WO2023162946A1 - 放射標識されたＦＡＰα親和性化合物およびその用途 - Google Patents

放射標識されたＦＡＰα親和性化合物およびその用途 Download PDF

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WO2023162946A1
WO2023162946A1 PCT/JP2023/006110 JP2023006110W WO2023162946A1 WO 2023162946 A1 WO2023162946 A1 WO 2023162946A1 JP 2023006110 W JP2023006110 W JP 2023006110W WO 2023162946 A1 WO2023162946 A1 WO 2023162946A1
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compound
group
cancer
formula
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French (fr)
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宜史 白神
悠一郎 角永
加珠子 兼田
直史 渡部
浩一 深瀬
敦史 下山
彩佳 麻生
拓 吉矢
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University of Osaka NUC
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Osaka University NUC
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Priority to AU2023223808A priority patent/AU2023223808A1/en
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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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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 radiolabeled FAP ⁇ affinity compound useful as a therapeutic and/or diagnostic agent for tumors or cancers, and a method for producing the same.
  • pancreatic cancer lesions cancer cells are thickly covered with a connective tissue called stroma, so even if anticancer drugs are administered, they are blocked by the stroma and cannot reach the cancer cells. As a result, the 5-year survival rate for pancreatic cancer is extremely low at less than 10%.
  • the stroma is a supporting tissue that supplies nutrients to cancer cells and supports their structure, and many solid cancers other than pancreatic cancer also develop stroma. Therefore, there is a demand for the development of a treatment method for cancers with abundant stroma.
  • Cancer-associated fibroblasts (CAF) that constitute the stroma highly express fibroblast activation protein ⁇ (FAP ⁇ ). Therefore, drugs that can specifically bind to FAP ⁇ can be expected to be effective in diagnosing solid cancers, and if they can destroy stroma and tumors, they can be expected to be effective in treating solid cancers.
  • CAF Cancer-associated fibroblasts
  • FAP ⁇ fibroblast activation protein ⁇
  • a chelating agent such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 68 Ga
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • 68 Ga halved Disclosed are agents comprising complex moieties formed with radionuclides such as 90 Y (half-life 64.0 hours), 203 Pb (half-life 51.9 hours), and the agents are It is stated that it can be used for imaging diagnosis of cancer. Drugs in which 18 F is introduced by chemical bonding have also been reported.
  • Patent Document 2 discloses ⁇ -(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ( DOTA-GA) and 111 In (half-life of 67.3 hours) are disclosed, and it is stated that the drug can be used for diagnostic imaging of cancer.
  • DOTA-GA ⁇ -(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • 111 In half-life of 67.3 hours
  • Non-Patent Document 1 chelating agents such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 64 Agents containing complex moieties formed with Cu or 225 Ac are disclosed and demonstrated to be effective in treating and imaging pancreatic cancer in human pancreatic cancer xenograft mice.
  • chelating agents such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 64 Agents containing complex moieties formed with Cu or 225 Ac are disclosed and demonstrated to be effective in treating and imaging pancreatic cancer in human pancreatic cancer xenograft mice.
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • 64 Agents containing complex moieties formed with Cu or 225 Ac are disclosed and demonstrated to be effective in treating and imaging pancreatic cancer in human pancreatic cancer
  • 211 At which is an ⁇ -emitting nuclide
  • 225 Ac which is the same ⁇ -emitting nuclide ( 211 At: 7.2 hours, 225 Ac: 10 days)
  • drugs labeled with 211 At has a short duration of action and can be treated on an outpatient basis.
  • it since it is a short-lived nuclide, it has the advantage of reducing the risk of prolongation of side effects, and is expected to be useful as a new anticancer agent.
  • the present invention is useful for the treatment and diagnosis of tumors or cancers that specifically bind to FAP ⁇ and express FAP ⁇ , such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, Effective in the treatment and diagnosis of solid cancers such as ovarian cancer, colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, and liver cancer (particularly pancreatic cancer), and the risk of prolonged side effects is reduced.
  • the aim is to provide a small drug.
  • a novel compound radiolabeled with a short-lived nuclide such as 211 At represented by the following formula (I-1) or (I-2). , which binds specifically to FAP ⁇ and treats and diagnoses FAP ⁇ -expressing tumors or cancers, such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer , colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, and other solid cancers (especially pancreatic cancer).
  • tumors or cancers such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer , colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, and other solid cancers (especially pancreatic cancer).
  • the present invention is as follows.
  • a radioactive moiety comprising an aryl group substituted with a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br, and fibroblast activation protein alpha (FAP ⁇ : a conjugate comprising a bioactive moiety having affinity for the Fibroblast activation protein ⁇ ).
  • FAP ⁇ a conjugate comprising a bioactive moiety having affinity for the Fibroblast activation protein ⁇ .
  • a radiolabeled compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof hereinafter also referred to as compound (I-1)).
  • X 1 represents a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br;
  • Ar 1 represents a C 6-14 aryl group;
  • p1 R a1 and R b1 each independently represents a hydrogen atom or a C 1-6 alkyl group;
  • m1 R c1 independently represents a C 1-6 alkyl group or a hydroxy group;
  • n1 R d1 each independently represent a halogen atom;
  • Z 1 represents an oxygen atom, a sulfur atom or NR f1 (wherein R f1 represents a hydrogen atom or a C 1-3 alkyl group);
  • L1 is (1) *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * indicates the binding site with CO, ** indicates the binding site with Z1 , L a1 is (i) a C 1-6
  • Z 1 is an oxygen atom or a sulfur atom
  • L 1 is represented by *-L d1 -L c1 -L b1 -L a1 -** (each symbol in the formula has the same meaning as above);
  • Z 1 is NR f1 (the symbols in the formula are as defined above), and L 1 is *-(NH-A b1 -CO) s1 -** (the symbols in the formula are as defined above);
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is a C 1-6 alkylene group, L b1 is a bond or -CO-, L c1 is a divalent cyclic amino group, and L d1 is (i) combination; (ii) *-(NH-A a1 -CO) r1 -*** (each symbol in the formula is as defined above), or (iii) *-NH-B a1 -OB b1 -CO-*** (Each symbol in the formula has the same meaning as above.) is.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is —CH 2 —(CH 2 —O—CH 2 ) q1 —CH 2 — (the symbols in the formula are as defined above); L b1 is a bond, L c1 is NR g1 (the symbols in the formula are as defined above), an oxygen atom or a sulfur atom, and L d1 is a bond. )
  • a radiolabeled compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof hereinafter also referred to as compound (I-2)).
  • X 2 represents a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br;
  • Ar 2 represents a C 6-14 aryl group;
  • p2 R a2 and R b2 each independently represent a hydrogen atom or a C 1-6 alkyl group;
  • m2 R c2 independently represent a C 1-6 alkyl group or a hydroxy group;
  • n2 R d2 are each independently a halogen atom;
  • Z 2 represents an oxygen atom, a sulfur atom or NR f2 (wherein R f2 represents a hydrogen atom or a C 1-3 alkyl group);
  • L2 is (1) *-L c2 -L b2 -L a2 -** (In the formula, * indicates the binding site with Re2 , ** indicates the binding site with Z2 , L a2 is (i) a C 1-6 alkylene group
  • R e2 represents a C 1-6 alkyl-carbonyl group;
  • the group R e2 -L 2 -Z 2 - represents a hydrogen atom;
  • L 3 is ***-(NH-A b2 -CO) s2 -**** (In the formula, *** indicates the binding site with CO, *** indicates the binding site with NH, each of the s2 NH-A b2 -CO independently represents an amino acid residue;
  • s2 represents an integer of 0-3.
  • R represents a hydrogen atom or a C 1-3 alkyl group
  • p2 represents an integer from 0 to 3
  • m2 represents an integer of 0 to 3
  • n2 represents an integer of 0-3.
  • Z 2 is an oxygen atom or a sulfur atom
  • L 2 is a linker represented by *-L c2 -L b2 -L a2 -** (each symbol in the formula has the same meaning as above);
  • Z 2 is NR f2 (the symbols in the formula are as defined above), and L 2 is *-(NH-A a2 -CO) r2 -** (each symbol in the formula is The compound or a pharmaceutically acceptable salt thereof according to [11] above, which is a linker represented by (synonymous).
  • a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [11] to [15] above, and a pharmaceutically acceptable carrier.
  • Tumor or cancer expressing fibroblast activation protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor , thyroid cancer, uterine cancer or liver cancer, the therapeutic agent according to the above [17]. [19] 16.
  • Tumor or cancer expressing fibroblast activation protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor , thyroid cancer, uterine cancer or liver cancer, the compound or a pharmaceutically acceptable salt thereof according to the above [19].
  • Fibroblast activation protein ⁇ in a mammal characterized in that a therapeutically effective amount of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof is administered to the mammal ( FAP ⁇ : A method of treating a tumor or cancer expressing Fibroblast activation protein ⁇ ).
  • FAP ⁇ A method of treating a tumor or cancer expressing Fibroblast activation protein ⁇ .
  • Tumor or cancer expressing fibroblast activation protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor , thyroid cancer, uterine cancer or liver cancer.
  • Tumor or cancer expressing fibroblast activation protein alpha is pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colorectal cancer, neuroendocrine tumor , thyroid cancer, uterine cancer or liver cancer.
  • a compound represented by formula (II-1) or a salt thereof (hereinafter also referred to as compound (II-1)).
  • Y 1 represents a boryl group (-B(OH) 2 ) or an ester group thereof;
  • Ar 1 represents a C 6-14 aryl group;
  • p1 R a1 and R b1 each independently represents a hydrogen atom or a C 1-6 alkyl group;
  • m1 R c1 independently represents a C 1-6 alkyl group or a hydroxy group;
  • n1 R d1 each independently represents a halogen atom;
  • Z 1 represents an oxygen atom, a sulfur atom or NR f1 (wherein R f1 represents a hydrogen atom or a C 1-3 alkyl group);
  • L1 is (1) *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * indicates the binding site with CO, ** indicates the binding site with Z1 ,
  • L a1 is (i) a C 1-6 alkylene group, or (ii) —CH 2 —(CH
  • a radiolabeled compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as compound (II-2)).
  • Y 2 represents a boryl group (-B(OH) 2 ) or an ester group thereof;
  • Ar 2 represents a C 6-14 aryl group;
  • p2 R a2 and R b2 each independently represent a hydrogen atom or a C 1-6 alkyl group;
  • m2 R c2 independently represent a C 1-6 alkyl group or a hydroxy group;
  • n2 R d2 are each independently a halogen atom;
  • Z 2 represents an oxygen atom, a sulfur atom or NR f2 (wherein R f2 represents a hydrogen atom or a C 1-3 alkyl group);
  • L2 is (1) *-L c2 -L b2 -L a2 -** (In the formula, * indicates the binding site with Re2 , ** indicates the binding site with Z2 ,
  • L a2 is (i) a C 1-6 alkylene group, or (ii) —CH 2 —(CH 2 —O
  • R e2 represents a C 1-6 alkyl-carbonyl group;
  • the group R e2 -L 2 -Z 2 - represents a hydrogen atom;
  • L 3 is ***-(NH-A b2 -CO) s2 -**** (In the formula, *** indicates the binding site with CO, *** indicates the binding site with NH, each of the s2 NH-A b2 -CO independently represents an amino acid residue;
  • s2 represents an integer of 0-3.
  • R represents a hydrogen atom or a C 1-3 alkyl group
  • p2 represents an integer from 0 to 3
  • m2 represents an integer of 0 to 3
  • n2 represents an integer of 0-3.
