atom directly bonded to a carbon atom constituting the ring from the compound represented by formula (12) below.
  • X 5 , X 6 , X 7 and X 8 each independently represent N, NR 14 or CR 15 ; R 14 and R 15 each independently represent a hydrogen atom, a group represented by formula (C1), or a substituent. When multiple R 14 and R 15 are present, they may be the same or different.
  • X9 represents a carbon atom or a nitrogen atom.
  • Q10 represents O, OH, or a hydrogen atom.
  • each bond indicated by a double line consisting of a solid line and a broken line is arbitrarily selected from the group consisting of a single bond and a double bond.
  • X5 , X6 , X7 , and X8 are each independently N, NR14 , or CR15 .
  • the adjacent X5 , X6 , X7 or X8 is preferably CR15 .
  • N and NR 14 are N and NR 14 .
  • the number of N and NR 14 is preferably 0 or 1, more preferably 0.
  • R 14 and R 15 each independently represent a hydrogen atom, a group represented by formula (C1), or a substituent.
  • the substituents are preferably substituents A or C.
  • the number of substituents A is preferably 0 or 1, more preferably 0.
  • X9 is a carbon atom or a nitrogen atom, preferably a nitrogen atom.
  • Q10 is O, OH, or a hydrogen atom, preferably O or OH, more preferably O.
  • the group represented by formula (B2) is preferably a group obtained by removing one hydrogen atom directly bonded to a carbon atom constituting the ring from the compound represented by formula (12) in which X 8 is CH. .
  • Examples of the group represented by formula (B2) in group B include groups represented by formulas (B2-1) to (B2-29) below. Among these, groups obtained by removing one hydrogen atom directly bonded to a carbon atom constituting a ring from the compound represented by formula (12) are represented by formulas (B2-6) to (B1-29). is a group.
  • the group represented by formula (B2) is preferably represented by formula (B2-6), formula (B2-10), formula (B2-12) to formula (B2-22), formula (B2-24) to formula ( B2-26), or a group represented by formula (B2-29), more preferably formula (B2-6), formula (B2-10), formula (B2-12) to formula (B2-18), formula (B2-24) to formula (B2-26), or a group represented by formula (B2-29), more preferably formula (B2-6), formula (B2-10), formula (B2-16), or a group represented by formula (B2-17).
  • * represents a bond.
  • X 20 is a carbon atom or P(OH), preferably a carbon atom. That is, the group represented by formula (B3) is preferably a carboxyl group.
  • the number of groups represented by formula (B3) in group B is 0 to 2, preferably 0 or 2, more preferably 0 is.
  • n2 is an integer of 1-5, preferably an integer of 1-4, more preferably 2 or 3.
  • L 10 represents a single bond or a divalent linking group optionally having a substituent.
  • Examples of L 10 include the same groups as L 1 in the groups represented by formulas (25) and (26).
  • R 16 is a hydrogen atom or a substituent, preferably a substituent.
  • Substituents on R 16 include hydrocarbyl groups on Substituent C.
  • Hydrocarbyl groups as R 16 are preferably alkyl groups in substituent C.
  • R 16 may combine with any L 10 to form a ring structure.
  • n2 is 2 or more, multiple X 10 may independently bond to adjacent groups in any direction.
  • the group represented by formula (C1) is preferably a group represented by formula (C1a) or a group represented by formula (C1b), more preferably a group represented by formula (C1a). .
  • n2 L 10 , R 16 and L 30 are as defined above.
  • L 30 represents a single bond or a divalent linking group which may have a substituent. Examples of L 30 are the same as L 3 in the group represented by formula (26).
  • Examples of the group represented by formula (C1) include groups represented by formulas (C1-1) to (C1-10). Among these, groups in which R 16 and L 10 are not bonded to each other to form a ring structure are groups represented by formulas (C1-1) to (C1-7). Among these, the group represented by formula (C1) is preferably a group represented by formula (C1-2), formula (C1-3), or formula (C1-6). Note that * represents a bond, and L30 represents a single bond or a divalent linking group which may have a substituent.
  • Q 1 , Q 2 , Q 3 , and Q 4 each independently represent a hydrogen atom, a group selected from Group A, a group selected from Group B, a group represented by formula (C1), or a substituent .
  • at least one of Q 1 , Q 2 , Q 3 and Q 4 is a group selected from group A.
  • At least one of Q 1 , Q 2 , Q 3 and Q 4 is preferably a group selected from group B, more preferably a group represented by formula (B1) in group B.
  • Q 2 and Q 3 are preferably groups selected from group B.
  • n is 2 or 3, multiple Q4 's may be the same or different.
  • each of Q 1 , Q 2 , Q 3 and Q 4 is preferably a group selected from group A or a group selected from group B rather than a hydrogen atom or a substituent.
