WO2022135325A1 - 成纤维细胞活化蛋白抑制剂 - Google Patents

成纤维细胞活化蛋白抑制剂 Download PDF

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WO2022135325A1
WO2022135325A1 PCT/CN2021/139590 CN2021139590W WO2022135325A1 WO 2022135325 A1 WO2022135325 A1 WO 2022135325A1 CN 2021139590 W CN2021139590 W CN 2021139590W WO 2022135325 A1 WO2022135325 A1 WO 2022135325A1
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cancer
unit
compound
fapi
acid
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French (fr)
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刘志博
丁洁
陈俊艺
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苏州药明博锐生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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 disclosure relates to the medical and diagnostic fields, in particular to compounds, chelates, compositions and uses thereof that inhibit fibroblasts.
  • Tumor is the second largest killer that threatens people's health.
  • a tumor can be thought of not only as a collection of malignant cells, but also as a collection of stromal cells, including vascular cells, inflammatory cells, and fibroblasts.
  • stromal cells including vascular cells, inflammatory cells, and fibroblasts.
  • 90% or more of the stroma may be present in the tumor.
  • a subset of fibroblasts called cancer-associated fibroblasts (CAFs) in the tumor stroma are involved in tumor growth, migration, and progression, and even become resistant and immunosuppressive to chemotherapy.
  • CAFs cancer-associated fibroblasts
  • the tumor microenvironment plays an important role in the occurrence and development of tumors, and the TME is centered on activated fibroblasts (CAFs).
  • Fibroblast activation protein FLP
  • DPP dipeptidyl peptidase
  • FAP is selectively expressed on the CAFs of more than 90% of epithelial malignant tumors, but hardly expressed in normal tissues, and has special biological characteristics and gene stability.
  • FAPs are widely expressed in the microenvironment of a variety of tumors, and thus different tumor entities, including pancreatic, breast, and lung cancers, can be targeted by targeting FAPs. Therefore, FAP can not only be used as a biological marker for early diagnosis of tumors, but also has good biological characteristics of targeted therapy, and is expected to play an important role in the clinical diagnosis and treatment of malignant tumors.
  • FAP inhibitors have not been in-depth.
  • the first FAP activity inhibitor to enter clinical trials was Talabostat, but it showed insufficient clinical activity in various cancers, so it did not continue to develop further.
  • some researchers used 131I-labeled anti-FAP antibody sibrotuzumab for tumor treatment research, but there were defects such as low clearance rate and lack of clinical activity.
  • One aspect of the present disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof,
  • C is a chelator unit; AB is an albumin binding unit; FAPI is a fibroblastin inhibitor unit.
  • the C units in general formula (I) are selected from:
  • the FAPI units in general formula (I) are selected from:
  • the C unit in general formula (I) is The FAPI unit is
  • the AB unit in formula (I) comprises a 4-iodo-phenyl end group
  • the AB unit passes through the terminal end in the FAPI unit An amide bond is formed to connect it to the FAPI unit, and the AB unit is connected to the C unit by forming an amide bond with the terminal carbonyl group in the C unit.
  • the compound of general formula (I) is selected from:
  • Another aspect of the present disclosure provides a chelate compound comprising a compound of formula (I) above and a radionuclide.
  • the radionuclide is selected from the group consisting of: 18 F, 51 Cr, 67 Ga, 68 Ga, 111 In, 99 mTc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 15 3Sm, 166 Ho , 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, One or more of 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th and 199 Ag.
  • the radionuclide is68Ga .
  • composition comprising or consisting of: at least one compound of formula (I) above, optionally and pharmaceutically acceptable adjuvants.
  • Yet another aspect of the present disclosure also provides use of the above-described chelate or pharmaceutical composition in the manufacture of a reagent or kit for diagnosing or treating a disease characterized by overexpression of fibroblast activating protein (FAP) in a subject use.
  • FAP fibroblast activating protein
  • Yet another aspect of the present disclosure also provides a method of diagnosing or treating a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, by administering to a subject in need of treatment an effective dose of the aforementioned chelating agent compound or pharmaceutical composition.
  • FAP fibroblast activation protein
  • Yet another aspect of the present disclosure also provides the aforementioned chelate or pharmaceutical composition for use in diagnosing or treating a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.
  • FAP fibroblast activation protein
  • the disease characterized by overexpression of fibroblast activation protein is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, and scarring, preferably, wherein the cancer is selected from breast Cancer, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophagus cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cell, bladder cancer, cholangiocarcinoma , clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, glioma, glioma, astrocytoma, cervical cancer, and prostate cancer one or more of.
  • FAP fibroblast activation protein
  • kits comprising or consisting of the above-mentioned chelate complex or pharmaceutical composition, and instructions for diagnosing or treating a disease.
  • Figure 1 shows the results of pharmacokinetic analysis in healthy mice using68Ga -TEFAPI-01, 02, 03 and 04.
  • Figure 2 shows PET/CT imaging using 68 Ga-FAPI-04, 68 Ga-TEFAPI-01, 86 Y-TEFAPI-02, 86 Y-TEFAPI-03, 86 Y-TEFAPI-04.
  • Figure 3 shows the comparison of 68Ga -FAPI-04 PET imaging between the TEFAPI-03 inhibited group and the non-inhibited group.
  • pharmaceutically acceptable means: a compound or composition that is chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or with the human or human with which it is used to prevent or treat a disease or disorder. Mammal compatible.