  • X 1 represents a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br; Y 1 represents a boryl group (-B(OH) 2 ) or an ester group thereof; Ar 1 represents a C 6-14 aryl group; p1 R a1 and R b1 each independently represents a hydrogen atom or a C 1-6 alkyl group; m1 R c1 independently represents a C 1-6 alkyl group or a hydroxy group; n1 R d1 each independently represents a halogen atom; Z 1 represents an oxygen atom, a sulfur atom or NR f1 (wherein R f1 represents a hydrogen atom or a C 1-3 alkyl group); L1 is (1) *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * indicates the binding site with CO, ** indicates the binding site with
  • Step 1 A compound represented by formula (II-1) or a salt thereof is selected from alkali metal iodides, alkali metal bromides, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide reacted with a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br in the presence of a reagent in water to give obtaining a radiolabeled compound or a pharmaceutically acceptable salt thereof.
  • a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br in the presence of a reagent in water to give obtaining a radiolabeled compound or a pharmaceutically acceptable salt thereof.
  • X 2 represents a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br;
  • Y 2 represents a boryl group (-B(OH) 2 ) or an ester group thereof;
  • Ar 2 represents a C 6-14 aryl group;
  • p2 R a2 and R b2 each independently represent a hydrogen atom or a C 1-6 alkyl group;
  • m2 R c2 independently represent a C 1-6 alkyl group or a hydroxy group;
  • n2 R d2 are each independently a halogen atom;
  • Z 2 represents an oxygen atom, a sulfur atom or NR f2 (wherein R f2 represents a hydrogen atom or a C 1-3 alkyl group);
  • L2 is (1) *-L c2 -L b2 -L a2 -** (In the formula, * indicates the binding site with Re2 ,
  • R e2 represents a C 1-6 alkyl-carbonyl group;
  • the group R e2 -L 2 -Z 2 - represents a hydrogen atom;
  • L 3 is ***-(NH-A b2 -CO) s2 -**** (In the formula, *** indicates the binding site with CO, *** indicates the binding site with NH, each of the s2 NH-A b2 -CO independently represents an amino acid residue;
  • s2 represents an integer of 0-3.
  • Step 2 The compound represented by formula (II-2) or a salt thereof is selected from alkali metal iodides, alkali metal bromides, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide reacted with a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br in the presence of a reagent in water to give obtaining a radiolabeled compound or a pharmaceutically acceptable salt thereof.
  • a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br in the presence of a reagent in water to give obtaining a radiolabeled compound or a pharmaceutically acceptable salt thereof.
  • the treatment and diagnosis of tumors or cancers that specifically bind to FAP ⁇ and express FAP ⁇ such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer.
  • cancer ovarian cancer, colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, and other solid cancers (especially pancreatic cancer).
  • pancreatic cancer sarcoma
  • esophageal cancer lung cancer
  • breast cancer breast cancer
  • prostate cancer head and neck cancer
  • cancer ovarian cancer, colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, and other solid cancers (especially pancreatic cancer).
  • FIG. 1 is a diagram showing an outline of basic operations for radiolabeling boronic acid compounds in Examples 1 to 14.
  • FIG. FIG. 2 is a diagram showing the analysis results of the reaction solution in Example 1 by thin layer chromatography (TLC).
  • FIG. 3 is a diagram showing the analysis results of the reaction solution in Example 2 by thin layer chromatography (TLC).
  • (a) is a diagram showing the analysis results in the case of 1 ⁇ g of raw material
  • (b) is a diagram showing the analysis results in the case of 10 ⁇ g of raw material.
  • FIG. 4 is a diagram showing the analysis results of the reaction solution in Example 3 by thin layer chromatography (TLC).
  • FIG. 5 is a diagram showing the analysis results of the reaction solution in Example 4 by thin layer chromatography (TLC).
  • FIG. 6 is a diagram showing the analysis results of the reaction solution in Example 5 by thin layer chromatography (TLC).
  • FIG. 7 is a diagram showing the analysis results of the reaction solution in Example 6 by thin layer chromatography (TLC).
  • (a) is a diagram showing the analysis results in the case of 1 ⁇ g of raw material, and (b) is a diagram showing the analysis results in the case of 10 ⁇ g of raw material.
  • FIG. 8 is a diagram showing the analysis results of the reaction solution in Example 7 by thin layer chromatography (TLC).
  • FIG. 9 is a diagram showing the analysis results of the reaction solution in Example 8 by thin layer chromatography (TLC).
  • FIG. 10 is a diagram showing the analysis results of the reaction solution in Example 9 by thin layer chromatography (TLC).
  • FIG. 11 is a diagram showing the analysis results of the reaction solution in Example 10 by thin layer chromatography (TLC).
  • (a) is a diagram showing the analysis results in the case of 10 ⁇ g of raw material
  • (b) is a diagram showing the analysis results in the case of 100 ⁇ g of raw material.
  • FIG. 12 is a diagram showing the analysis results of the reaction solution in Example 11 by thin layer chromatography (TLC).
  • 13 is a diagram showing the analysis results of the reaction solution by thin layer chromatography (TLC) in Example 12.
  • FIG. 14 is a diagram showing the analysis results of the reaction solution by thin layer chromatography (TLC) in Example 13.
  • TLC thin layer chromatography
  • FIG. 15 is a diagram showing the analysis results of the reaction solution in Example 14 by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • FIG. 16 is a diagram showing the analysis results of the reaction solution in Example 15 by thin layer chromatography (TLC).
  • 17 is a diagram showing the results of thin-layer chromatography (TLC) analysis of the reaction solution and the eluate in Example 16.
  • TLC thin layer chromatography
  • FIG. 18 is a graph showing the uptake of 211 At-labeled FAPI derivatives into FAP ⁇ /293 cells.
  • FIG. 19(a) is a graph showing the uptake of 211 At-labeled FAPI derivatives into lung cancer cells (A549), and FIG. 19(b) shows the uptake of 211 At-labeled FAPI derivatives into breast cancer cells (MDA-MB-231).
  • (a) is a graph showing tumor growth in mice
  • (b) is a graph showing changes in body weight.
  • halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • C 1-3 alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms, examples of which include methyl, ethyl, propyl and isopropyl. be done.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl etc.
  • it is a “C 1-3 alkyl group”.
  • aryl group means an aromatic cyclic hydrocarbon group, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl and the like. mentioned. A C 6-14 aryl group is preferred, and a phenyl group is more preferred. As used herein, “C 6-14 aryl group” means an aromatic cyclic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl , 1-anthryl, 2-anthryl, 9-anthryl and the like. A phenyl group is preferred.
  • C 6-14 aryl-C 1-3 alkyl group means the above “C 1-3 alkyl group” substituted with the above “C 6-14 aryl group", for example benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 2-(1-naphthyl)ethyl and the like.
  • a phenyl-C 1-3 alkyl group is preferred.
  • phenyl-C 1-3 alkyl group means the above “C 1-3 alkyl group” substituted with phenyl, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl and the like.
  • C 1-6 alkyl-carbonyl group refers to a group represented by the formula R'C(O)-- (wherein R' represents a C 1-6 alkyl group). Examples include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl and the like.
  • C 1-6 alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms, such as —CH 2 —, —(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -CH(CH 3 )-, -C(CH 3 ) 2- , -CH(C 2 H 5 )-, -CH(C 3 H 7 )-, -CH(CH(CH 3 ) 2 )-, -(CH(CH 3 )) 2 -, -CH 2 - CH(CH 3 )—, —CH(CH 3 )—CH 2 —, —CH 2 —CH 2 —C(CH 3 ) 2 —, —C(CH 3 ) 2 —CH 2 —CH 2 —, —CH 2 -CH 2 -CH 2 -CH 2 -CH 2
  • C 2-4 alkylene group means a linear or branched alkylene group having 2 to 4 carbon atoms, such as —(CH 2 ) 2 —, — (CH 2 ) 3 -, -(CH 2 ) 4 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH(C 3 H 7 ) -, -CH(CH(CH 3 ) 2 )-, -(CH(CH 3 )) 2 -, -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 -, etc. .
  • divalent cyclic amino group means a divalent group excluding H from the amino group (-NH-) of a cyclic amine and one H from other sites, Specifically, it is represented by the following structure.
  • Ring D in addition to one nitrogen atom, may contain a heteroatom selected from an oxygen atom, a sulfur atom or a nitrogen atom, and may have a substituent, a 3- to 8-membered represents a saturated or unsaturated cyclic amine, W represents a carbon atom, CR h (wherein R h represents a hydrogen atom or a C 1-3 alkyl group) or a nitrogen atom. ) W is preferably a nitrogen atom. That is, the "divalent cyclic amino group” is preferably a divalent cyclic diamino group.
  • divalent cyclic diamino groups include piperazine-1,4-diyl, dihydropyrazine-1,4-diyl, tetrahydropyrazine-1,4-diyl, tetrahydropyrimidine-1,3-diyl, hexahydropyrimidine -1,3-diyl, dihydropyridazine-1,2-diyl, tetrahydropyridazine-1,2-diyl, hexahydropyridazine-1,2-diyl, 1,2-diazepane-1,2-diyl, 1,3 -diazepane-1,3-diyl, 1,4-diazepane-1,4-diyl, dihydro-1,2-diazepine-1,2-diyl, tetrahydro-1,2-diazepine-1,2-diyl, hexa
  • amino acid residue means a divalent group obtained by removing H from the amino group of an amino acid and OH from the carboxy group.
  • the amino acid in the "amino acid residue” is not particularly limited as long as it has an amino group and a carboxy group, and may be natural (L-type), non-natural (D-type), or artificial amino acids. Further, the above amino acid may be any of ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid and the like.
  • the "amino acid residue” may be a cyclic amino acid residue as shown below.
  • ⁇ -amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, arginine, histidine, glutamine, asparagine, phenylalanine, tyrosine, ⁇ -methyltyrosine, tryptophan, ornithine, thyroxine, proline, 3,4-dihydroxyphenylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine, ⁇ -aminobutyric acid, norvaline, norleucine, homonorleucine, 1,2,4- triazole-3-alanine, 2-aminoadipic acid, propargylglycine, allylglycine, ⁇ -cyclobutylmethylg
  • amino acids described above When the amino acid described above has a functional group in its side chain, the functional group may be protected/modified.
  • amino acids include ⁇ -Boc-lysine, ⁇ -Z-lysine, ⁇ -Fmoc-lysine, ⁇ -Bn-aspartic acid, ⁇ -Bn-glutamic acid and the like.
  • a divalent group in which H is removed from the amino group of such an amino acid and OH is removed from the carboxy group is also included in the “amino acid residue”.
  • the above-described amino acids may have substituents on their side chains.
  • amino acids include 4-azidophenylalanine, 3-azidophenylalanine, 3-azidotyrosine, 2-azidotyrosine and their ⁇ -methyl amino acids.
  • a divalent group in which H is removed from the amino group of such an amino acid and OH is removed from the carboxy group is also included in the “amino acid residue”.
  • the steric configuration of the amino acids described above is not particularly limited, and may be any of D-, L-, and DL-configurations (that is, R-, S-, and R/S-configurations).
  • a divalent residue derived from an amino sugar or a derivative thereof means a divalent group obtained by removing H from the amino group and H from the hydroxyl group of the amino sugar or its derivative.
  • the amino sugar in the "bivalent residue derived from amino sugar or derivative thereof” refers to a sugar in which at least one of the hydroxyl groups is replaced with an amino group, for example, monosaccharides such as glucosamine and galactosamine, and monosaccharides thereof and is not particularly limited as long as it is a saccharide having a hydroxyl group and an amino group.
  • Derivatives of amino sugars include those in which the hydroxyl groups (not involved in binding) of the above amino sugars are protected/modified.
  • the steric configuration of the above amino sugar or derivative thereof is not particularly limited.
  • boryl group (--B(OH) 2 )
  • ester group of boryl group includes, for example, groups shown below.
  • R 4 represents a C 1-6 alkyl group.