  • Q 1 and Q 4 are preferably groups selected from group A or groups selected from group B.
  • the total number of substituents that Q 1 , Q 2 , Q 3 and Q 4 can take is preferably 0 to 2.
  • divalent linking groups include alkylene groups such as a methylene group, ethylene group, propylene group, butylene group, and pentyl group.
  • R is a divalent linking group that may have a substituent.
  • the substituent is substituent A, substituent B or substituent C, preferably substituent A or substituent C.
  • the number of substituents A is preferably 0 or 1.
  • Examples of the divalent linking group for R include an alkylene group, an arylene group, and a heteroarylene group.
  • the divalent linking group may be a group formed by combining these.
  • the divalent linking group is preferably an alkylene group.
  • the number of carbon atoms in R is not particularly limited, but preferably 1 to 18.
  • the alkylene group for R is a divalent group in which two hydrogen atoms directly bonded to carbon atoms constituting a saturated aliphatic hydrocarbon are removed.
  • Alkylene groups include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, and hexylene groups. A portion of —CH 2 — in these alkylene groups may be substituted with —O—.
  • the number of carbon atoms in the alkylene group is not particularly limited, it is preferably 1 to 8.
  • the arylene group in R is a divalent group excluding two hydrogen atoms directly bonded to the carbon atoms constituting the aromatic hydrocarbon.
  • Arylene groups include phenylene groups, biphenylene groups, terphenylene groups, naphthylene groups, anthracenylene groups and the like.
  • Arylene groups are preferably phenylene groups.
  • the number of carbon atoms in the arylene group is not particularly limited, it is preferably 6 to 18.
  • Heteroarylene groups in R are for example heterocyclic groups such as pyridine, pyrazine, pyrimidine, pyrrole, N-alkylpyrrole, furan, thiophene, thiazole, imidazole, oxazole, benzofuran, benzothiophene, isoquinoline, quinazoline, benzimidazole, quinoline. It is a divalent group in which two hydrogen atoms directly bonded to carbon atoms constituting a compound are removed.
  • a heteroarylene group is preferably a pyridylene group. Although the number of carbon atoms in the heteroarylene group is not particularly limited, it is preferably 3 to 18.
  • the divalent linking group formed by combining an alkylene group, an arylene group, and a heteroarylene group includes a combination in which a phenylene group, a methylene group, and a phenylene group are linked in order, and a combination in which a methylene group, a phenylene group, and a methylene group are linked in order.
  • a combination, a combination in which a pyridylene group, a methylene group and a pyridylene group are bonded in order, and the like can be mentioned.
  • Z 1 , Z 2 , Z 3 and Z 4 each independently represent a single bond or a divalent linking group which may have a substituent.
  • divalent linking groups include hydrocarbylene groups.
  • Examples of the hydrocarbylene group are the same as the hydrocarbylene group for L1 .
  • the substituent is substituent A, substituent B or substituent C, preferably substituent A or substituent C.
  • the number of substituents A is preferably 0 or 1.
  • the substituents are preferably substituent A, hydrocarbyl groups, aryl groups, or heteroaryl groups, more preferably substituent A or hydrocarbyl groups.
  • the compound represented by formula (1) is preferably a compound represented by the following formula (1A) in which n is 1.
  • Examples of the compound represented by the formula (1) include compounds represented by the following formulas (1Aa-1) to (1Aa-24), and the following formulas (1Ab-1) to (1Ab-9). , compounds represented by the following formulas (1B-1) to (1B-3), and compounds represented by the following formulas (1C-1) to (1C-10). be done.
  • Sp represents "a structure having an affinity for an antigen".
  • the compound represented by formula (1) is preferably a compound represented by formula (2) below.
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • R A represents an optionally substituted divalent linking group having 2 to 8 carbon atoms.
  • -Z 2A -Q 2A and -Z 3A -Q 3A are represented by the following formulas (15a), (15b), (15c), (15d), (15e), (15f), and (15g) ) represents a group selected from the group consisting of groups represented by —Z 4A —Q 4A represents a group selected from the group consisting of groups represented by the following formulas (15a), (15b), (15c), (15d), and (15e).
  • R A is an optionally substituted divalent linking group having 2 to 8 carbon atoms.
  • R A is preferably an optionally substituted divalent hydrocarbylene group having 2 to 8 carbon atoms.
  • Examples of the hydrocarbylene group for RA are the same as the hydrocarbylene group for L1 .
  • -Z 2 -Q 2 and -Z 3 -Q 3 are preferably groups represented by formula (15c), formula (15d), formula (15e), formula (15f), or formula (15g) .
  • -Z 2 -Q 2 and -Z 3 -Q 3 may be the same or different.