  • subject or “patient” in this application includes humans and mammals.
  • treatment may also include prophylaxis.
  • solvate refers to a complex formed by combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a solvent. It will be appreciated that any solvate of a compound of formula (I) for use in the diagnosis or treatment of the diseases or conditions described herein, while likely to provide different properties (including pharmacokinetic properties), will not In this experiment, compounds of formula (I) will be obtained, such that the use of compounds of formula (I) encompasses the use of any solvates of compounds of formula (I), respectively.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof may be isolated as a solvate, and therefore any such solvate is included within the scope of the present invention.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable salts refers to relatively nontoxic addition salts of compounds of the present disclosure. See, eg, S.M. Berge et al. "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19.
  • Suitable pharmaceutically acceptable salts of the compounds of the present disclosure may be, for example, acid addition salts of sufficiently basic compounds of the present disclosure carrying a nitrogen atom in the chain or ring, such as acid addition salts with the following inorganic acids: For example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, or acid addition salts with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, Caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentane propionic acid, 3-hydroxy- 2-Naphthoic acid, Niacin, Pamoic acid, Pectic acid, Persulfuric acid, 3-Pheny
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an ammonium salt or a Acceptable salts of cationic organic bases, such as salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1 , 6-Hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol.
  • basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides compounds such as benzyl and phenethyl bromide.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl and dipentyl sulfate
  • long chain halides such as decyl, lauryl, myr
  • acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid by any of a variety of known methods.
  • the alkali metal and alkaline earth metal salts of the acidic compounds of the present disclosure are prepared by reacting them with an appropriate base by various known methods.
  • the present invention includes all possible salts of the disclosed compounds, either as a single salt or as any mixture of said salts in any ratio.
  • compound of the present disclosure may include: the compound represented by formula (I), its pharmaceutically acceptable salts, its solvates, and its pharmaceutically acceptable salts' solvents compounds, and their mixtures.
  • the compounds of the present disclosure may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired.
  • Asymmetric carbon atoms can exist in the (R) or (S) configuration, giving racemic mixtures in the case of one asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers .
  • asymmetry may also exist due to hindered rotation about a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound.
  • Preferred compounds are those that produce the more desirable biological activity. Isolated, purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the disclosed compounds are included within the scope of the present invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.
  • chelator units with respect to compounds of general formula (I) refer to molecular fragments derived from chelators.
  • a chelator unit is a molecular fragment derived from 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), which may be through one of the carboxyl groups of DOTA amide formation and introduced into the compound of general formula (I).
  • DOTA 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid
  • Fibroblastin inhibitor units referred to in this disclosure with respect to compounds of general formula (I) refer to molecular fragments derived from fibroblastin inhibitors.
  • the inhibitor is a FAPI series compound disclosed in Table 1 and Table 3 of WO2019154886A1
  • the "fibroblastin inhibitor unit” is a molecular fragment obtained by removing R 8 in the FAPI series compound.
  • the "albumin-binding unit” referred to in the present disclosure for the compound of general formula (I) refers to a molecular fragment having a high affinity for albumin, and the molecular fragment has a chelator unit and a fibroblastin inhibitor unit linked the group.
  • the "FAPI unit and the C unit together" mentioned in the present disclosure for the compound of the general formula (I) does not mean that the FAPI unit and the C unit are directly connected in the compound of the general formula (I), but refers to a false situation, That is, the FAPI unit and the C unit in the compound of the general formula (I) are extracted and connected (the albumin-binding unit in the middle is removed).
  • the present disclosure employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and coordination chemistry. Unless otherwise specified, the present disclosure adopts traditional methods of mass spectrometry and elemental analysis, and each step and condition may refer to the conventional operation steps and conditions in the art.
  • reagents and starting materials used in the present disclosure are commercially available or can be prepared by conventional chemical synthesis methods.
  • the term “optional” is used herein to describe an event, meaning that the event may or may not occur.
  • the term “optionally substituted” refers to being unsubstituted or having at least one non-hydrogen substituent that does not destroy the intended properties possessed by the unsubstituted analog.
  • the expression “optionally, and pharmaceutically acceptable excipients” as used herein means that pharmaceutically acceptable excipients may or may not be present in the pharmaceutical composition.
  • the number of “substitutions” can be one or more; when there are more than one, it can be 2, 3 or 4. In addition, when the number of the "substitution” is plural, the “substitution” may be the same or different.
  • substitution can be arbitrary unless otherwise specified.
  • C 1 -C 10 alkyl refers to a straight or branched alkane chain containing from 1 to 10 carbon atoms.
  • representative examples of C 1 -C 6 alkyl include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tert-amyl (C 5 ), n-hexyl (C 6 ) and the like.
  • lower alkyl refers to straight or branched chain alkyl groups having 1 to 4 carbon atoms.
  • Substituted alkyl refers to an alkyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents.
  • haloalkyl refers to an alkyl group having one or more halogen substituents including, but not limited to, such as -CH2Br , -CH2I , -CH2Cl , -CH2F , -CHF2, and - groups like CF 3 .
  • alkylene refers to a divalent hydrocarbon group as described above for “alkyl” but having two points of attachment.
  • a methylene group is a -CH2- group and an ethylene group is a -CH2 - CH2- group.
  • alkoxy and alkylthio refer to an alkyl group as described above attached via an oxygen bond (-O-) or sulfur bond (-S-), respectively.