  • protected amino acid residue means an amino acid residue whose functional group is protected when the amino acid residue has a functional group. When it has an amino group, it is protected with an amino-protecting group such as a tert-butoxycarbonyl group (Boc group), and when it has a carboxy group, it is protected with a carboxy-protecting group such as a tert-butyl group.
  • Boc group tert-butoxycarbonyl group
  • carboxy-protecting group such as a tert-butyl group.
  • hydroxy protecting group includes, for example, benzyl group, p-methoxybenzyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group, trityl group, tert-butyl group, tert-butyldimethylsilyl group ( TBS group), tetrahydropyranyl group, benzylidene group (formation of benzylidene acetal), isopropylidene group (formation of dimethylacetal), acetyl group, benzoyl group and the like.
  • amino-protecting group includes, for example, 9-fluorenylmethyloxycarbonyl group (Fmoc group), tert-butoxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz group), trichloroethoxy A carbonyl group (Troc group) and the like can be mentioned.
  • carboxy-protecting group includes, for example, tert-butyl group, benzyl group, C 1-2 alkyl group (methyl group, ethyl group) and the like.
  • the "mercapto-protecting group” includes, for example, a benzyl group, p-methoxybenzyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group, trityl group, tert-butyl group, tert-butyldimethylsilyl group ( TBS group), tetrahydropyranyl group, isopropylidene group (formation of dimethylthioacetal), acetyl group, benzoyl group and the like.
  • the conjugates of the invention are A radioactive moiety comprising an aryl group substituted with a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br, and fibroblast activation protein alpha (FAP ⁇ : Fibroblast activation protein ⁇ ) contains a bioactive moiety that has affinity.
  • a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br
  • FAP ⁇ Fibroblast activation protein alpha
  • the aryl group is preferably a C 6-14 aryl group, more preferably a phenyl group.
  • the aryl group includes 211 At ( ⁇ -ray emitting nuclide), 210 At ( ⁇ -ray emitting nuclide), 131 I ( ⁇ -ray emitting nuclide), 125 I (X-ray emitting nuclide), 124 I (positron emitting nuclide), 123 I ( ⁇ -ray emitting), 77 Br (Auger electron emitting) and 76 Br (positron emitting).
  • substitution position is not particularly limited, for example, when the aryl group is a phenyl group, the 3-position or 4-position is preferred.
  • Radioactive moieties containing such aryl groups include radionuclide - substituted aryl - C 0- It preferably contains 3 alkyl groups (preferably aryl-C 1-3 alkyl groups, more preferably phenyl-C 1-3 alkyl groups). Specifically, the following formula:
  • X represents a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br;
  • Ar represents a C 6-14 aryl group;
  • p R a and R b each independently represents a hydrogen atom or a C 1-6 alkyl group;
  • each of the m R c independently represents a substituent (eg, a C 1-6 alkyl group or a hydroxy group);
  • p represents an integer of 0 to 3 (preferably an integer of 1 to 3);
  • m represents an integer of 0 to 3;
  • Radioactive moieties containing structures represented by are preferred.
  • physiologically active portion is not limited as long as it has affinity for fibroblast activation protein ⁇ . Preferred, in particular, the following formula:
  • One embodiment of the conjugate of the present invention includes a radiolabeled compound (I-1).
  • X 1 is 211 At ( ⁇ -ray emitting nuclide), 210 At ( ⁇ -ray emitting nuclide), 131 I ( ⁇ -ray emitting nuclide), 125 I (X-ray emitting nuclide), 124 I (positron emitting nuclide), 123 I (gamma-emitting radionuclides), 77 Br (Auger electron-emitting radionuclides) and 76 Br (positron-emitting radionuclides) are shown.
  • the half-lives of these radionuclides are 7.2 hours for 211 At, 8.3 hours for 210 At, 8.04 days for 131 I, 59.4 days for 125 I, 4.2 days for 124 I, 123 13.2 hours for I, 57 hours for 77 Br and 16 hours for 76 Br.
  • the bonding position of X 1 on Ar 1 is not particularly limited, for example, when Ar 1 is a phenyl group, the 3-position or 4-position is preferred.
  • Ar 1 each represents a C 6-14 aryl group. In one aspect, Ar 1 is preferably a phenyl group. Each m1 R c1 independently represents a C 1-6 alkyl group (eg, methyl) or a hydroxy group. m1 represents an integer of 0-3. In one aspect, m1 is preferably zero.
  • p1 R a1 and R b1 each independently represents a hydrogen atom or a C 1-6 alkyl group. In one aspect, p1 R a1 and R b1 are preferably hydrogen atoms. p1 represents an integer of 1-3. In one aspect, p1 is preferably 1 or 2 from the viewpoint of reaction yield and stability.
  • n1 R d1 independently represents a halogen atom.
  • n1 R d1 are preferably fluorine atoms.
  • n1 represents an integer of 0-3.
  • n1 is preferably an integer of 0-2.
  • Z 1 represents an oxygen atom, a sulfur atom or NR f1 (symbols in the formulas are as defined above).
  • L1 is (1) *-L d1 -L c1 -L b1 -L a1 -** (Each symbol in the formula has the same meaning as above.)
  • a linker represented by or (2) *-(NH-A b1 -CO) s1 -** (Each symbol in the formula has the same meaning as above.) indicates a linker represented by .
  • Z 1 and L 1 include the following aspects (A1) and (B1).
  • A1) Z 1 is an oxygen atom or a sulfur atom (preferably an oxygen atom), and L 1 is *-L d1 -L c1 -L b1 -L a1 -** (each symbol in the formula is is synonymous with).
  • B1) Z 1 is NR f1 (the symbols in the formula are as defined above), and L 1 is *-(NH-A b1 -CO) s1 -** (the symbols in the formula are The same definition as above).
  • preferred aspects of L1 include the following aspects (A1-1) and (A1-2).
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -**
  • * is the binding site with CO
  • ** is the binding site with Z1
  • L a1 is a C 1-6 alkylene group
  • L b1 is a bond or -CO-
  • L c1 is a divalent cyclic amino group
  • L d1 is (i) combination;
  • *-(NH-A a1 -CO) r1 -*** (each symbol in the formula is as defined above), or
  • *-NH-B a1 -OB b1 -CO-*** (Each symbol in the formula has the same meaning as above.) is. )
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -**
  • * is the binding site with CO
  • ** is the binding site with Z1
  • L a1 is —CH 2 —(CH 2 —O—CH 2 ) q1 —CH 2 — (the symbols in the formula are as defined above)
  • L b1 is a bond
  • L c1 is NR g1 (the symbols in the formula are as defined above), an oxygen atom or a sulfur atom
  • L d1 is (i) combine, or (ii) *-NH-B a1 -OB b1 -CO-*** (each symbol in the formula has the same meaning as above); is. )
  • L a1 represents a C 1-6 alkylene group. In one aspect, L a1 is preferably a C 2-4 alkylene group. In the embodiment (A1-1), L c1 represents a divalent cyclic amino group. In one aspect, L c1 is preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group. In one embodiment, L c1 is more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1, 4-diyl.
  • the "divalent cyclic amino group” binds to L b1 and L d1 in formula (I-1), but has the following structure
  • the nitrogen atom may be bound to L b1 and W may be bound to L d1 , or the nitrogen atom may be bound to L d1 and W is bound to L b1 , but the nitrogen atom may be bound to L d1 and W binds to L b1 .
  • preferred aspects include the following aspects (A1-1-1) to (A1-1-5).
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b1 is a bond, L c1 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered a (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L d1 is a bond.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b1 is a bond, L c1 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered a (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L d1 is *—NH—B a1 —O— B b1 -CO-*** (Each symbol in the formula has the same meaning as above.) is.
  • -NH-B a1 -O- denotes a divalent residue derived from an aminosugar or derivative thereof.
  • -NH-B a1 -O- is preferably a divalent residue derived from monosaccharides such as glucosamine and galactosamine, more preferably a divalent residue derived from glucosamine.
  • B b1 represents a C 1-6 alkylene group. In one aspect, B b1 is preferably a C 2-4 alkylene group.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b1 is -CO-, L c1 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered a (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L d1 is a bond. ) The aspect which is a linker represented by.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b1 is a bond, L c1 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered a (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L d1 is *-(NH-A a1 -CO ) r1 -*** (each symbol in the formula has the same meaning as defined above). ) The aspect which is a divalent 3- to
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b1 is -CO-, L c1 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, more preferably a divalent 3- to 8-membered a (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl), and L d1 is *-(NH-A a1 -CO ) r1 -*** (each symbol in the formula has the same meaning as defined above). )
  • L d1 is *-
  • each r1 NH-A a1 -CO independently represents an amino acid residue.
  • r1 NH-A a1 -CO is preferably a 4-azidophenylalanine residue.
  • r1 represents an integer of 1-3.
  • r1 is preferably 1.
  • L d1 is preferably a 4-azidophenylalanine residue.
  • L a1 represents —CH 2 —(CH 2 —O—CH 2 ) q1 —CH 2 — (wherein q1 represents an integer of 0 to 5). In one aspect, q1 is preferably an integer of 1-3.
  • L c1 represents NR g1 (wherein R g1 represents a hydrogen atom or a C 1-3 alkyl group), an oxygen atom or a sulfur atom. In one aspect, R g1 is preferably a hydrogen atom. In one aspect, L c1 is preferably NR g1 (the symbols in the formula are as defined above), more preferably NH.
  • preferred aspects include the following aspects (A1-2-1) and (A1-2-2).
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is —CH 2 —(CH 2 —O—CH 2 ) q1 —CH 2 — (the symbols in the formula are as defined above); L b1 is a bond, L c1 is NR g1 (symbols in the formula are as defined above), and L d1 is a bond. ) The aspect which is a linker represented by.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (In the formula, * is the binding site with CO, ** is the binding site with Z1 , L a1 is —CH 2 —(CH 2 —O—CH 2 ) q1 —CH 2 — (the symbols in the formula are as defined above); L b1 is a bond, L c1 is NR g1 (the symbols in the formula are as defined above), and L d1 is *—NH—B a1 —O—B b1 —CO-*** (each symbol in the formula has the same meaning as above.) is. ) The aspect which is a linker represented by.
  • -NH-B a1 -O- denotes a divalent residue derived from an aminosugar or derivative thereof.
  • -NH-B a1 -O- is preferably a divalent residue derived from monosaccharides such as glucosamine and galactosamine, more preferably a divalent residue derived from glucosamine.
  • B b1 represents a C 1-6 alkylene group. In one aspect, B b1 is preferably a C 2-4 alkylene group.
  • Z 1 represents NR f1 (wherein R f1 represents a hydrogen atom or a C 1-3 alkyl group). In one aspect, R f1 is preferably a hydrogen atom. In one aspect, Z 1 is preferably NH. In the embodiment of (B1), L 1 is *-(NH-A b1 -CO) s1 -** (wherein s1 NH-A b1 -CO independently represent an amino acid residue). , s1 represents an integer from 1 to 3.). In one aspect, s1 NH-A b1 -CO is preferably a glycine residue. In one aspect, s1 is preferably 1. In one aspect, L1 is preferably a glycine residue.
  • the chiral C-atom in the radiolabeled compound (I-1) may be in the S or R configuration.
  • the radiolabeled compound (I-1) has optical isomers based on the chiral C atom, any optical isomer and any mixture thereof in any proportion may be ).
  • compound (I-1) has the following formula (I'-1):
  • radiolabeled compound (I-1) examples include the following.
  • Another embodiment of the conjugate of the present invention includes a radiolabeled compound (I-2).
  • X 2 is 211 At ( ⁇ -ray emitting nuclide), 210 At ( ⁇ -ray emitting nuclide), 131 I ( ⁇ -ray emitting nuclide), 125 I (X-ray emitting nuclide), 124 I (positron emitting nuclide), 123 I (gamma-emitting radionuclides), 77 Br (Auger electron-emitting radionuclides) and 76 Br (positron-emitting radionuclides) are shown.