  • Z 4 —Q 4 is preferably a group represented by formula (15a), formula (15b), or formula (15c), more preferably a group represented by formula (15a) or formula (15b) is.
  • the compound represented by formula (2) preferably has 0 or 1 substituent A, and since it can be used in combination with a "structure having affinity for an antigen", it has one substituent A. It is more preferable to have
  • the compound represented by formula (1) includes compounds represented by formulas (1-1) to (1-74) below. These compounds may have a substituent.
  • Sp represents "a structure having an affinity for an antigen".
  • the compound represented by formula (1) is preferably a compound represented by formula (2), formula (1-1) to formula (1-3), formula (1-7) to formula (1 -12), formulas (1-14) to (1-20), formulas (1-23), formulas (1-34), formulas (1-36) to formulas (1-42), formulas (1- 46) to formula (1-51), formula (1-53) to formula (1-60), formula (1-66) to formula (1-68), or compounds represented by formula (1-71) , more preferably formula (1-1) to formula (1-3), formula ( 1-7 ) to formula (1- 12), formula (1-14), formula (1-15), formula (1-17), formula (1-18), formula (1-34), formula (1-36) to formula (1-42) ), formula (1-46) ⁇ formula (1-51), formula (1-53), formula (1-54), formula (1-57) ⁇ formula (1-60), formula (1-66) ⁇ formula (1
  • the compound of this embodiment may form a salt by interacting with an acid or base, or may be hydrated.
  • acids that may form salts include hydrochloric acid, bromic acid, iodic acid, phosphoric acid, acetic acid, sulfuric acid, nitric acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and tetrafluoroboric acid. , hexafluorophosphoric acid, tetraphenylboric acid, and the like.
  • the acid is preferably hydrochloric acid or bromic acid.
  • the salt structure with an acid includes, for example, a salt structure in which the nitrogen site in the compound of the present embodiment interacts with an acid.
  • Examples of the base that may form a salt include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; substances; quaternary ammonium hydroxides such as tetramethylammonium hydroxide and tetrabutylammonium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like and alkali metal hydrogen carbonate.
  • the salt structure with a base includes, for example, a salt structure in which the proton of the carboxylic acid site in the compound of the present embodiment is replaced with another cation.
  • some protons may move within the molecule.
  • one or two protons in the carboxylic acid may move to the vicinity of the nitrogen atom in the ethylenediamine structure or the nitrogen atom in the hydroxyquinoline structure. good.
  • compounds that can be Q 1 , Q 2 , Q 3 and Q 4 can be linked to sites that can be Z 1 , Z 2 , Z 3 and Z 4 It can be produced by appropriately combining known techniques.
  • a compound having an aldehyde structure and a compound having an amino group are combined in a solvent such as ethanol. and a method of reacting with a reducing agent such as sodium borohydride after mixing inside.
  • a compound having a carboxylic acid structure and a compound having an amino group are known to be used, as exemplified in the following formula (32). and mixing in a solvent such as DMF using a condensing agent.
  • phenol can be derived by protecting the OH site of phenol by benzylation and then debenzylating and deprotecting it.
  • the compound of the present embodiment can be produced by appropriately introducing a protecting group and then deprotecting it.
  • the compound represented by the formula (1) can be obtained by combining known techniques such as the methods of forming the binding sites exemplified by the above formulas (30) to (32).
  • a compound having a carboxylic acid structure and a compound having an amino group, which are examples of starting materials in each reaction, are also produced by appropriately combining methods for synthesizing known carboxylic acid derivatives and amino compound derivatives. can do.
  • a compound partially having the structure of the substituent B is synthesized. It can be produced by appropriately combining known techniques.
  • a compound having a nitro group is used as a diamine compound to synthesize an intermediate product.
  • the nitro moiety is converted to an amine in a solvent such as ethanol by a common reducing agent such as using palladium and hydrogen, and then mixed with thiophosgene in a solvent such as chloroform to obtain formula (A-1 ) can be prepared.
  • Radioactive metal complex having a ligand derived from the compound of the present embodiment will be described.
  • the radioactive metal element interacts with the above compound. More specifically, the heteroatom in the compound interacts with the radioactive metal element, and interacts with the nitrogen atom and/or oxygen atom in the hydroxyquinoline ring in the compound represented by formula (1). ing. Interactions are usually coordinate bonds.
  • the radioactive metal complex is a heteroatom of the compound represented by formula (1) (e.g., nitrogen atom in nitrogen-containing heterocyclic group, nitrogen atom in primary to tertiary amine, -OH (including -O- ) and oxygen atoms in —CO 2 H (including —CO 2 — ), and the number of coordinate bonds is preferably 4 to 12, more preferably 8 ⁇ 10.