  • substituted alkoxy and substituted alkylthio refer to substituted alkyl groups attached via an oxygen bond or a sulfur bond, respectively.
  • Lower alkoxy is the group OR where R is lower alkyl (an alkyl group containing from 1 to 4 carbon atoms).
  • halogen refers to fluorine, chlorine, iodine or bromine.
  • albumin as a drug carrier has become more and more extensive, and it is often used to improve the hemodynamic properties of drugs, thereby increasing the blood half-life.
  • Albumin is the most abundant protein in human plasma and is responsible for various storage and transportation tasks in the body. Compared with normal tissue, tumor tissue has abundant blood vessels and larger vascular endothelial space. Albumin, as a macromolecular substance, can penetrate into tumor tissue but cannot enter normal tissue. In addition, substances with smaller molecular weight are cleared faster from tumor stroma. , and macromolecules are retained, this effect is also known as the enhanced permeability and retention effect (EPR) of macromolecules in tumor tissue.
  • EPR enhanced permeability and retention effect
  • the tumor microenvironment has high expression of receptors that bind albumin, such as the gp60 receptor and SPARC134, which further retain albumin in the vicinity of the tumor.
  • albumin as a carrier for anticancer drugs not only improves the half-life of these drugs, but also improves delivery to and retention in tumors.
  • the albumin drug loading system mainly includes chemically coupled and physically bound albumin drug loading.
  • the albumin binding agent is linked with the chelator unit and the FAP inhibitor unit to form a small molecule compound (TEFAPI) that can be dual-targeted with FAP and albumin, with the purpose of prolonging the blood circulation half-life of the FAPI molecule, increasing the tumor uptake.
  • TEFAPI small molecule compound
  • the present disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof,
  • C is a chelator unit
  • AB is an albumin binding unit
  • FAPI is a fibroblastin inhibitor unit.
  • the C unit is derived from a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethyl acetate Diaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylene triamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).
  • a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethyl acetate Diaminetetraacetic acid (EDTA),
  • the C unit is It is derived from 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), which can form an amide through one of the carboxyl groups of DOTA and introduced into the compound of general formula (I).
  • DOTA 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid
  • the C unit is It is derived from 11,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), which can form an amide through one of the carboxyl groups of NOTA and introduced into the compound of general formula (I).
  • NOTA 11,4,7-triazacyclononane-1,4,7-triacetic acid
  • the C unit in the compound of formula (I) is selected from:
  • the FAPI unit in the compound of formula (I) is selected from
  • the FAPI unit and the C unit in the compound of general formula (I) satisfy the following conditions:
  • the new compound obtained by the connection is selected from:
  • the compound of general formula (I) can be regarded as the compound FAPI-02, FAPI-04, FAPI-21, FAPI-34, FAPI-42, FAPI-46, FAPI-52, FAPI -69, FAPI-70, FAPI-71, FAPI-72, FAPI-73, FAPI-74 were inserted into the molecular structure of albumin-binding unit AB.
  • Compounds FAPI-02, FAPI-04, FAPI-21, FAPI-34, FAPI-42, FAPI-46, FAPI-52, FAPI-69, FAPI-70, FAPI-71, FAPI-72, FAPI-73, FAPI -74 is disclosed in WO2019154886A1 as a FAP inhibitor.
  • the FAPI unit and the C unit in the compound of the general formula (I) satisfy the following conditions: if the FAPI unit and the C unit are connected (remove the albumin binding unit in the middle), the resulting The new compound is selected from: FAPI-04, FAPI-21 or FAPI-46. In one embodiment, the FAPI unit and the C unit in the compound of general formula (I) satisfy the following conditions: if the FAPI unit and the C unit are connected (remove the albumin binding unit in the middle), the new The compound is FAPI-04.
  • the AB unit contains a 4-iodo-phenyl end group.
  • the AB unit is connected to the terminal end in the FAPI unit An amide bond is formed to connect it to the FAPI unit, and the AB unit is connected to the C unit by forming an amide bond with the terminal carbonyl group in the C unit.
  • the compound of general formula (I) is selected from:
  • the present disclosure also provides a chelate compound comprising:
  • the chelator unit chelates directly with the radionuclide (eg, 68Ga chelates with a chelator unit derived from DOTA), or the radionuclide is introduced indirectly through chelation with other metals (eg, , Al 3+ is chelated with a chelator unit derived from DOTA, and the radionuclide 18 F is introduced into the chelate in the form of a counter ion).
  • the radionuclide eg, 68Ga chelates with a chelator unit derived from DOTA
  • the radionuclide is introduced indirectly through chelation with other metals
  • Al 3+ is chelated with a chelator unit derived from DOTA
  • the radionuclide 18 F is introduced into the chelate in the form of a counter ion.
  • the radionuclide is selected from the group consisting of: 18 F, 51 Cr, 67 Ga, 68 Ga, 111 In, 99 mTc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 15 3Sm, 166 Ho, 86 Y, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu , 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th and 199 Ag.
  • the radionuclide is 68 Ga.
  • the present disclosure also provides a pharmaceutical composition comprising or consisting of:
  • the pharmaceutical composition comprises or consists of at least one of the chelates described above. In another embodiment, the pharmaceutical composition comprises or consists of at least one of the above-mentioned chelates and a pharmaceutically acceptable excipient.
  • compositions of the present disclosure must or may optionally also contain pharmaceutically acceptable excipients for formulating the chelate for the intended route of administration.