  • the half-lives of these radionuclides are 7.2 hours for 211 At, 8.3 hours for 210 At, 8.04 days for 131 I, 59.4 days for 125 I, 4.2 days for 124 I, 123 13.2 hours for I, 57 hours for 77 Br and 16 hours for 76 Br.
  • the binding position of X2 on Ar2 is not particularly limited, but for example, when Ar2 is a phenyl group, the 3- or 4-position is preferred.
  • Ar 2 each represents a C 6-14 aryl group. In one aspect, Ar 2 is preferably a phenyl group. Each m2 R c2 independently represents a C 1-6 alkyl group (eg, methyl) or a hydroxy group. m2 represents an integer of 0-3. In one aspect, m2 is preferably zero.
  • p2 R a2 and R b2 each independently represent a hydrogen atom or a C 1-6 alkyl group. In one aspect, p2 R a2 and R b2 are preferably hydrogen atoms. p2 represents an integer of 0-3. In one aspect, p2 is preferably an integer from 1 to 3, more preferably 1.
  • n2 Rd2 's each independently represent a halogen atom.
  • n2 R d2 are preferably fluorine atoms.
  • n2 represents an integer of 0-3.
  • n2 is preferably an integer of 0-2.
  • Z 2 represents an oxygen atom, a sulfur atom or NR f2 (symbols in the formulas are as defined above).
  • L2 is (1) *-L c2 -L b2 -L a2 -** (Each symbol in the formula has the same meaning as above.)
  • a linker represented by or (2) *-(NH-A a2 -CO) r2 -** (Each symbol in the formula has the same meaning as above.) indicates a linker represented by .
  • Z 2 and L 2 include the following aspects (A2) and (B2).
  • A2) Z 2 is an oxygen atom or a sulfur atom, and L 2 is *-L c2 -L b2 -L a2 -** (each symbol in the formula has the same meaning as defined above); An embodiment that is a linker.
  • B2) Z 2 is NR f2 (the symbols in the formula are as defined above), and L 2 is *-(NH-A a2 -CO) r2 -** (each symbol in the formula has the same meaning as above).
  • preferred aspects of L2 include the following aspects (A2-1) and (A2-2).
  • L 2 is *-L c2 -L b2 -L a2 -** (In the formula, * is the binding site with CO, ** is the binding site with Z2 , L a2 is a C 1-6 alkylene group, L b2 is a bond or —CO—, and L c2 is a divalent cyclic amino group. )
  • L 2 is *-L c2 -L b2 -L a2 -** (In the formula, * is the binding site with CO, ** is the binding site with Z2 , L a2 is —CH 2 —(CH 2 —O—CH 2 ) q2 —CH 2 — (the symbols in the formula are as defined above); L b2 is a bond, and L c2 is NR g2 (the symbols in the formula are as defined above), an oxygen atom or a sulfur atom. ) The aspect which is a linker represented by.
  • L a2 represents a C 1-6 alkylene group. In one aspect, L a2 is preferably a C 2-4 alkylene group. In the embodiment (A2-1), L c2 represents a divalent cyclic amino group. In one aspect, L c2 is preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group. In one aspect, L c2 is more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1, 4-diyl.
  • the "divalent cyclic amino group” binds to L b2 and R e2 in formula (I-2), but has the following structure
  • the nitrogen atom may be bound to L b2 and W may be bound to Re2, or the nitrogen atom may be bound to R e2 and W may be bound to L b2 , but the nitrogen atom may be bound to R e2 and W binds to L b2 .
  • preferred aspects include the following aspects (A2-1-1) to (A2-1-2).
  • L 2 is *-L c2 -L b2 -L a2 -** (In the formula, * is the binding site with CO, ** is the binding site with Z2 , L a2 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b2 is a bond, and L c2 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group, and more It is preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl). ) The aspect which is a linker represented by.
  • L 2 is *-L c2 -L b2 -L a2 -** (In the formula, * is the binding site with CO, ** is the binding site with Z2 , L a2 is a C 1-6 alkylene group (preferably a C 2-4 alkylene group), L b2 is —CO— and L c2 is a divalent cyclic amino group (preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) cyclic diamino group , more preferably a divalent 3- to 8-membered (preferably 5- to 8-membered, more preferably 6-membered) saturated cyclic diamino group, particularly preferably piperazine-1,4-diyl). ) The aspect which is a linker represented by.
  • L a2 represents —CH 2 —(CH 2 —O—CH 2 ) q2 —CH 2 — (wherein q2 represents an integer of 0 to 5). In one aspect, q2 is preferably an integer of 1-3.
  • L c2 represents NR g2 (wherein R g2 represents a hydrogen atom or a C 1-3 alkyl group), an oxygen atom or a sulfur atom. In one aspect, R g2 is preferably a hydrogen atom. In one aspect, L c2 is preferably NR g2 (the symbols in the formula are as defined above), more preferably NH.
  • Z 2 represents NR f2 (wherein R f2 represents a hydrogen atom or a C 1-3 alkyl group). In one aspect, R f2 is preferably a hydrogen atom. In one aspect Z 2 is preferably NH. In the embodiment of (B2), L 2 is *-(NH-A a2 -CO) r2 -** (wherein r2 NH-A a2 -CO independently represent an amino acid residue). , r2 represents an integer of 1 to 3). In one aspect, r2 NH-A a2 -CO is preferably a glycine residue. In one aspect, r2 is preferably 1. In one aspect, L2 is preferably a glycine residue.
  • R e2 represents a C 1-6 alkyl-carbonyl group. In one aspect, R e2 is preferably an acetyl group. Alternatively, the group R e2 -L 2 -Z 2 - represents a hydrogen atom.
  • L 3 is ***-(NH-A b2 -CO) s2 -**** (In the formula, *** indicates the binding site with CO, *** indicates the binding site with NH, each of the s2 NH-A b2 -CO independently represents an amino acid residue; s2 represents an integer of 0-3. ) indicates a linker represented by . In one aspect, s2 is preferably zero.
  • R represents a hydrogen atom or a C 1-3 alkyl group. In one aspect, R is preferably a hydrogen atom.
  • radiolabeled compound (I-2) may be in the S or R configuration.
  • the radiolabeled compound (I-2) has optical isomers based on the chiral C-atom, any optical isomer and any mixture thereof in any proportion may be used as a radiolabeled compound (I-2 ).
  • compound (I-2) has the following formula (I'-2):
  • Suitable specific examples of the radiolabeled compound (I-2) include the following.
  • Compound (I-1) or (I-2) may be in the form of a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts include, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, Inorganic salts such as barium salts, ammonium salts, etc., and if the compound has a basic functional group, for example, with inorganic acids such as hydrogen chloride, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid salts or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
  • inorganic acids such as hydrogen chloride, hydrobromic acid, nitric acid, sulfuric acid, phosphoric
  • such salts include, for example, metal salts (e.g., alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts, magnesium salts, and barium salts); metal salts), ammonium salts, salts with organic bases (e.g. trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine), salts with inorganic acids (e.g.
  • hydrochloric acid hydrobromic acid, nitric acid, sulfuric acid
  • salts with organic acids eg, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid
  • organic acids eg, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid
  • the radiolabeled compound (I-1) can be produced by a method including step 1 below.
  • Y 1 represents a boryl group (-B(OH) 2 ) or its ester group.
  • Y 1 is preferably a boryl group (-B(OH) 2 ) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group (pinacol ester group).
  • Step 1 comprises reacting boronic acid compound (II-1) in the presence of a reagent selected from alkali metal iodides, alkali metal bromides, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide, reacting in water with a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br to obtain a radiolabeled compound (I-1) is.
  • a reagent selected from alkali metal iodides, alkali metal bromides, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide
  • the boronic acid compound (II-1) is a novel compound, and preferred specific examples thereof include the following.
  • Boronic acid compound (II-1) can be produced by the method described later. Since the reaction in this step is carried out in water, the boronic acid compound (II-1) may be in free form or salt form as long as it can be dissolved in water. Alternatively, it may be used by dissolving in a weakly basic aqueous solution such as an aqueous sodium bicarbonate solution.
  • alkali metal iodides include potassium iodide and sodium iodide, among which potassium iodide is preferably used.
  • alkali metal bromides include sodium bromide and potassium bromide.
  • Suitable combinations of radionuclides and the above reagents include: (1) a combination wherein the radionuclide is 211 At or 210 At and said reagent is selected from potassium iodide, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide; (2) a combination wherein the radionuclide is 123 I, 124 I, 125 I or 131 I and said reagent is selected from N-bromosuccinimide and N-chlorosuccinimide; (3) a combination wherein the radionuclide is 76 Br or 77 Br and the reagent is N-chlorosuccinimide; are mentioned.
  • the above reagents may be used alone or in combination of two or more.
  • the above reagents are usually used in the form of an aqueous solution.
  • the radionuclide is 211 At or 131 I and the reagent is selected from potassium iodide and N-bromosuccinimide.
  • the radionuclide is 211 At and the reagent is potassium iodide and embodiments in which the radionuclide is 131 I and the reagent is N-bromosuccinimide.
  • the above reagent may be used in an amount capable of oxidizing or reducing the radionuclide, and is usually used in large excess relative to the radionuclide. It is used at a concentration of 2 mol/L, more preferably 0.001-0.1 mol/L.
  • Radionuclides are usually used in reactions in the form of aqueous solutions. If necessary, for the purpose of stabilizing the radionuclides, an alkaline aqueous solution such as sodium hydroxide or buffer solution may be added to the aqueous solution.
  • an alkaline aqueous solution such as sodium hydroxide or buffer solution may be added to the aqueous solution.
  • the radionuclide is 211 At
  • bismuth is irradiated with helium particles accelerated to 28 MeV by a cyclotron
  • 209 Bi( ⁇ ,2n) 211 At produces 211 At
  • the target material 209 Bi is heated and dissolved.
  • a stock solution of 211 At is prepared by allowing 211 At to transpire and collect in a cold trap and dissolving it in water.
  • an alkaline aqueous solution such as sodium hydroxide or buffer solution may be added.
  • the radionuclide is 210 At
  • bismuth is irradiated with helium particles accelerated to 29 MeV or higher in a cyclotron to produce 210 At by the nuclear reaction of 209 Bi( ⁇ ,3n) 210 At, and then the same operation as above is performed. to prepare a 210 At aqueous solution.
  • the radionuclide is 123 I, it is available as Na 123 I aqueous solution.
  • radionuclide When the radionuclide is 124 I, tellurium is irradiated with proton particles accelerated by a cyclotron to produce 124 I by the nuclear reaction of 124 Te(p,n) 124 I. After that, 124 Te of the target material is dissolved, and 124 I is produced. of sodium hydroxide solution is prepared. When the radionuclide is 125 I, it is available as Na 125 I aqueous solution. When the radionuclide is 131 I, it is available as Na 131 I aqueous solution.
  • radionuclide When the radionuclide is 76 Br, tellurium is irradiated with proton particles accelerated by a cyclotron, and 76 Br is produced by the nuclear reaction of 76 Se(p,n) 76 Br . of sodium hydroxide solution is prepared.
  • radionuclide When the radionuclide is 77 Br, tellurium is irradiated with proton particles accelerated by a cyclotron, and 77 Br is produced by the nuclear reaction of 77 Se(p,n) 77 Br . of sodium hydroxide solution is prepared.
  • 211 At has a half-life of 7.2 hours
  • 210 At At has a half-life of 8.3 hours
  • 123 I has a half-life of 13.2 hours
  • 76 Br has a half-life of 16 hours.
  • the boronic acid compound (II-1) is usually used in large excess relative to the radionuclide, but from the viewpoint of reaction efficiency and economic efficiency, it is preferably 0.00001 mol with respect to 1 Bq to 1,000 GBq of the radionuclide. /l to 0.5 mol/l, more preferably 0.0001 mol/l to 0.2 mol/l.