  • the compound of this embodiment can three-dimensionally exhibit the above interaction when a radioactive metal element is bound. The presence or absence of the formation of coordinate bonds can be confirmed by specifying the distance between the radioactive metal element and the heteroatom by structural optimization calculation using software that can simulate the 3D molecular structure that is in widespread use. .
  • the radiometal element is 89 Zr or 225 Ac.
  • the radiometal element may be an uncharged or charged ion, preferably a charged ion.
  • the radioactive metal element When the radioactive metal element is charged, it preferably has a valence of 1 to 4, more preferably 2 to 4, and even more preferably 89 Zr 4+ or 225 Ac 3+ .
  • Both 89 Zr 4+ and 225 Ac 3+ are radioactive metal elements in which the outermost electron shell has a closed-shell structure. It is known that it is difficult to form a complex compared to
  • the number of radioactive metal elements present in one molecule of the radioactive metal complex may be one or two or more. It is preferably one or two, more preferably one.
  • the number of types of radioactive metal elements present in one molecule of the radioactive metal complex may be one or two or more. One type is preferable.
  • the radioactive metal complex may contain a counterion for making the radioactive metal complex electrically neutral. If the radiometal complex is positively charged, an anion is chosen to neutralize it.
  • Anions include, for example, fluoride ion, chloride ion, bromide ion, iodide ion, sulfide ion, oxide ion, hydroxide ion, hydride ion, phosphate ion, acetate ion, sulfate ion, nitric acid ions, bicarbonate ions, trifluoroacetate ions, trifluoromethanesulfonate ions, tetrafluoroborate ions, and the like.
  • the anion is preferably hydrochloride or acetate. If the metal complex is negatively charged, a cation is chosen to neutralize it. Examples of cations include protons, ammonium ions, tetraalkylammonium ions, tetraarylphosphonium ions, and the like. A plurality of counterions may be present, and they may be the same or different.
  • the radioactive metal complex may contain neutral molecules such as the solvent used during the reaction or purification of the radioactive metal complex.
  • neutral molecules include water, methanol, ethanol, n-propanol, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, acetone, chloroform, acetonitrile, benzonitrile, triethylamine, pyridine. , diethyl ether, acetic acid, propionic acid, hydrochloric acid, oxalic acid and the like.
  • a plurality of neutral molecules may exist, and they may be the same or different.
  • the radioactive metal complex is preferably one of formulas (J-1) to (J-3) and formula (J-7) obtained by coordinating a radioactive metal element to the compound represented by formula (2).
  • M represents 89 Zr or 225 Ac. Dashed lines between M and heteroatoms represent possible interactions. Note that dashed lines between M and heteroatoms are for convenience and do not necessarily mean that interactions exist on all dashed lines.
  • the radioactive metal complex represented by the above formula may have a counterion and/or a neutral molecule as described above, and the ligand derived from the above compound has a substituent. good too.
  • Sp represents "a structure having an affinity for an antigen".
  • Multiple Ms in formula (J-71-3) may be the same or different, and are preferably the same.
  • the method for producing a radioactive metal complex of the present embodiment includes a labeling step of mixing a reactant that imparts 89 Zr or 225 Ac and the compound represented by formula (1) to provide reaction conditions.
  • the radioactive metal complex of the present embodiment can be obtained, for example, by organically synthesizing the compound of the present embodiment, and then adding the obtained compound as a reactant for imparting a radioactive metal element (hereinafter referred to as a "radioactive metal-imparting agent"). There is.) It is obtained by mixing with and reacting. The amount of the radioactive metal imparting agent to be reacted can be appropriately adjusted according to the desired radioactive metal complex.
  • radioactive metal imparting agent examples include acetates, fluorides, chlorides, bromides, iodides, sulfates, carbonates, nitrates, acetates, hydroxides, and perchlorates of the above-exemplified radioactive metal elements. , trifluoroacetate, trifluoromethanesulfonate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate, oxalate and the like.
  • the radiometal donating agent is preferably a chloride of a radiometal element.
  • the radioactive metal donating agent may be a hydrate.
  • reaction between the compound and the radioactive metal imparting agent is preferably carried out in a solvent (that is, reaction solvent).
  • reaction solvents include water, acetic acid, propionic acid, hydrochloric acid, aqueous ammonia, methanol, ethanol, n-propanol, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, acetone, and chloroform. , acetonitrile, benzonitrile, triethylamine, pyridine, diethyl ether and the like.
  • the reaction solvent may be used singly or in combination of two or more.
  • the reaction solvent may contain other components such as acids, bases and buffers for adjusting the pH of the reaction solution. Examples of acids include acids that may form the above salts. Examples of bases include bases that may form the above salts.
  • buffering agents include linear amine monosulfonic acids such as N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES); 2-morpholinoethanesulfonic acid (MES) and 3-morpholinopropanesulfonic acid.