  • Adjuvants include, but are not limited to, diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, coating materials, and the like. Excipients are generally described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • excipients include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, Hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxydioctate hydroxystearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, lactose monohydrate, magnesium stearate, mannitol , microcrystalline cellulose, etc.
  • Agents that can be used to formulate the composition for the intended route of administration include:
  • acidulants examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
  • Alkalizing agents include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);
  • Buffers examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, sodium citrate anhydrous, and sodium citrate dihydrate); and the like.
  • fibroblast activating protein is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring, preferably wherein the cancer is selected from breast cancer, pancreatic cancer , Small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophagus cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell kidney Carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, glioma, glioma, astrocytoma,
  • FAP fibroblast activating protein
  • kits comprising or consisting of the above-mentioned chelate complex or the above-mentioned pharmaceutical composition, and instructions for diagnosing or treating a disease.
  • the disease is the above-mentioned disease characterized by overexpression of fibroblast activation protein.
  • the starting materials for the examples are commercially available and/or can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. Those skilled in the art of organic synthesis will appropriately select reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiments, and work-up) in the following synthetic methods. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the reagents and reactions presented.
  • the synthetic reagents and starting materials can be purchased in China through general commercial channels.
  • Suppliers include Sinopharm Chemical Reagent Co., Ltd., Saen Chemical Technology (Shanghai) Co., Ltd., Jiuding Chemical (Shanghai) Technology Co., Ltd., Beijing Bailingwei Technology Co., Ltd. Co., Ltd., Beijing Tongguang Fine Chemical Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Beijing Inoke Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma Aldrich (Shanghai) Trading Co., Ltd.
  • the key starting materials are marked with the CAS number on the circuit diagram.
  • TEFAPI-01, TEFAPI-02, TEFAPI-03, TEFAPI-04 were synthesized through the above chemical routes. Specifically, it can be decomposed into 6 parts: block 7a synthesis, block 7b-d synthesis, block 12 synthesis, block 13 synthesis, block 20 synthesis, and block connection 6 parts, which have certain pre-requirements.
  • Trt-Cl resin (3.85g, 76.3mmol, 1eq)/dichloromethane (500mL) solution was added 71989-26-9 (42.90g, 91.56mmol, 1.2eq), N,N-diisopropyl Ethylamine (29.58 g, 228.90 mmol, 39.87 mL, 3 eq) was stirred at room temperature and sparged with nitrogen for 48 hours.
  • the germanium gallium generator was rinsed with 5 mL of 0.6M high-purity hydrochloric acid to obtain a Ga-68 hydrochloric acid solution. Take 1 mL of the rinsed Ga-68 solution, add 100 ⁇ l 3M sodium hydroxide and 130 ⁇ l 3M sodium acetate to adjust the acidity, the final pH is 4.0, add 50 ⁇ g TEFAPI-06 precursor, and heat the reaction mixture to 90 °C, Hold for 10 minutes. The reaction solution was passed through a C18 cartridge to remove free ions, and then the C18 cartridge was eluted with an ethanol solution. The labeled 68Ga -TEFAPI series molecules were obtained.
  • mice taken 37MBq-labeled product, add 200 microliters of normal saline for dilution, and use an insulin syringe to extract the medicine for later use, wherein the ethanol content of the medicine is not higher than 5%.
  • Healthy mice were anesthetized and placed on the PET/CT collection bed, and an indwelling needle was placed in the tail vein. Connect the syringe to the indwelling needle, and start the PET data collection at the zero time of pushing the needle. The collection time points were 0-60 minutes, 2 hours, 3 hours, 4 hours, and 5 hours, respectively. After the acquisition, professional software was used to reconstruct the data.
  • the reconstruction conditions were that the data was reconstructed every minute for the first 5 minutes, the data was reconstructed every 5 minutes from 5 to 60 minutes, and the data was reconstructed at the remaining time points.
  • the collected data were processed by PET reconstruction software to obtain continuous images, as shown in Figure 1A.
  • a fixed area was delineated at the mouse's heart to obtain SUV-Mean and SUV-Max values at the heart.
  • the obtained SUV was simulated in the data processing software. to obtain the corresponding blood half-life,
  • the germanium gallium generator was rinsed with 5 mL of 0.6M high-purity hydrochloric acid to obtain a Ga-68 hydrochloric acid solution. Take 1 mL of the rinsed Ga-68 solution, add 100 microliters of 3M sodium hydroxide and 130 microliters of 3M sodium acetate to adjust the acidity, the final pH is 4.0, add 50 micrograms of TEFAPI series precursors, and heat the reaction mixture to 90 °C, Hold for 10 minutes. The reaction solution was passed through a C18 cartridge to remove free ions, and then the C18 cartridge was eluted with an ethanol solution. The labeled 68Ga -TEFAPI molecule was obtained.
  • the labeled 68Ga -TEFAPI molecules were diluted with normal saline and injected with 3.7MBq per mouse.
  • PET scan imaging was performed at 0.5 h, 1 h, and 2 h, and reconstruction was performed with PET image processing software. The resulting image is shown below, and it can be seen that the probe has significant uptake at the tumor site.
  • Y-86 is a positron nuclide with a half-life of up to 14.6 hours and can be radiolabeled with DOTA, so it is very suitable for long-term detection of the distribution of TEFAPI molecules in vivo.