  • the above reaction is carried out by mixing the boronic acid compound (II-1), the above reagent and the radionuclide, and there is no particular limitation on the mixing order.
  • an aqueous solution of a radioactive nuclide and then an aqueous solution of the reagent are added to an aqueous solution of the boronic acid compound (II-1), or an aqueous solution of the reagent and an aqueous solution of the radioactive nuclide are added to an aqueous solution of the boronic acid compound (II-1).
  • More preferred is a method of adding an aqueous solution of a radionuclide and then an aqueous solution of the above reagents to an aqueous solution of the boronic acid compound (II-1).
  • the reaction is carried out in water, ie in a system free of organic solvents.
  • the above reaction is carried out at 0-95°C, preferably 10-80°C.
  • the reaction time is 1 minute to 3 hours, preferably 1 minute to 1 hour. Completion of the reaction is confirmed by the disappearance of free radionuclide by thin layer chromatography (TLC) analysis.
  • the reaction solution does not contain an organic solvent or a toxic reagent, so that it can be immediately formulated into an injection or the like without isolating the radiolabeled compound (I-1).
  • the reaction between the boronic acid compound (II-1) and a radionuclide is an electrophilic substitution reaction and/or a nucleophilic substitution reaction. Since the introduction site of the radionuclide in the boronic acid compound (II-1) is the benzene ring, particularly in the case of 211 At or 210 At, it can be successfully introduced into the benzene ring.
  • the radiolabeled compound (I-1) may be purified in order to remove by-products.
  • This purification is preferably performed by a solid phase extraction column.
  • the solid-phase extraction column one commonly used in the technical field can be used.
  • ascorbic acid or ascorbate may be added to a final concentration of 0.01% to 10%, preferably 0.1% to 5%. This makes it possible to suppress decomposition of the radiolabeled compound (I-1) and retain it for a long period of time.
  • radiolabeled compound (I-1) can be obtained with a high radiochemical yield (RCY) of 60% or more, particularly 80% or more, especially 90% or more. Also, a radiolabeled compound (I-1) can be obtained with a high radiochemical purity (RCP) of 80% or more, particularly 90% or more, especially 95% or more.
  • RY radiochemical yield
  • RCP radiochemical purity
  • radiolabeled compound (I-2) can be produced by the method shown in Scheme 2 below.
  • Y 2 represents a boryl group (-B(OH) 2 ) or its ester group.
  • Y 2 is preferably a boryl group (-B(OH) 2 ) or a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group (pinacol ester group).
  • step 2 comprises reacting boronic acid compound (II-2) in the presence of a reagent selected from alkali metal iodides, alkali metal bromides, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide; reacting in water with a radionuclide selected from 211 At, 210 At, 131 I, 125 I, 124 I, 123 I, 77 Br and 76 Br to obtain a radiolabeled compound (I-2) is.
  • a reagent selected from alkali metal iodides, alkali metal bromides, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide
  • the boronic acid compound (II-2) is a novel compound, and preferred specific examples thereof include the following.
  • Boronic acid compound (II-2) can be produced by the method described later. Since the reaction in this step is carried out in water, the boronic acid compound (II-2) may be in free form or salt form as long as it can be dissolved in water. Alternatively, it may be used by dissolving in a weakly basic aqueous solution such as an aqueous sodium bicarbonate solution.
  • alkali metal iodides include potassium iodide and sodium iodide, among which potassium iodide is preferably used.
  • alkali metal bromides include sodium bromide and potassium bromide.
  • Suitable combinations of radionuclides and the above reagents include: (1) a combination wherein the radionuclide is 211 At or 210 At and said reagent is selected from potassium iodide, sodium bromide, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and hydrogen peroxide; (2) a combination wherein the radionuclide is 123 I, 124 I, 125 I or 131 I and said reagent is selected from N-bromosuccinimide and N-chlorosuccinimide; (3) a combination wherein the radionuclide is 76 Br or 77 Br and the reagent is N-chlorosuccinimide; are mentioned.
  • the above reagents may be used alone or in combination of two or more.
  • the above reagents are usually used in the form of an aqueous solution.
  • the radionuclide is 211 At or 131 I and the reagent is selected from potassium iodide and N-bromosuccinimide.
  • the radionuclide is 211 At and the reagent is potassium iodide and embodiments in which the radionuclide is 131 I and the reagent is N-bromosuccinimide.
  • the above reagent may be used in an amount capable of oxidizing or reducing the radionuclide, and is usually used in large excess relative to the radionuclide. It is used at a concentration of 2 mol/L, more preferably 0.001-0.1 mol/L.
  • Radionuclides are usually used in reactions in the form of aqueous solutions. If necessary, for the purpose of stabilizing the radionuclides, an alkaline aqueous solution such as sodium hydroxide or buffer solution may be added to the aqueous solution.
  • an alkaline aqueous solution such as sodium hydroxide or buffer solution may be added to the aqueous solution.
  • the radionuclide is 211 At
  • bismuth is irradiated with helium particles accelerated to 28 MeV by a cyclotron
  • 209 Bi( ⁇ ,2n) 211 At produces 211 At
  • the target material 209 Bi is heated and dissolved.
  • a stock solution of 211 At is prepared by allowing 211 At to transpire and collect in a cold trap and dissolving it in water.
  • an alkaline aqueous solution such as sodium hydroxide or buffer solution may be added.
  • the radionuclide is 210 At
  • bismuth is irradiated with helium particles accelerated to 29 MeV or higher in a cyclotron to produce 210 At by the nuclear reaction of 209 Bi( ⁇ ,3n) 210 At, and then the same operation as above is performed. to prepare a 210 At aqueous solution.
  • the radionuclide is 123 I, it is available as Na 123 I aqueous solution.
  • radionuclide When the radionuclide is 124 I, tellurium is irradiated with proton particles accelerated by a cyclotron to produce 124 I by the nuclear reaction of 124 Te(p,n) 124 I. After that, 124 Te of the target material is dissolved, and 124 I is produced. of sodium hydroxide solution is prepared. When the radionuclide is 125 I, it is available as Na 125 I aqueous solution. When the radionuclide is 131 I, it is available as Na 131 I aqueous solution.
  • radionuclide When the radionuclide is 76 Br, tellurium is irradiated with proton particles accelerated by a cyclotron, and 76 Br is produced by the nuclear reaction of 76 Se(p,n) 76 Br . of sodium hydroxide solution is prepared.
  • radionuclide When the radionuclide is 77 Br, tellurium is irradiated with proton particles accelerated by a cyclotron, and 77 Br is produced by the nuclear reaction of 77 Se(p,n) 77 Br . of sodium hydroxide solution is prepared.
  • 211 At has a half-life of 7.2 hours
  • 210 At At has a half-life of 8.3 hours
  • 123 I has a half-life of 13.2 hours
  • 76 Br has a half-life of 16 hours.
  • the boronic acid compound (II-2) is usually used in large excess relative to the radionuclide, but from the viewpoint of reaction efficiency and economic efficiency, it is preferably 0.00001 mol with respect to 1 Bq to 1,000 GBq of the radionuclide. /l to 0.5 mol/l, more preferably 0.0001 mol/l to 0.2 mol/l.
  • the above reaction is carried out by mixing the boronic acid compound (II-2), the above reagent and the radionuclide, and there are no particular restrictions on the mixing order.
  • an aqueous solution of a radioactive nuclide and then an aqueous solution of the reagent are added to an aqueous solution of the boronic acid compound (II-2), or an aqueous solution of the reagent and an aqueous solution of the radioactive nuclide are added to an aqueous solution of the boronic acid compound (II-2).
  • More preferred is a method of adding an aqueous solution of a radionuclide and then an aqueous solution of the above reagents to an aqueous solution of the boronic acid compound (II-2).
  • the reaction is carried out in water, ie in a system free of organic solvents.
  • the above reaction is carried out at 0-95°C, preferably 10-80°C.
  • the reaction time is 1 minute to 3 hours, preferably 1 minute to 1 hour. Completion of the reaction is confirmed by the disappearance of free radionuclide by thin layer chromatography (TLC) analysis.
  • the reaction solution does not contain an organic solvent or a toxic reagent, so that it can be immediately formulated into an injection or the like without isolating the radiolabeled compound (I-2).
  • the reaction between the boronic acid compound (II-2) and a radionuclide is an electrophilic substitution reaction and/or a nucleophilic substitution reaction. Since the introduction site of the radionuclide in the boronic acid compound (II-2) is the benzene ring, particularly in the case of 211 At or 210 At, it can be successfully introduced into the benzene ring.
  • the radiolabeled compound (I-2) may be purified, if necessary, in order to remove by-products.
  • This purification is preferably performed by a solid phase extraction column.
  • the solid-phase extraction column one commonly used in the technical field can be used.
  • ascorbic acid or ascorbate may be added to a final concentration of 0.01% to 10%, preferably 0.1% to 5%. This makes it possible to suppress decomposition of the radiolabeled compound (I-2) and retain it for a long period of time.
  • a radiolabeled compound (I-2) can be obtained with a high radiochemical yield (RCY) of 60% or more, particularly 80% or more, especially 90% or more. Also, a radiolabeled compound (I-2) can be obtained with a high radiochemical purity (RCP) of 80% or more, particularly 90% or more, especially 95% or more.
  • RY radiochemical yield
  • RCP radiochemical purity
  • L 1 is *-L c1 -L b1 -L a1 -** (each symbol in the formula is as defined above) (that is, L 1 is *-L d1 -
  • a boronic acid compound (IIa-1) which is L c1 -L b1 -L a1 -** and L d1 is a bond) can be produced according to the method shown in Scheme 3 below.
  • P a1 represents a protecting group (amino protecting group, hydroxy protecting group, mercapto protecting group), Hal a1 represents a bromine atom or a chlorine atom, and other symbols are as defined above.
  • L c1 is NR g1 (the symbols in the formula are as defined above) or a divalent cyclic amino group
  • P a1 is an amino-protecting group, preferably a tert-butoxycarbonyl group (Boc group) is.
  • L c1 is an oxygen atom
  • P a1 is a hydroxy protecting group.
  • P a1 is a mercapto protecting group.
  • Hal a1 is preferably a bromine atom.
  • Step 3-1 is a step of reacting compound (1) with compound (2) to obtain compound (3).
  • the reaction is carried out in the presence of a base in a solvent.
  • Compound (1) and compound (2) may be commercially available products, or may be produced by a synthesis method known per se.
  • the amount of compound (2) to be used is generally 2-10 mol, preferably 2-5 mol, per 1 mol of compound (1).
  • Examples of the base include inorganic bases such as potassium carbonate and cesium carbonate.
  • the amount of the base to be used is generally 2-20 mol, preferably 4-15 mol, per 1 mol of compound (1).
  • Solvents include N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, acetonitrile and the like.
  • the reaction is usually carried out at a temperature of 25 to 100°C, preferably 50 to 80°C, for 6 to 24 hours, preferably 10 to 24 hours.
  • the compound (3) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 3-2 is a step of converting compound (3) to compound (4).
  • the reaction is carried out by treatment with a base in a solvent.
  • a base for example, it is carried out in a mixed solvent of tetrahydrofuran/1,4-dioxane/water in the presence of an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • a methyl ester is obtained, and subsequently hydrolyzed using lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. in a mixed solvent of tetrahydrofuran/1,4-dioxane/water to give the compound Convert to (4).
  • the reaction is usually carried out at -20 to 40°C, preferably 0 to 30°C, for usually 10 minutes to 24 hours, preferably 0.5 to 2 hours.
  • the compound (4) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 3-3 is a step of reacting compound (4) with compound (5) to obtain compound (6).
  • the reaction may be carried out in a solvent in the presence of a condensing agent, After converting compound (4) into a reactive derivative (eg, acid chloride) in a solvent, the reaction may be carried out in the presence of a base.