  • TES N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid
  • MES 2-morpholinoethanesulfonic acid
  • 3-morpholinopropanesulfonic acid 3-morpholinopropanesulfonic acid
  • monosulfonic acids having a morpholine ring such as (MOPS); 2-[4-(2-hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid (HEPES), piperazine-1,4-bis(2-ethanesulfonic acid) ) (PIPES) disulfonic acid having a piperazine ring in its structure; straight-chain aliphatic monocarboxylic acids such as acetic acid and lactic acid; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; straight-chain fatty acids such as malonic acid and tartaric acid aromatic dicarboxylic acids such as phthalic acid; and/or salts thereof.
  • the labeling step is preferably performed in the presence of a reaction solvent containing a buffer in one embodiment.
  • the reaction temperature is usually -10 to 200°C, preferably 0 to 100°C, more preferably 10 to 40°C.
  • the labeling step is preferably performed at 40° C. or below in one embodiment.
  • the reaction time is generally 1 minute to 1 week, preferably 1 minute to 24 hours, more preferably 1 minute to 6 hours.
  • an appropriate pH can be selected according to each radioactive metal element.
  • a pH of 2.0 to 7.5 is preferred when the metal-donating agent is a reactant that imparts 225 Ac.
  • the concentration of the compound during the reaction is usually 1 nM to 100 mM, preferably 100 nM to 1 mM, more preferably 1 ⁇ M to 100 ⁇ M.
  • the molar concentration of the radioactive metal imparting agent during the reaction is usually 0.1 pM to 100 ⁇ M, preferably 1 pM to 10 ⁇ M.
  • the radioactivity of the radioactive metal imparting agent at the start of the reaction is usually 1 kBq to 1000 GBq, preferably 10 kBq to 100 GBq.
  • reaction solvent reaction temperature
  • reaction time reaction time
  • concentration during the reaction can be appropriately optimized according to the type of compound, the type of radioactive metal imparting agent, and the like.
  • the reaction temperature is preferably 40° C. or lower, more preferably 37° C. or lower.
  • the concentration of the compound during the reaction is preferably less than 100 ⁇ M.
  • the desired amount of radioactive metal complex can be obtained without aggregation, deposition, or precipitation of structures that have affinity for the targeting molecule.
  • the amount of radioactivity at the start of the reaction should be set to an arbitrary amount or less with which the structure can stably react. is preferred. Thereby, a radiometal complex with high radiochemical purity can be obtained.
  • the method for purification after the reaction is selected from filtration filters, membrane filters, columns filled with various known fillers, various chromatographic methods, etc. be able to.
  • Radiometal donating agents that donate 89 Zr and 225 Ac can be produced, for example, using a cyclotron, or can be conveniently obtained from appropriate institutions that deal with radioactive elements.
  • the radioactive metal is 89 Zr
  • the 89 Y target is irradiated with protons, and a solution obtained by dissolving the irradiated 89 Y target with acid is used as a trap capable of trapping 89 Zr.
  • the solution is passed through a column cartridge or the like carrying the agent. After that, the column cartridge is washed, and acid is passed through it to recover 89 Zr.
  • the radioactive metal is 225 Ac
  • the 226 Ra target is irradiated with accelerated particles, and the solution obtained by dissolving the irradiated 226 Ra target with acid is placed in a column carrying a collector capable of collecting 225 Ac. Liquid is passed through a cartridge, etc. After that, the column cartridge is washed and 225 Ac can be recovered by passing an acid through it.
  • a radioactive metal complex having a substituent A can be obtained by reacting a compound having a substituent A with a radioactive metal-providing agent, and reacting a compound having a substituent B with a radioactive metal-providing agent to form a complex. After that, it can also be obtained by performing a binding reaction between the “structure having affinity for the antigen” and the “crosslinkable site” exemplified in the above formulas (20) to (22).
  • the radioactive metal complex having the substituent A is preferably obtained by reacting the compound having the substituent A with a metal imparting agent, from the viewpoint of reducing the number of steps using the radioactive metal.
  • Radioactive metal scavenger comprising the compound represented by formula (1) of this embodiment.
  • the capture target of the radioactive metal capture agent is 89 Zr or 225 Ac.
  • the compound represented by formula (1) can coordinate to both 89 Zr and 225 Ac, it can be suitably used as a radioactive metal scavenger targeting 89 Zr or 225 Ac. can. More specifically, it can be used as a radioactive metal trapping agent that traps 89 Zr, and can also be used as a radioactive metal trapping agent that traps 225 Ac.
  • Preferred aspects of the compound represented by formula (1) are the same as above. Therefore, redundant description is omitted here.
  • the radioactive metal scavenger for example, by mixing a composition containing the compound represented by formula (1) with a solution containing 89 Zr and/or 225 Ac, and 89 Zr and/or 225 Ac to form a complex to capture 89 Zr and/or 225 Ac as a complex.