  • Take 1 mL of Y-86 hydrochloric acid solution add 100 ⁇ l 3M sodium hydroxide, 130 ⁇ l 3M sodium acetate to adjust the acidity, the final pH is 4.0, add 50 ⁇ g TEFAPI-precursor, and heat the reaction mixture to 90 ° C for 10 minutes .
  • the reaction solution was passed through a C18 cartridge to remove free ions, and then the C18 cartridge was eluted with an ethanol solution.
  • the labeled 86 Y-TEFAPI molecule was obtained.
  • TEFAPI-03 had the highest tumor SUVmax, Tumor/blood Ratio, and Tumor/muscle Ratio.
  • TEFAPI-03 As a representative molecule in the competition inhibition experiment and we performed PET imaging before and after inhibition in the same batch of mice.
  • Tumor-bearing mice were therefore imaged with68Ga -FAPI-04 to confirm that the mice had tumor uptake.
  • these two mice were injected with 300 micrograms of TEFAPI-03 molecule, and 12 hours later, PET molecular imaging of68Ga -FAPI-04 was performed in the mice injected with TEFAPI-06 molecule . Imaging results 30 minutes after injection showed that the imaging of 68Ga -FAPI-04 in the same mouse without TEFAPI-03 molecules showed significant uptake in the tumor, while PET imaging after injection showed no tumor in the mouse. Extra intake.
  • the present disclosure illustrates through the above examples that after the introduction of albumin binding units into FAPI molecules, the blood circulation time of a series of small molecules such as TEFAPI is greatly improved compared with FAPI-04, and the tumor uptake is also effectively improved.
  • a series of small molecules such as TEFAPI
  • the tumor uptake is also effectively improved.
  • Using the long half-life positron nuclide Y-86 it can effectively detect the distribution of small molecules in the living body and fully understand the metabolic status of the molecules.
  • TEFAPI-03 has a long residence time and basically no nuclide residues in metabolic organs.

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Abstract

公开了通式(I)的化合物或者其药学可接受的盐、立体异构体或溶剂合物，其中C为螯合剂单元；AB为白蛋白结合单元；FAPI为成纤维活化蛋白抑制剂单元。还公开了上述化合物与放射性核素的螯合物、药物组合物以及它们作为成纤维细胞活化蛋白抑制剂用于诊断和治疗疾病的用途。 C-AB-FAPI (I)

Description

成纤维细胞活化蛋白抑制剂
相关申请的交叉引用
本申请要求于2020年12月21日提交的中国专利申请序列号202011521361.2的优先权的权益，所述申请通过引用整体并入本文。
技术领域
本公开涉及医疗和诊断领域，具体涉及抑制成纤维活化蛋白的化合物、螯合物、组合物及其用途。
背景技术
肿瘤是威胁人们健康的第二大杀手。肿瘤不仅可以被认为是恶性细胞的集合，也可以被认为是基质细胞的集合，其中包括血管细胞、炎症细胞和成纤维细胞。在有纤维增生反应的肿瘤如乳腺癌、结肠癌和胰腺癌中，肿瘤中的间质可能会达到90％或以上。肿瘤间质中的一种被称为癌症相关成纤维细胞(cancer associated fibroblasts,CAFs)的成纤维细胞亚群，会参与肿瘤的生长、迁移和进展甚至对化学疗法产生抵抗和免疫抑制。
肿瘤微环境(tumour mocroenvironment,TME)在肿瘤的发生发展过程中起到了重要作用，TME以活化的成纤维细胞(CAFs)为核心。成纤维活化蛋白(fibroblast activation protein,FAP)是一种II型跨膜丝氨酸蛋白水解酶，属于二肽基肽酶(DPP)家族。FAP选择性地表达于90％以上的上皮恶性肿瘤的CAFs上，而在正常组织中几乎不表达，具有特殊的生物学特性和基因稳定性。FAP在多种肿瘤的微环境中广泛表达，因此可以通过靶向FAP来靶向不同的肿瘤实体，包括胰腺癌，乳腺癌和肺癌。因此FAP既可以作为肿瘤早期诊断的生物学标志物，又具有良好的靶向治疗生物学特性，有望在恶性肿瘤的临床诊断和治疗方面发挥重要作用。