  • a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • the amount of compound (5) to be used is generally 1-10 mol, preferably 2-5 mol, per 1 mol of compound (4).
  • Condensing agents include 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), hexafluorophosphate (benzotriazole- 1-yloxy)tripyrrolidinophosphonium (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (benzotriazol-1-yloxy)tris(dimethyl)hexafluorophosphate amino)phosphonium (BOP), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), diisopropylcarbodiimide (DIC) and the like.
  • HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • HATU, EDC and PyBOP are preferably used.
  • the amount of the condensing agent to be used is generally 1-10 mol, preferably 1-3 mol, per 1 mol of compound (4).
  • bases include organic bases such as N,N-diisopropylethylamine (DIEA) and triethylamine (TEA).
  • DIEA N,N-diisopropylethylamine
  • TEA triethylamine
  • the amount of the base to be used is generally 1-10 mol, preferably 2-5 mol, per 1 mol of compound (4).
  • the reaction is preferably carried out in the presence of additives such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt).
  • additives such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt).
  • the amount of the additive to be used is generally 1-10 mol, preferably 1-3 mol, per 1 mol of compound (4).
  • Solvents include N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), acetonitrile and the like.
  • the reaction is usually carried out at a temperature of 0 to 60°C, preferably 0 to 30°C, for 6 to 72 hours, preferably 6 to 48 hours.
  • the compound (6) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 3-4 is a step of subjecting compound (6) to deprotection to obtain compound (7).
  • a deprotection method is appropriately selected according to the type of protecting group.
  • P a1 is a tert-butoxycarbonyl group (Boc group)
  • compound (7) can be obtained by treating compound (6) under acidic conditions.
  • Treatment under acidic conditions includes acid treatment using trifluoroacetic acid (TFA) or the like.
  • TFA trifluoroacetic acid
  • the acid treatment may be performed in a solvent such as dichloromethane or dichloroethane.
  • the compound (7) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 3-5 is a step of reacting compound (7) with compound (8) to obtain compound (IIa-1).
  • compound (IIa-1) when L c1 is NR g1 (the symbols in the formula are as defined above) or a divalent cyclic amino group, this step is carried out in the same manner as in step 3-3.
  • compound (8) a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • the compound (IIa-1) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (each symbol in the formula is as defined above) and L d1 is *
  • the boronic acid compound (IIb-1), which is -(NH-A a1 -CO) r1 -*** (each symbol in the formula is as defined above) is produced according to the method shown in Scheme 4 below. can do.
  • Pb1 represents an amino-protecting group, and other symbols are as defined above.
  • P b1 is preferably a tert-butoxycarbonyl group (Boc group).
  • Step 4-1 is a step of reacting compound (7) with compound (9) to obtain compound (10).
  • compound (9) a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • L c1 is NR g1 (the symbols in the formula are as defined above) or a divalent cyclic amino group
  • this step is carried out in the same manner as in step 3-3.
  • the compound (10) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 4-2 is a step of subjecting compound (10) to deprotection to obtain compound (11). This step is performed in the same manner as step 3-4. After completion of the reaction, the compound (11) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 4-3 is a step of reacting compound (11) with compound (8) to obtain compound (IIb-1). This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (IIb-1) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • L 1 is *-L d1 -L c1 -L b1 -L a1 -** (each symbol in the formula is as defined above) and L d1 is * Boronic acid compound (IIc-1), which is -NH-B a1 -O-B b1 -CO-*** (each symbol in the formula is as defined above) can be prepared by the method shown in Scheme 5 below. can be manufactured according to
  • Pc1 represents an amino-protecting group, and other symbols are as defined above.
  • P c1 is preferably a tert-butoxycarbonyl group (Boc group).
  • Step 5-1 is a step of reacting compound (7) with compound (12) to obtain compound (13). This step is carried out by converting compound (12) into an active ester such as pentafluorophenyl ester and then reacting it with compound (7).
  • Compound (12) may be produced by a synthesis method known per se, or may be produced by the method described below.
  • the hydroxy group present in the divalent residue derived from the amino sugar or derivative thereof is preferably protected, and the protective group includes a tert-butyldimethylsilyl group (TBS group) and benzylidene. groups (formation of benzylidene acetals), and the like.
  • Conversion to pentafluorophenyl ester is carried out by reacting compound (12) with pentafluorophenyl trifluoroacetate in a solvent in the presence of a base.
  • the amount of pentafluorophenyl trifluoroacetate to be used is generally 1-10 mol, preferably 2-8 mol, per 1 mol of compound (12).
  • bases include organic bases such as pyridine, triethylamine and N,N-diisopropylethylamine (DIEA).
  • the amount of the base to be used is generally 1-10 mol, preferably 2-8 mol, per 1 mol of compound (12).
  • Solvents include N,N-dimethylformamide (DMF), dichloromethane, tetrahydrofuran (THF) and the like.
  • the reaction is usually carried out at -20 to 60°C, preferably 0 to 30°C, for usually 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • the obtained pentafluorophenyl ester is subjected to a reaction with compound (7) after performing operations such as concentration.
  • the reaction is carried out in a solvent in the presence of a base.
  • the amount of pentafluorophenyl ester to be used is generally 1-10 mol, preferably 1-3 mol, per 1 mol of compound (7).
  • the base examples include organic bases such as N,N-diisopropylethylamine (DIEA), triethylamine (TEA) and pyridine.
  • the amount of the base to be used is generally 1-30 mol, preferably 2-25 mol, per 1 mol of compound (7).
  • Solvents include N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane and the like.
  • the reaction is usually carried out at -20 to 60°C, preferably 0 to 30°C, for 1 to 48 hours, preferably 1 to 24 hours. After completion of the reaction, the compound (13) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 5-2 is a step of subjecting compound (13) to deprotection to obtain compound (14). This step is performed in the same manner as step 3-4. After completion of the reaction, the compound (14) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 5-3 is a step of reacting compound (14) with compound (8) to give compound (IIc-1). This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (IIc-1) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 5-4 is a step of reacting compound (15) with trichloroacetonitrile to obtain compound (16).
  • the reaction is carried out in the presence of a base in a solvent.
  • a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • the hydroxy group present in the divalent residue derived from the amino sugar or derivative thereof is preferably protected, and the protecting group includes a tert-butyldimethylsilyl group (TBS group) and benzylidene. groups (formation of benzylidene acetals), and the like.
  • P c1 is preferably a trichloroethoxycarbonyl group (Troc group).
  • the amount of trichloroacetonitrile to be used is generally 1-20 mol, preferably 5-15 mol, per 1 mol of compound (15).
  • the base include inorganic and organic bases such as cesium carbonate, potassium carbonate, diazabicycloundecene and the like.
  • the amount of the base to be used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (15).
  • solvents include dichloromethane, dichloroethane, toluene, acetonitrile and the like.
  • the reaction is usually carried out at -20 to 50°C, preferably 0 to 30°C, for usually 10 minutes to 12 hours, preferably 0.5 to 4 hours.
  • the compound (16) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 5-5 is a step of reacting compound (16) with compound (17) to give compound (18).
  • the reaction is carried out in the presence of a Lewis acid or protonic acid in a solvent.
  • a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • the amount of compound (17) to be used is generally 0.1-10 mol, preferably 0.5-5 mol, per 1 mol of compound (16).
  • Lewis acid or protonic acid examples include trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, trifluoromethanesulfonic anhydride, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid, and the like. are mentioned.
  • the amount of Lewis acid or protonic acid to be used is generally 0.001-10 mol, preferably 0.001-1 mol, per 1 mol of compound (16).
  • solvents examples include dichloromethane, dichloroethane, tetrahydrofuran (THF), diethyl ether, cyclopentyl methyl ether (CPME), acetonitrile, toluene, and the like.
  • the reaction may be performed under an argon atmosphere. Also, the reaction may be carried out in the presence of molecular sieves. The reaction is usually carried out at -78 to 50°C, preferably -20 to 30°C, for usually 10 minutes to 24 hours, preferably 0.5 to 4 hours. After completion of the reaction, the compound (18) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Compound (18) may be subjected to a transformation of the protecting group (P c1 ), for example, the trichloroethoxycarbonyl group (Troc group), in order to use the compound (12) obtained in the next step as a starting material in Scheme 5. , may be converted to a tert-butoxycarbonyl group (Boc group).
  • P c1 the protecting group
  • Troc group the trichloroethoxycarbonyl group
  • Step 5-6 is a step of subjecting compound (18) to hydrolysis to obtain compound (12).
  • the hydrolysis is performed according to a conventional method, for example, using lithium hydroxide in a mixed solvent of tetrahydrofuran/1,4-dioxane/water.
  • the compound (12) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • a boronic acid compound (IId-1) in which L 1 is *-(NH-A b1 -CO) s1 -** (each symbol in the formula is as defined above) in the boronic acid compound (II-1) ) can be prepared according to the method shown in Scheme 6 below.
  • P d1 represents an amino-protecting group, and other symbols are as defined above.
  • P d1 is preferably a tert-butoxycarbonyl group (Boc group).
  • Step 6-1 is a step of reacting compound (1) with compound (19) to obtain compound (20).
  • compound (19) a commercially available product may be used, or it may be produced by a synthesis method known per se. This step is performed in the same manner as step 3-3.
  • the compound (20) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 6-2 is a step of converting compound (20) into compound (21). This step is performed in the same manner as step 3-2. After completion of the reaction, the compound (21) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 6-3 is a step of reacting compound (21) with compound (5) to obtain compound (22). This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (22) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 6-4 is a step of subjecting compound (22) to deprotection to obtain compound (23). This step is performed in the same manner as step 3-4. After completion of the reaction, the compound (23) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 6-5 is a step of reacting compound (23) with compound (8) to obtain compound (IId-1). This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (IId-1) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • a boronic acid compound (IIa-2) in which L 2 is *-L c2 -L b2 -L a2 -** (each symbol in the formula is as defined above) in the boronic acid compound (II-2) can be prepared according to the method shown in Scheme 7 below.
  • P a2 represents an amino-protecting group
  • Resin represents a resin used in peptide synthesis, and other symbols are as defined above.
  • P a2 is preferably a 9-fluorenylmethyloxycarbonyl group (Fmoc group).
  • Resins used in peptide synthesis represented by Resin include resins used in solid-phase synthesis, such as Cl-Trt(2-Cl)-Resin.
  • Step 7-1 is a step of subjecting compound (24) to deprotection to obtain compound (25).
  • the reaction is carried out according to a conventional method . ) using secondary amines such as piperidine, pyrrolidine and morpholine.
  • Compound (24) can be produced by a known synthetic method.
  • the compound (25) can be obtained by carrying out usual work-up and, if necessary, purifying by column chromatography or the like.
  • Step 7-2 is a step of reacting compound (25) with compound (26) to give compound (27).
  • Compound (26) can be synthesized by a method similar to that of Scheme 3. Alternatively, it can be produced by the method described below. This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (27) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 7-3 is a step of subjecting compound (27) to resin removal to obtain compound (28).
  • the resin removal method is appropriately selected according to the type of resin. For example, when the resin is Cl-Trt(2-Cl)-Resin, it is treated with a hexafluoro-2-propanol (HFIP)/chloroform (TCM) solution. After the completion of the reaction, the detached resin is removed, followed by usual post-treatment, and if necessary, purification by column chromatography or the like, whereby compound (28) can be obtained.
  • HFIP hexafluoro-2-propanol
  • TCM chloroform
  • Step 7-4 is a step of reacting compound (28) with compound (29) to give compound (IIa-2).
  • the reaction is carried out by converting compound (28) into an active ester such as pentafluorophenyl ester and then reacting it with compound (29).
  • Conversion to a pentafluorophenyl ester is carried out by reacting compound (28) with pentafluorophenyl trifluoroacetate in a solvent in the presence of a condensing agent.