  • the captured complex can be isolated and recovered by the same method as for isolating and purifying the radioactive metal complex in the production method of the radioactive metal complex.
  • the composition containing the compound represented by formula (1) may be, for example, a solution of the compound represented by formula (1). Such a solution may be obtained by dissolving the compound represented by formula (1) in the reaction solvent exemplified above.
  • the solution containing 89 Zr and/or 225 Ac may be, for example, a solution obtained by dissolving the above radioactive metal imparting agent in one of the above reaction solvents.
  • the conditions for using the radioactive metal scavenger can be appropriately optimized according to the type of compound, the type of radioactive metal imparting agent, etc.
  • Preferred aspects of the conditions (reaction solvent, reaction temperature, reaction time, concentration during reaction, etc.) when using the radioactive metal scavenger are the same as the preferred aspects of the conditions in the above method for producing a radioactive metal complex. you can
  • the structure of the compound was confirmed by known methods such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the resulting brown powder was dissolved in 1.5 mL of chloroform, added to 8.0 g of diethyl ether, the brown precipitate generated was removed by filtration, and the filtrate was evaporated to remove the solvent and dried. was dissolved in 120 mg of chloroform, and the resulting yellow precipitate was added dropwise to a mixture of 3.0 g of heptane and 3.0 g of diethyl ether, which was collected by filtration and dried under reduced pressure to yield a yellow powder compound (a-7) obtained at 9.1%. Identification data of the obtained compound (a-7) are shown below.
  • the pale-yellow residue was dissolved in 520 mg of heavy tetrahydrofuran, and 74.0 mg of heavy water prepared by mixing 1.00 mg (1.52 ⁇ mol) of compound (a-13) and 0.17 mg (1.68 ⁇ mol) of triethylamine was added at room temperature. Stirred for an hour. The solvent was distilled off from the reaction solution, and the residue was suspended in water and filtered. The filtrate was dried under reduced pressure to obtain compound (a-14) as a yellow solid with a yield of 67%. The formation of the resulting compound (a-14) was confirmed by mass spectrometry as described below.
  • Example 1-1 The above formula (1-3) was used as the ligand.
  • the ligand was dissolved in water to prepare a solution containing 10 mmol/L of the ligand. 0.5 ⁇ L of this solution, 16.6 ⁇ L of a solution containing 89 Zr ions as a radioactive metal source (solvent: 0.1 mol/L hydrochloric acid, radioactivity concentration 108 MBq/mL), and 0.78 mol/L containing 150 mmol/L of gentisic acid.
  • a reaction mixture of 16.7 ⁇ L of acetate buffer (pH: 5.5) and 16.2 ⁇ L of water was reacted at 37° C. to obtain a 89 Zr complex solution. The reaction time was 60 minutes.
  • the labeling rate of the 89 Zr complex in this example was 89%.
  • Example 1-2 The above formula (1-9) was used as the ligand.
  • the ligand was dissolved in water to prepare a solution containing 10 mmol/L of the ligand. 0.5 ⁇ L of this solution, 16.6 ⁇ L of a solution containing 89 Zr ions as a radioactive metal source (solvent: 0.1 mol/L hydrochloric acid, radioactivity concentration 118 MBq/mL), and 0.78 mol/L containing 150 mmol/L of gentisic acid.
  • a reaction mixture of 16.7 ⁇ L of acetate buffer (pH: 5.5) and 16.2 ⁇ L of water was reacted at 37° C. to obtain a 89 Zr complex solution. The reaction time was 60 minutes.
  • the labeling rate of the 89 Zr complex in this example was 100%.
  • Example 1-3 The above formula (1-10) was used as the ligand. Labeling was performed under the same conditions as in Example 1-1. The labeling rate of the 89 Zr complex in this example was 100%.
  • Examples 1-4 The above formula (1-67) was used as the ligand.
  • the ligand was dissolved in a water/DMSO mixture (1:3) to obtain a solution containing 2.5 mmol/L of the above ligand. 1 ⁇ L of this solution, 16.6 ⁇ L of a solution containing 89 Zr ions as a radioactive metal source (solvent: 0.1 mol/L hydrochloric acid, radioactivity concentration 345 MBq/mL), and 0.78 mol/L acetate buffer containing 150 mmol/L of gentisic acid A reaction mixture of 16.7 ⁇ L of liquid (pH: 5.5) and 15.7 ⁇ L of water was reacted at 37° C. to obtain a 89 Zr complex solution.