目前，对FAP的抑制剂研究尚不深入，第一个进入临床试验的FAP活性抑制剂为Talabostat，但其在各种癌症中表现出不充分的临床活性，因此没有继续进一步的发展。后来有研究者利用 131I标记抗FAP的抗体sibrotuzumab进行肿瘤治疗研究，但存在低清除率和缺乏临床活性等缺陷。
近两年来，德国海德堡大学Haberkorn,Uwe团队开发了一系列基于喹啉的小分子放射性药物靶向FAP进行诊断和治疗，参见WO2019154886A1。所生成的抑制剂能够快速且几乎完全的与人类和小鼠的FAP结合，重要的是，它与DPP家族成员DPP4没有交叉反应，因此为进一步的发展奠定了基础。通过将这种FAP抑制剂(fibroblast activation protein inhibitor,FAPI)与螯合剂DOTA连接便形成了具有良好药代动力学特性的放射性核素示踪剂。整个示踪剂中最受关注的为FAPI-04，它对FAP有较高亲和力，示踪剂迅速从血液中清除，并被肾脏清除。这些特性使 68Ga-FAPI-04PET/CT的肿瘤显像具有高对比度和高灵敏度。但FAPI-04在体内的快速清除限制其在肿瘤核素治疗中的应用。因此在保留其优异靶向性并解决FAP抑制剂小分子的循环时间短的问题是尤为期望的。
发明内容
本公开的一个方面提供一种通式(I)的化合物或者其药学可接受的盐、异构体或溶剂合物，
C-AB-FAPI       (I)
其中C为螯合剂单元；AB为白蛋白结合单元；FAPI为成纤维活化蛋白抑制剂单元。 在一些实施方案中，通式(I)中的C单元选自：
Figure PCTCN2021139590-appb-000001
Figure PCTCN2021139590-appb-000002
或者
Figure PCTCN2021139590-appb-000003
在一些实施方案中，通式(I)中的FAPI单元选自：
Figure PCTCN2021139590-appb-000004
Figure PCTCN2021139590-appb-000005
或者
Figure PCTCN2021139590-appb-000006
在一些具体实施方案中，通式(I)中的C单元为
Figure PCTCN2021139590-appb-000007
FAPI单元为
Figure PCTCN2021139590-appb-000008
在一些实施方案中，通式(I)中的AB单元包含4-碘-苯基末端基团
Figure PCTCN2021139590-appb-000009
在一些实施方案中，通式(I)中的AB单元选自
Figure PCTCN2021139590-appb-000010
其中R选自
Figure PCTCN2021139590-appb-000011
其中n＝1、2或3。
在一些实施方案中，AB单元通过与FAPI单元中的末端
Figure PCTCN2021139590-appb-000012
Figure PCTCN2021139590-appb-000013
形成酰胺键将其与FAPI单元相连，AB单元通过与C单元中的末端羰基形成酰胺键将其与C单元相连。
在一些具体实施方案中，通式(I)的化合物选自：
Figure PCTCN2021139590-appb-000014
Figure PCTCN2021139590-appb-000015
或者它们的药学可接受的盐、异构体或溶剂合物。
本公开的另一个方面提供一种螯合物，其包含上述式(I)化合物和放射性核素。
在一些实施方案中，放射性核素选自： 18F、 51Cr、 67Ga、 68Ga、 111In、 99mTc、 186Re、 188Re、 139La、 140La、 175Yb、 153Sm、 166Ho、 86Y、 88Y、 90Y、 149Pm、 165Dy、 169Er、 177Lu、 47Sc、 142Pr、 159Gd、 212Bi、 213Bi、 72As、 72Se、 97Ru、 109Pd、 105Rh、 101mRh、 119Sb、 128Ba、 123I、 124I、 131I、 197Hg、 211At、 151Eu、 153Eu、 169Eu、 201Tl、 203Pb、 212Pb、 64Cu、 67Cu、 188Re、 186Re、 198Au、 225Ac、 227Th和 199Ag中的一种或多种。
在一些具体实施方案中，放射性核素为 68Ga。
本公开的再一个方面提供一种药物组合物，其包含或组成为：至少一种上述式(I)化合物，任选地和药学上可接受的辅料。
本公开的又一个方面还提供上述螯合物或药物组合物在制备用于诊断或治疗在受试者中以成纤维细胞激活蛋白(FAP)过度表达为特征的疾病的试剂或试剂盒中的用途。
本公开的又一个方面还提供一种诊断或治疗在受试者中以成纤维细胞激活蛋白(FAP)过度表达为特征的疾病的方法，通过向需要治疗的受试者施用有效剂量的上述螯合物或药物组合物。
本公开的又一个方面还提供用于诊断或治疗在受试者中以成纤维细胞激活蛋白(FAP)过度表达为特征的疾病的上述螯合物或药物组合物。
在一些实施方案中，成纤维细胞激活蛋白(FAP)过度表达为特征的疾病选自癌症、慢性炎症、动脉粥样硬化、纤维化、组织重塑和瘢痕病，优选地，其中癌症选自乳腺癌、胰腺癌、小肠癌、结肠癌、直肠癌、肺癌、头颈癌、卵巢癌、肝细胞癌、食道癌、下咽癌、鼻咽癌、喉癌、骨髓瘤细胞、膀胱癌、胆管细胞癌、透明细胞肾癌、神经内分泌肿瘤、致癌性骨软化症、肉瘤、CUP(原发性未知癌)、胸腺癌、胶质瘤、神经胶质瘤、星形细胞瘤、子宫颈癌和前列腺癌的一种或多种。
本公开的又一个方面还提供一种试剂盒，其包含或组成为上述螯合物或药物组合物，以及用于诊断或治疗疾病的说明书。
附图说明
为了更清楚地说明本公开实施例的技术方案，下面将对实施例的附图作简单地介绍，显而易见地，下面描述中的附图仅仅涉及本公开的一些实施例，而非对本发明的限制。
图1示出了利用 68Ga-TEFAPI-01、02、03及04进行健康小鼠药物动力学分析结果。