  • the amount of pentafluorophenyl trifluoroacetate to be used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (28).
  • Condensing agents include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and the like.
  • the amount of the condensing agent to be used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (28).
  • Solvents include tetrahydrofuran (THF), N,N-dimethylformamide (DMF), chloroform, acetonitrile, dichloromethane and the like.
  • the reaction is usually carried out at -20 to 50°C, preferably 0 to 30°C, for 1 to 48 hours, preferably 1 to 24 hours.
  • the obtained pentafluorophenyl ester is subjected to the reaction with compound (29).
  • compound (29) a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • the reaction is carried out in the same manner as the reaction of pentafluorophenyl ester and compound (7) described in Step 5-1, but the base, solvent and the like are not limited to those used in Step 5-1.
  • the compound (IIa-2) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • compound (26′) in which L c2 is a divalent cyclic diamino group (piperazine-1,4-diyl etc.) can also be produced according to the following method. .
  • Pb2 represents an amino-protecting group, and other symbols are as defined above.
  • Pb2 is preferably a tert-butoxycarbonyl group (Boc group).
  • Step 7-5 is a step of reacting compound (1) with compound (30) to obtain compound (31).
  • compound (30) a commercially available product may be used, or it may be produced by a synthesis method known per se. This step is performed in the same manner as step 3-1.
  • the compound (31) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 7-6 is a step of reacting compound (31) with compound (32) to give compound (33).
  • the reaction is carried out in the presence of sodium iodide in a solvent.
  • compound (32) a commercially available product may be used, or it may be produced by a synthesis method known per se.
  • the amount of compound (32) to be used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (31).
  • the amount of sodium iodide to be used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (31).
  • Solvents include N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile and the like.
  • the reaction is usually carried out at 0 to 80°C, preferably 20 to 60°C, for 1 to 48 hours, preferably 4 to 30 hours.
  • the compound (33) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 7-7 is a step of subjecting compound (33) to deprotection and acylation (introduction of R e2 ) to give compound (26′).
  • Deprotection is carried out in the same manner as in step 3-4.
  • Acylation is carried out by reacting the deprotected form with an acylating agent corresponding to Re2 in a solvent in the presence of a base.
  • Acylating agents include acetic anhydride, acetyl chloride and the like.
  • the amount of the acylating agent to be used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (33).
  • Bases include pyridine, triethylamine (TEA), N,N-diisopropylethylamine (DIEA) and the like.
  • the amount of the base to be used is generally 1-20 mol, preferably 1-10 mol, per 1 mol of compound (33). Alternatively, it is added as a solvent.
  • Solvents include N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), pyridine, triethylamine and the like.
  • the reaction is usually carried out at -20 to 60°C, preferably 0 to 30°C, for usually 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • the compound (26') can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • a boronic acid compound (IIa-2) in which L 2 is *-L c2 -L b2 -L a2 -** (each symbol in the formula is as defined above) in the boronic acid compound (II-2) can also be prepared according to the method shown in Scheme 8 below.
  • Step 8-1 is a step of reacting compound (34) with compound (29) to give compound (35).
  • compound (34) a commercially available product may be used, or it may be produced by a synthesis method known per se. This step is performed in a manner similar to step 7-4. After completion of the reaction, the compound (35) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 8-2 is a step of subjecting compound (35) to deprotection to obtain compound (36). This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (36) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 8-3 is a step of reacting compound (36) with compound (26) to give compound (IIa-2). This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (IIa-2) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • a boronic acid compound (IIb-2) in which L 2 is *-(NH-A a2 -CO) r2 -** (each symbol in the formula is as defined above) in the boronic acid compound (II-2) ) can be prepared according to the method shown in Scheme 9 below.
  • Step 9-1 is a step of reacting compound (36) with compound (37) to give compound (IIa-2).
  • Compound (37) can be synthesized by a method similar to that of Scheme 6. Alternatively, it can be produced by the method described below. This step is performed in the same manner as step 3-3. After completion of the reaction, the compound (IIb-2) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Step 9-2 is a step of subjecting compound (38) to deprotection and acylation (introduction of R e2 ) to give compound (37).
  • Compound (38) can be produced by a method similar to Scheme 6. This step is performed by the same method as step 7-7. After completion of the reaction, the compound (37) can be obtained by carrying out usual post-treatment and, if necessary, purifying by column chromatography or the like.
  • Reaction conditions such as solvents and reaction temperatures in each step of the production method of the present invention described above are described in detail as representative examples in Synthesis Examples and Examples below, but are not necessarily limited to them. A person skilled in the art can appropriately select each based on general knowledge in organic synthesis.
  • radiolabeled compounds (I-1) and (I-2) thus produced are activated by fibroblast activation protein ⁇ (FAP ⁇ ). It specifically binds and accumulates in cancer-associated fibroblasts (CAF). It destroys the stroma by emitting alpha rays to damage cells. In addition, since cancer cells themselves may express FAP ⁇ , a stronger therapeutic effect can be exhibited by simultaneously damaging both the stroma and cancer cells. Thus, since radiolabeled compound (I) targets cells that express FAP ⁇ , radiolabeled compound (I) containing a therapeutically effective radionuclide can be used in cancer stroma expressing FAP ⁇ .
  • FAP ⁇ fibroblast activation protein ⁇
  • Therapeutically effective radionuclides include 211 At, 210 At, 131 I, 125 I and 77 Br. Also, since radiolabeled compound (I) targets cells expressing FAP ⁇ , radiolabeled compound (I) containing an imaging-effective radionuclide can be used to image FAP ⁇ -expressing tumors or cancers. and thus may be useful for diagnosis. Imaging-effective radionuclides include 211 At, 131 I, 124 I, 123 I, 77 Br and 76 Br.
  • Compound (I) radiolabeled with a radionuclide selected from 211 At, 131 I, 124 I, 123 I, 77 Br and 76 Br may be subjected to positron emission tomography (PET) or single photon emission tomography (SPECT). ) for imaging.
  • PET positron emission tomography
  • SPECT single photon emission tomography
  • Tumors or cancers expressing FAP ⁇ include pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, colon cancer, neuroendocrine tumor, thyroid cancer, Solid cancers such as uterine cancer and liver cancer can be mentioned. Therefore, radiolabeled compound (I) is effective for treatment and imaging of these solid cancers, especially pancreatic cancer.
  • the dose of radiolabeled compound (I) used for therapeutic or diagnostic purposes is generally determined according to the radionuclide used, the patient's body weight, age, sex, treatment/diagnosis site, and the like. For example, in the case of human subjects, the effective dose of compound (I) radiolabeled with 211 At is approximately 100 MBq to 900 MBq.
  • a radiolabeled compound (I) is usually mixed with a pharmaceutically acceptable carrier and used as a pharmaceutical composition.
  • Pharmaceutically acceptable carriers refer to biocompatible solutions that have been carefully considered in terms of sterility, pH, isotonicity, stability, etc., and include any and all solvents and diluents (sterile saline, sodium chloride injection). , Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection and other aqueous buffers), dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and the like. can.
  • a pharmaceutically acceptable carrier can also contain stabilizers, preservatives, antioxidants, or other additives known to those of skill in the art.
  • compositions for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids
  • These formulations can be prepared according to a conventional method. Liquid preparations for oral administration or injection are preferred.
  • Such liquid preparations are prepared by dissolving radiolabeled compound (I) in water, but may be dissolved in physiological saline or glucose solution if necessary, and buffers and preservatives may be added. may Moreover, as described above, a reducing agent such as ascorbic acid can be further contained.
  • the active ingredients may be mixed with pH adjusters such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, and glucose, if necessary.
  • Dissolve in distilled water for injection with an isotonicity agent such as , filter aseptically and fill in ampoules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. and freeze-dry in vacuum to prepare a dissolution type injection for use. good too.
  • an isotonicity agent such as , filter aseptically and fill in ampoules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. and freeze-dry in vacuum to prepare a dissolution type injection for use.
  • lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may be added to the active ingredient and emulsified in water to form an emulsion for injection.
  • the half-lives of the radionuclides contained in the radiolabeled compound (I) are 7.2 hours for 211 At, 8.3 hours for 210 At, 8.04 days for 131 I, 59.4 days for 125 I, Given the short duration of 4.2 days for 124 I, 13.2 hours for 123 I, 57 hours for 77 Br, and 16 hours for 76 Br, the dose of radiolabeled compound required for administration should be administered immediately prior to administration to the subject. It is desirable to prepare pharmaceutical compositions to contain (I).
  • Tetrahydrofuran/1,4-dioxane/water (4/2/1) mixed solvent (5.3 mL) and potassium carbonate (73.4 mg, 531 ⁇ mol) were added to the obtained compound 15, and the mixture was stirred overnight at room temperature.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with dichloromethane, and washed with water and saturated brine. After drying the obtained organic layer with sodium sulfate, sodium sulfate was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by high performance liquid chromatography to obtain 11.8 mg of compound 16 as a white solid (64% yield in 2 steps).
  • N,N-dimethylformamide 510 ⁇ L
  • pyridine 2.1 ⁇ L, 25.5 ⁇ mol
  • pentafluorophenyl trifluoroacetate 4.3 ⁇ L, 25.5 ⁇ mol
  • N,N-dimethylformamide 1.0 mL
  • compound 37 5.09 ⁇ mol, synthesized in Reference Example 1 described later
  • N,N-diisopropylethylamine 4.3 ⁇ L, 24.4 ⁇ mol
  • N,N-dimethylformamide (1.8 mL), pyridine (7.1 ⁇ L, 88.1 ⁇ mol), pentafluorophenyl trifluoroacetate (15.0 ⁇ L, 88.1 ⁇ mol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction solution was concentrated under reduced pressure, it was dried in vacuum to obtain compound 26 as a white solid. N,N-dimethylformamide (800 ⁇ L), compound 12 (7.9 mg, 17.6 ⁇ mol), and N,N-diisopropylethylamine (84.5 ⁇ L, 14.7 ⁇ mol) were added to the obtained compound 26, and the mixture was stirred overnight at room temperature. .
  • reaction mixture was purified by reverse-phase HPLC, and the fraction containing the desired product was lyophilized to obtain compound 44 as a lyophilized powder (0.15 g, 69%).
  • HPLC Purity 99.3%, ESI-MS MH+: 613.3 (Theory: 613.3)
  • reaction solution was purified by reverse-phase HPLC, and the fraction containing the desired product was lyophilized to obtain compound 49 as a lyophilized powder (0.14 g, 50%).
  • HPLC Purity 99.9%, ESI-MS MH+: 613.3 (Theory: 613.3)
  • Fmoc-Gly and 4-quinolinecarboxylic acid were deprotected with 20% piperidine/NMP and condensed with PyAOP-DIEA to extend the peptide chain.
  • a 20% HFIP/TCM solution was added to the resulting protected peptide resin, stirred at room temperature for 1 hour, and then the resin was filtered off. After distilling off the solvent under reduced pressure, diethyl ether was added to solidify, and the precipitate was collected by filtration and dried to obtain compound 52 (0.33 g, 47%).
  • the Borono-FAPI derivative synthesized in Synthesis Example was labeled with 211 At according to the basic procedure shown below. The outline is shown in FIG. 0.1 or 1% Borono-FAPI derivative (1 ⁇ g, 10 ⁇ g or 100 ⁇ g), 7% Meiron solution (10 ⁇ L), water (90 ⁇ L), 211 At aqueous solution (0.5- 10 MBq, 1-10 ⁇ L) and 0.1 M potassium iodide (KI) solution (30 ⁇ L) were added, and the mixture was heated and reacted at 50° C. or 80° C. for 45 minutes. This reaction solution was passed through a solid-phase extraction cartridge (Oasis HLB, Waters) and retained.