  • solvent 0.1 mol/L hydrochloric acid, radioactivity concentration 345 MBq/mL
  • 0.78 mol/L acetate buffer containing 150 mmol/L of gentisic acid
  • the reaction time was 60 minutes. Using thin layer chromatography (manufactured by Agilent, model number SGI0001, developing solvent: 0.1 mol / L EDTA solution (pH: 5.0)), all 89 Zr including unreacted 89 Zr (developed to the tip of the solvent) The percentage of the radioactivity count of the 89 Zr complex (origin component) to the radioactivity count was defined as the labeling rate.
  • the labeling rate of the 89 Zr complex in this example was 91%.
  • Examples 1-5 The above formula (1-71) was used as the ligand.
  • the ligand was dissolved in a water/DMSO mixture (1:1) to give a solution containing 2.5 mmol/L of the above ligand. 2 ⁇ L of this solution, 16.6 ⁇ L of a solution containing 89 Zr ions as a radioactive metal source (solvent: 0.1 mol/L hydrochloric acid, radioactivity concentration 96 MBq/mL), and 0.78 mol/L acetate buffer containing 150 mmol/L of gentisic acid A reaction mixture of 16.7 ⁇ L of liquid (pH: 5.5) and 14.7 ⁇ L of water was allowed to react at 37° C. to obtain a 89 Zr complex solution. The reaction time was 60 minutes. The labeling rate of the 89 Zr complex in this example calculated using thin layer chromatography in the same manner as in Example 1-1 was 96%.
  • Example 2-1 The above formula (1-3) was used as the ligand.
  • the ligand was dissolved in water to prepare a solution containing 10 mmol/L of the ligand. 20 ⁇ L of this solution, 100 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactivity concentration 27.5 MBq/mL), and 0.5 mol/L ammonium acetate buffer (pH 6.0).
  • a reaction mixture of 80 ⁇ L and 200 ⁇ L of water was allowed to react at room temperature to obtain a 225 Ac complex solution. The reaction time was 60 minutes.
  • the 225 Ac complex (The percentage of the radioactivity count of (developed to the tip of the solvent) was defined as the labeling rate.
  • the labeling rate of the 225 Ac complex in this example was 51%.
  • Example 2-2 The above formula (1-9) was used as the ligand.
  • the ligand was dissolved in water to prepare a solution containing 10 mmol/L of the ligand. 0.4 ⁇ L of this solution, 20 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactivity concentration 30.4 MBq/mL), and 0.5 mol/L ammonium acetate buffer (pH 6.0).
  • solvent 0.2 mol/L hydrochloric acid, radioactivity concentration 30.4 MBq/mL
  • ammonium acetate buffer pH 6.0
  • the percentage of radioactive counts of the 225 Ac complex (developed to the solvent tip) relative to the total 225 Ac radioactive counts including unreacted 225 Ac (origin component) was calculated. labeling rate.
  • the labeling rate of the 225 Ac complex in this example was 94%.
  • Example 2-3 The above formula (1-10) was used as the ligand. The procedure was carried out under the same conditions as in Example 2-1, except that the ligand was dissolved in water to obtain a solution containing 10 mmol/L of the above ligand. The labeling rate of the 225 Ac complex in this example was 98%.
  • Example 2-4 The above formula (1-10) was used as the ligand.
  • the ligand was dissolved in water to prepare a solution containing 1 mmol/L of the above ligand. 0.4 ⁇ L of this solution, 20 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactivity concentration 24.6 MBq/mL), and 0.5 mol/L ammonium acetate buffer (pH 6.0).
  • solvent 0.2 mol/L hydrochloric acid, radioactivity concentration 24.6 MBq/mL
  • ammonium acetate buffer pH 6.0
  • the percentage of radioactive counts of the 225 Ac complex (developed to the solvent tip) relative to the total 225 Ac radioactive counts including unreacted 225 Ac (origin component) was calculated. labeling rate.
  • the labeling rate of the 225 Ac complex in this example was 84%.
  • Example 2-5 The above formula (1-67) was used as the ligand.
  • the ligand was dissolved in a water/DMSO mixture (1:3) to obtain a solution containing 2.5 mmol/L of the above ligand.
  • 1.6 ⁇ L of this solution 20 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactivity concentration 13.5 MBq/mL), and 0.5 mol/L MES buffer (pH 7.5). ) and 42.4 ⁇ L of water were reacted at 37° C. to obtain a 225 Ac complex solution.
  • the reaction time was 60 minutes.
  • the percentage of radioactive counts of the 225 Ac complex (developed to the solvent tip) relative to the total 225 Ac radioactive counts including unreacted 225 Ac (origin component) was calculated. labeling rate.
  • the labeling rate of the 225 Ac complex in this example was 94%.
  • Example 2-6 The above formula (1-68) was used as the ligand.