图2示出了利用 68Ga-FAPI-04、 68Ga-TEFAPI-01、 86Y-TEFAPI-02、 86Y-TEFAPI-03、 86Y-TEFAPI-04的PET/CT显像。
图3示出了TEFAPI-03抑制组和非抑制组 68Ga-FAPI-04PET成像对比。
具体实施方式
为使本公开实施例的目的、技术方案和优点更加清楚，下面将结合本公开实施例的附图，对本公开实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本公开的一部分实施例，而不是全部的实施例。基于所描述的本公开的实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明可在不偏离本发明基本属性的情况下以其它具体形式来实施。应该理解的是，在不冲突的前提下，本发明的任一和所有实施方案都可与任一其它实施方案或多个其它实施方案中的技术特征进行组合以得到另外的实施方案。本发明包括这样的组合得到另外的实施方案。
本公开中提及的所有出版物和专利在此通过引用以它们的全部内容纳入本公开。如果通过引用纳入的任何出版物和专利中使用的用途或术语与本公开中使用的用途或术语冲突，那么以本公开的用途和术语为准。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的通常含义。倘若对于某术语存在多个定义，则以本文定义为准。
除非另有说明，当公开或要求保护任何类型的范围时，意图单独公开或要求保护该范围可有理由涵盖的各可能的数值，包括涵盖在其中的任何子范围。例如取代基个数为1至5表明该范围内的整数，其中1-5应理解包括1、2、3、4、5，也包括1-4和1-3的子范围。
本公开的说明书应该被解释为与化学键的法则和原理一致。在一些情况下，可能为了在给定的位置适应取代基而除去氢原子。
本公开中使用的“包括”、“含有”或者“包含”等类似的词语意指出现该词前面的要素涵 盖出现在该词后面列举的要素及其等同，而不排除未记载的要素。本文所用的术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…组成”、或“由…组成”。
术语“药学上可接受的”在本申请中是指：化合物或组合物在化学上和/或在毒理学上与构成制剂的其它成分和/或与用其预防或治疗疾病或病症的人类或哺乳动物相容。
术语“受试者”或“患者”在本申请中包括人类和哺乳动物。
在本申请的上下文中，除非作出相反的具体说明，术语“治疗”也可包括预防。
术语“溶剂合物”在本申请中指的是通过组合式(I)化合物或其药学上可接受的盐和溶剂而形成的复合物。应理解的是，在诊断或治疗本申请所述的疾病或病症中使用的式(I)化合物的任何溶剂合物尽管可能提供不同的性质(包括药代动力学性质)，但是一旦吸收至受试者中，会得到式(I)化合物，使得式(I)化合物的使用分别涵盖式(I)化合物的任何溶剂合物的使用。
术语“水合物”指的是上述术语“溶剂合物”中溶剂为水的情形。
应进一步理解，式(I)化合物或其药学上可接受的盐可以溶剂合物形式分离，并且因此任何所述溶剂合物皆包括于本发明的范围内。例如，式(I)化合物或其药学上可接受的盐可以未溶剂化形式以及与药学上可接受的溶剂(诸如，水、乙醇等)形成的溶剂化形式存在。
术语“药学上可接受的盐”是指本公开化合物的相对无毒的加成盐。例如，参见S.M.Berge等人“Pharmaceutical Salts”，J.Pharm.Sci.1977,66,1-19。
本公开化合物的适合的药学上可接受的盐可以是例如在链或环中携带氮原子的具有足够碱性的本公开化合物的酸加成盐，例如与如下无机酸形成的酸加成盐：例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸，或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸或硫氰酸。
另外，具有足够酸性的本发明化合物的另一种适合的药学上可接受的盐是碱金属盐例如钠盐或钾盐，碱土金属盐例如钙盐或镁盐，铵盐，或与提供生理学上可接受的阳离子的有机碱形成的盐，例如与如下物质形成的盐：N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。另外，碱性含氮基团可用如下试剂季铵化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二烷基酯，例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯；长链卤化物例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。
本领域技术人员还会认识到，所要求保护的化合物的酸加成盐可通过多种已知方法中的任意一种使所述化合物与适当的无机酸或有机酸反应来制备。或者，本公开的酸性化合物的碱金属盐和碱土金属盐通过各种已知的方法使其与适当的碱反应来制备。
本发明包括本公开化合物的所有可能的盐，其可为单一盐或所述盐的任意比例的任意混合物。
应理解，本申请所用的术语“本公开化合物”根据语境可包括：式(I)所示的化合物、 其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、以及它们的混合物。
本公开的化合物可包含一个或多个不对称中心，视期望的各种取代基的位置和性质而定。不对称碳原子可以(R)或(S)构型存在，在具有一个不对称中心的情况下得到外消旋混合物，并且在具有多个不对称中心的情况下得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳环。
优选的化合物是那些能产生更期望的生物活性的化合物。本公开化合物的分离的、纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物均包括在本发明的范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
本公开针对通式(I)的化合物提及的“螯合剂单元”是指衍生自螯合剂的分子片段。例如螯合剂单元是衍生自1,4,7,10-四氮杂环十二烷-N,N',N,N'-四乙酸(DOTA)的分子片段，其可以是通过DOTA的一个羧基形成酰胺