  • a solid-phase extraction cartridge Oasis HLB, Waters
  • the HLB cartridge was washed with 1.0 mL water (fraction E1). Next, 0.5 mL of 40% ethanol solution and 0.5 mL of 100% ethanol were sequentially passed through this HLB cartridge to elute the target substance (fractions E2 and E3). Collect 1-2 ⁇ L each of the reaction solution and fraction E2 (or E3), and determine the radiochemical yield (RCY, %) and radiochemical purity (RCP, %) by thin-layer chromatography (TLC). Ta. The radiochemical yield was calculated by the following formula.
  • Radiochemical yield (%) (radioactivity of target compound in thin layer plate/total radioactivity in thin layer plate) x 100 Specific 211
  • chemical structures of products, and quality analysis results (TLC) are shown below for each Borono-FAPI derivative.
  • fraction E3 After washing by passing 1 mL of water (fraction E1) through the same HLB cartridge, 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through.
  • the target compound was eluted in fraction E3.
  • the RCY was 14.1% when the starting material was 1 ⁇ g, and the RCY was 98.0% and the RCP was 99.9% when the starting material was 10 ⁇ g.
  • FIG. 3 shows the TLC results of the reaction solution.
  • fraction E3 After washing by passing 1 mL of water (fraction E1) through the same HLB cartridge, 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through.
  • the target compound was eluted in fraction E3.
  • the RCY was 1.6% when the mass of the raw material was 1 ⁇ g, and the RCY was 77.8% and the RCP was 91.7% when the mass of the raw material was 100 ⁇ g.
  • FIG. 5 shows the TLC results of the reaction solution.
  • fraction E3 After washing by passing 1 mL of water (fraction E1) through the same HLB cartridge, 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through.
  • the target compound was eluted in fraction E3.
  • the RCY was 58.7% when the mass of the raw material was 1 ⁇ g, and the RCY was 98.8% and the RCP was 99.5% when the mass of the raw material was 10 ⁇ g.
  • FIG. 7 shows the TLC results of the reaction solution.
  • FIG. 10 shows the TLC results of the reaction solution.
  • fraction E3 After washing by passing 1 mL of water (fraction E1) through the same HLB cartridge, 0.5 mL of 40% ethanol (fraction E2) and 0.5 mL of 100% ethanol (fraction E3) were passed through.
  • the target compound was eluted in fraction E3.
  • RCY When 10 ⁇ g of raw material was used, RCY was 55.9%, and when 100 ⁇ g of raw material was used, RCY was 62.0% and RCP was 70.4%.
  • FIG. 11 shows the TLC results of the reaction solution.
  • FIG. 12 shows the TLC results of the reaction solution.
  • the target compound was eluted in fraction E2.
  • RCY was 96.3% when 1 ⁇ g of the raw material was used, and RCY was 98.6% when 10 ⁇ g of the raw material was used.
  • FIG. 13 shows the TLC results of the reaction solution.
  • FIG. 15 shows the TLC results of the reaction solution.
  • FIG. 16 shows the TLC results of the reaction solution.
  • Table 1 summarizes the RCY% and RCP% of the radiolabeled products obtained in Examples.
  • C0, C1 and C2 in brackets indicate the alkylene chain length between the phenyl group with the borono group and the carbonyl group.
  • a high reaction yield of RCY>90% was obtained with 10 ⁇ g of starting material.
  • the alkylene chain length was 0 (Examples 4, 9 and 10)
  • the reaction yield was low and did not reach 90% even with 100 ⁇ g of the starting material (Examples 4 and 10).
  • the purity after purification was low (RCP ⁇ 92%) and the stability of the product was also found to be low.
  • the alkylene chain length affects the reaction yield. It was shown that one or more carbon atoms is preferable.
  • 131 I labeling was carried out according to the basic procedure for 211 At labeling.
  • FIG. 17 shows the TLC results of the reaction solution and the eluate. Borono(C1)-Pip-6Qui-FAPI(H) was also found to be useful for the synthesis of iodide.
  • Test Example 1 Incorporation of 211 At-labeled FAPI derivative into FAP ⁇ /293 cells
  • Human embryonic kidney cells 293 HEK293
  • FAP ⁇ /293 cells into which the human fibroblast activation protein (FAP ⁇ ) gene was incorporated
  • At-labeled FAPI derivative 8 compounds (Gly(1,F) (Example 8), PEG(1,F) (Example 5), PIP(1,F) (Example 1), PIP(1, H)-8Qui (Example 3), Ac-PIP (Example 13), PEG4(1,H) (Example 7), GlcN-PEG(1,F) (Example 11), PEG(1,H ) (Example 6)) was added to each cell, incubated for 30 minutes, the supernatant was removed by aspiration, and then 0.1N sodium hydroxide solution was added to lyse the cells, and the intracellular radioactivity was Measured with a gamma counter.
  • all compounds were specifically taken up by FAP ⁇ , since the uptake in FAP ⁇ -positive cells was higher than that in FAP ⁇ -negative cells.
  • Test Example 2 Uptake of 211 At-labeled FAPI derivatives into FAP ⁇ /A549 or FAP ⁇ /MDA-MB-231 cells
  • Human non-small cell lung cancer cell line (A549), human triple-negative (hormone receptor estrogen receptor and progesterone) a breast cancer cell line (MDA-MB-231) in which the receptor and HER2 protein are absent), and cells transfected with the human fibroblast-activating protein (FAP ⁇ ) gene (FAP ⁇ /A549, FAP ⁇ /MDA-MB-231) were used in experiments as cancer cells with low FAP ⁇ expression and cancer cells with high FAP ⁇ expression (mimic after higher-order tissue formation), respectively.
  • 2 ⁇ 10 4 of each cell was plated on a 24-well plate and cultured for 2 days.
  • PANC-1 human pancreatic cancer cells
  • the treatment and diagnosis of tumors or cancers that specifically bind to FAP ⁇ and express FAP ⁇ such as pancreatic cancer, sarcoma, esophageal cancer, lung cancer, breast cancer, prostate cancer, head and neck cancer.
  • cancer ovarian cancer, colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, and other solid cancers (especially pancreatic cancer).
  • pancreatic cancer sarcoma
  • esophageal cancer lung cancer
  • breast cancer breast cancer
  • prostate cancer head and neck cancer
  • cancer ovarian cancer, colorectal cancer, neuroendocrine tumors, thyroid cancer, uterine cancer, liver cancer, and other solid cancers (especially pancreatic cancer).

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118388451A (zh) * 2024-06-28 2024-07-26 四川大学 一种放射性标记的成纤维细胞活化蛋白抑制剂及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019027059A1 (ja) * 2017-08-04 2019-02-07 国立大学法人大阪大学 放射標識されたアリール化合物の製造方法
WO2019083990A2 (en) 2017-10-23 2019-05-02 The Johns Hopkins University IMAGING AND RADIATION THERAPY AGENTS TARGETING α-FIBROBLAST ACTIVATION PROTEIN α (FAP-α)
WO2019154866A1 (en) 2018-02-06 2019-08-15 Apollo Tyres Global R&D B.V. Rubber composition for tyres with good wet grip and rolling resistance properties
CN112023064A (zh) * 2020-11-03 2020-12-04 南京大为科创服务有限责任公司 用于标记核素211At的成纤维细胞活化蛋白抑制剂的锡基衍生物及其制备方法和应用
JP2021512949A (ja) * 2018-02-06 2021-05-20 ウニベルジテート ハイデルベルク Ｆａｐ阻害物質
WO2021197519A1 (en) * 2020-03-30 2021-10-07 Ustav Organicke Chemie A Biochemie Av Cr, V. V. I. Compounds for inhibition of fibroblast activation protein
JP2022026194A (ja) 2020-07-30 2022-02-10 昭和電工パッケージング株式会社 熱交換器

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019027059A1 (ja) * 2017-08-04 2019-02-07 国立大学法人大阪大学 放射標識されたアリール化合物の製造方法
WO2019083990A2 (en) 2017-10-23 2019-05-02 The Johns Hopkins University IMAGING AND RADIATION THERAPY AGENTS TARGETING α-FIBROBLAST ACTIVATION PROTEIN α (FAP-α)
JP2021500373A (ja) * 2017-10-23 2021-01-07 ザ・ジョンズ・ホプキンス・ユニバーシティ 線維芽細胞活性化タンパク質α（ＦＡＰ−α）を標的とする撮像剤および放射線療法用薬剤
WO2019154866A1 (en) 2018-02-06 2019-08-15 Apollo Tyres Global R&D B.V. Rubber composition for tyres with good wet grip and rolling resistance properties
JP2021512949A (ja) * 2018-02-06 2021-05-20 ウニベルジテート ハイデルベルク Ｆａｐ阻害物質
WO2021197519A1 (en) * 2020-03-30 2021-10-07 Ustav Organicke Chemie A Biochemie Av Cr, V. V. I. Compounds for inhibition of fibroblast activation protein
JP2022026194A (ja) 2020-07-30 2022-02-10 昭和電工パッケージング株式会社 熱交換器
CN112023064A (zh) * 2020-11-03 2020-12-04 南京大为科创服务有限责任公司 用于标记核素211At的成纤维细胞活化蛋白抑制剂的锡基衍生物及其制备方法和应用

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ASO AYAKA, KANEDA-NAKASHIMA KAZUKO, NABETANI HINAKO, KADONAGA YUICHIRO, SHIRAKAMI YOSHIFUMI, WATABE TADASHI, YOSHIYA TAKU, MOCHIZU: "Substrate Study for Dihydroxyboryl Astatine Substitution Reaction with Fibroblast Activation Protein Inhibitor (FAPI)", CHEMISTRY LETTERS, CHEMICAL SOCIETY OF JAPAN,NIPPON KAGAKUKAI, JP, vol. 51, no. 11, 5 November 2022 (2022-11-05), JP , pages 1091 - 1094, XP093087207, ISSN: 0366-7022, DOI: 10.1246/cl.220391 *
J NUCL MED, vol. 61, 2020, pages 563 - 569
MA HUAN, LI FEIZE, SHEN GUOHUA, CAI HUAWEI, LIU WEIHAO, LAN TU, YANG YUANYOU, YANG JIJUN, LIAO JIALI, LIU NING: "Synthesis and Preliminary Evaluation of 131 I-Labeled FAPI Tracers for Cancer Theranostics", MOLECULAR PHARMACEUTICS, AMERICAN CHEMICAL SOCIETY, US, vol. 18, no. 11, 1 November 2021 (2021-11-01), US , pages 4179 - 4187, XP093087205, ISSN: 1543-8384, DOI: 10.1021/acs.molpharmaceut.1c00566 *
MA HUAN; LI FEIZE; SHEN GUOHUA; PAN LILI; LIU WEIHAO; LIANG RANXI; LAN TU; YANG YUANYOU; YANG JIJUN; LIAO JIALI; LIU NING: "In vitro and in vivo evaluation of 211At-labeled fibroblast activation protein inhibitor for glioma treatment", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 55, 5 January 2022 (2022-01-05), AMSTERDAM, NL, pages 116600, XP086924678, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2021.116600 *
MELETTA ROMANA, MüLLER HERDE ADRIENNE, CHIOTELLIS ARISTEIDIS, ISA MALSOR, RANCIC ZORAN, BOREL NICOLE, AMETAMEY SIMON, KR&#228: "Evaluation of the Radiolabeled Boronic Acid-Based FAP Inhibitor MIP-1232 for Atherosclerotic Plaque Imaging", MOLECULES, SPRINGER VERLAG, BERLIN, DE, vol. 20, no. 2, 1 January 2015 (2015-01-01), DE , pages 2081 - 2099, XP055832871, ISSN: 1433-1373, DOI: 10.3390/molecules20022081 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118388451A (zh) * 2024-06-28 2024-07-26 四川大学 一种放射性标记的成纤维细胞活化蛋白抑制剂及其制备方法和应用

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