  • the ligand was dissolved in DMSO to prepare a solution containing 10 mmol/L of the above ligand. 0.4 ⁇ L of this solution, 20 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactivity concentration 18.8 MBq/mL), and 0.5 mol/L MES buffer (pH 7.5). ) and 43.6 ⁇ L of water were reacted at 37° C. to obtain a 225 Ac complex solution. The reaction time was 60 minutes.
  • Examples 2-7 The above formula (1-71) was used as the ligand.
  • the ligand was dissolved in a water/DMSO mixture (1:3) to obtain a solution containing 2.5 mmol/L of the above ligand.
  • 16 ⁇ L of this solution 20 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactivity concentration 36.4 MBq/mL), and 0.5 mol/L ammonium acetate buffer (pH 6.0).
  • a reaction mixture of 16 ⁇ L and 28 ⁇ L of water was allowed to react at room temperature to obtain a 225 Ac complex solution. The reaction time was 60 minutes.
  • the percentage of radioactivity counts of the 225 Ac complex (developed to the solvent tip) relative to the total 225 Ac radioactivity counts including unreacted 225 Ac (origin component) was calculated. labeling rate.
  • the labeling rate of the 225 Ac complex in this example was 96%.
  • Gly is glycine
  • Pro is proline
  • Asp is aspartic acid
  • Cys is cysteine
  • Ala is alanine
  • Tyr is tyrosine
  • His is histidine
  • Glu glutamic acid
  • Leu leucine
  • Val means valine
  • Trp means tryptophan
  • Phe means phenylalanine.
  • a solution containing the peptide DSG (disuccinimidyl glutarate) and an antibody (Trastuzumab, manufactured by Roche, model number H5152H02) was added at 0.02 mol/ The mixture was mixed with L acetic acid/sodium acetate buffer (pH 6.0) and allowed to react at room temperature for 60 minutes to obtain a solution containing the peptide-modified antibody.
  • This peptide-modified antibody is obtained by site-specifically modifying the Fc region of the antibody with the above peptide.
  • Synthesis Example 14 ⁇ Synthesis of ligand-modified antibody> The above formula (1-67) was used as the ligand.
  • the ligand was dissolved in a water/DMSO mixture (1:3) to obtain a solution containing 2.5 mmol/L of the above ligand. 47.8 ⁇ L of this solution and 400 ⁇ L of the peptide-modified antibody (15 mg/mL) were mixed, and the azide group at the terminal of the peptide and the DBCO (dibenzocyclooctyl) group of the ligand were click-reacted at 37°C. The reaction time was 60 minutes. Further, the ligand-modified antibody solution was purified using an ultrafiltration filter (manufactured by Merck, model number: UFC803096).
  • Example 3-1 The ligand-modified antibody described above was used as the ligand.
  • the ligand-modified antibody was dissolved in 20 mM MES buffer (pH 6.0) to obtain a solution containing 150 ⁇ mol/L of the above ligand. 26.7 ⁇ L of this solution, 20 ⁇ L of a solution containing 225 Ac ions as a radioactive metal source (solvent: 0.2 mol/L hydrochloric acid, radioactive concentration 18.2 MBq/mL), and 0.5 mol/L MES buffer (pH 6.0 ) and 17.3 ⁇ L of water were reacted at room temperature to obtain a 225 Ac complex solution. The reaction time was 60 minutes.
  • the percentage of radioactivity counts of the 225 Ac complex (origin component) relative to the total 225 Ac radioactivity counts including unreacted 225 Ac (developed to the solvent front) was calculated. labeling rate.
  • the labeling rate of the 225 Ac complex in this example was 96%.

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Abstract

L'invention concerne un complexe métallique radioactif. Ce complexe métallique radioactif possède un élément métallique radioactif et un ligand dérivé d'un composé représenté par la formule (1). L'élément métallique radioactif consiste en ８９Ｚｒ ou ２２５Ａｃ.　(1) [Dans la formule (1), n représente un entier de 0 à 3.　Ｑ１, Ｑ２, Ｑ３ et Ｑ４ représentent un groupe choisi dans un ensemble (A), un groupe choisi dans un ensemble (B), un groupe représenté par la formule (C1), ou similaire. Au moins un élément parmi Ｑ１, Ｑ２, Ｑ３ et Ｑ４ consiste en un groupe choisi dans un ensemble (A), et parmi Ｑ１, Ｑ２, Ｑ３ et Ｑ４ le nombre de groupes représentés par la formule (B3) dans l'ensemble (B) est compris entre 0 et 2. L'ensemble (A) est constitué par un groupe représenté par la formule (A1), ou similaire. (A1) L'ensemble (B) est constitué par un groupe représenté par la formule (B1), un groupe représenté par la formule (B3), ou similaire.　（Ｂ１）（Ｂ３）　Ｚ１, Ｚ２, Ｚ３ et Ｚ４ représentent un groupe de liaison divalent. R représente également un groupe de liaison divalent.]
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