Figure PCTCN2021139590-appb-000016
而引入到通式(I)的化合物中。
本公开针对通式(I)的化合物提及的“成纤维活化蛋白抑制剂单元”是指衍生自成纤维活化蛋白抑制剂的分子片段。例如，当抑制剂是WO2019154886A1的表1和表3中公开的FAPI系列化合物，“成纤维活化蛋白抑制剂单元”是该FAPI系列化合物中去除R 8得到的分子片段。
本公开针对通式(I)的化合物提及的“白蛋白结合单元”是指具有与白蛋白高亲合力的分子片段，并且该分子片段具有与螯合剂单元和成纤维活化蛋白抑制剂单元相连的基团。
本公开针对通式(I)的化合物提及的“FAPI单元和C单元一起构成”并不是指在通式(I)的化合物中FAPI单元和C单元直接连接，而是指一种假象情形，即将通式(I)的化合物中的FAPI单元和C单元抽出来连接(去掉中间的白蛋白结合单元)。
应该理解，在本公开中使用的单数形式(如“一种”)可包括复数指代，除非另有规定。
除非另有指明，本公开采用分析化学、有机合成化学和配位化学的标准命名及标准实验室步骤和技术。除非另有说明，本公开采用质谱、元素分析的传统方法，各步骤和条件可参照本领域常规的操作步骤和条件。
本公开所用试剂和原料是市售可得的或者可通过常规化学合成方法制得的。
本文使用术语“任选”来描述某一情形是指该情形可发生也可不发生。例如，术语“任选取代的”是指为未取代的或者具有至少一个不破坏由未取代的类似物所拥有的目的性能的非氢取代基。例如，针对药物组合物，本文使用的表述“任选地，和药学上可接受的辅料”表示药学上可接受的辅料可存在于药物组合物中，也可以不存在于药物组合物中。
本公开中，如无特殊说明，所述的“取代”的个数可为一个或多个；当为多个时，可为2个、3个或4个。并且，当所述的“取代”的个数为多个时，所述的“取代”可相同或不同。
本公开中，“取代”的位置，如未做特别说明，位置可为任意。
本文使用的术语“C 1-C 10烷基”是指含有1-10个碳原子的直链或支链烷烃链。例如，C 1-C 6烷基的代表性实例包括但不限于甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3–戊烷基(C 5)、新戊基(C 5)、3-甲基-2-丁烷基(C 5)、叔戊基(C 5)和正己基(C 6)等。术语“低级烷基”是指具有1至4个碳原子的直链或支链烷基。“经取代的烷基”指在任何可用连接点处经一个或多个取代基优 选1至4个取代基取代的烷基。术语“卤代烷基”是指具有一个或多个卤素取代基的烷基，其包括但不限于如-CH 2Br、-CH 2I、-CH 2Cl、-CH 2F、-CHF 2及-CF 3那样的基团。
本文使用的术语“亚烷基”是指如以上就“烷基”所述但具有两个连接点的二价烃基。例如，亚甲基为-CH 2-基团，亚乙基为-CH 2-CH 2-基团。
本文使用的术语“烷氧基”及“烷基硫基”指分别经由氧键(-O-)或硫键(-S-)连接的如上所述的烷基。术语“经取代的烷氧基”及“经取代的烷基硫基”指分别经由氧键或硫键连接的经取代的烷基。“低级烷氧基”为基团OR，其中R为低级烷基(含有1至4个碳原子的烷基)。
本文使用的术语“卤素”是指氟、氯、碘或溴。
白蛋白作为药物载体的应用已越来越广泛，常被用来改善药物的血流动力学特性，从而提高血流半衰期。白蛋白是人体血浆中含量最丰富的蛋白质，承担着体内各种贮存和运输工作。与正常组织相比，肿瘤组织的血管丰富、血管内皮间隙较大，白蛋白作为大分子物质，能够渗入肿瘤组织而不能进入正常组织，另外，分子量较小的物质从肿瘤间质中清除较快，而大分子被截留，这种效应又被称为大分子物质在肿瘤组织的透过性增强及滞留效应(enhanced permeability and retention effect,EPR)。此外，肿瘤微环境有结合白蛋白的受体高表达，例如gp60受体和SPARC134，它们进一步使白蛋白保留在肿瘤附近。因此，使用白蛋白作为抗癌药物的载体不仅改善了这些药物的半衰期，而且还改善了向肿瘤的递送和在肿瘤中的保留。白蛋白载药体系主要包括化学偶联和物理结合的白蛋白载药。
本公开将白蛋白结合剂与螯合剂单元和FAP抑制剂单元进行连接，从而形成能与FAP和白蛋白进行双靶向的小分子化合物(TEFAPI)，目的在于延长FAPI分子的血液循环半衰期，增加肿瘤摄取。
本公开提供了一种通式(I)的化合物或者其药学可接受的盐、异构体或溶剂合物，
C-AB-FAPI(I)
其中C为螯合剂单元；AB为白蛋白结合单元；FAPI为成纤维活化蛋白抑制剂单元。
在一种实施方式中，C单元衍生自选自以下的螯合剂：1,4,7,10-四氮杂环十二烷-N,N',N,N'-四乙酸(DOTA)、乙二胺四乙酸(EDTA)、1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)、三亚乙基四胺(TETA)、亚氨基二乙酸、二亚乙基三胺-N,N,N',N',N”-五乙酸(DTPA)、双-(羧甲基咪唑)甘氨酸或6-肼基吡啶-3-羧酸(HYNIC)。
例如，C单元为
Figure PCTCN2021139590-appb-000017
其衍生自1,4,7,10-四氮杂环十二烷-N,N',N,N'-四乙酸(DOTA)，其可以通过DOTA的一个羧基形成酰胺
Figure PCTCN2021139590-appb-000018
而引入到通式(I)的化合物中。
例如，C单元为
Figure PCTCN2021139590-appb-000019
其衍生自11,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)，其可以通过NOTA的一个羧基形成酰胺
Figure PCTCN2021139590-appb-000020
而引入到通式(I)的化合物中。
在一种实施方式中，通式(I)的化合物中的C单元选自：
Figure PCTCN2021139590-appb-000021
Figure PCTCN2021139590-appb-000022
或者
Figure PCTCN2021139590-appb-000023
在一种实施方式中，通式(I)的化合物中的FAPI单元选自
Figure PCTCN2021139590-appb-000024
Figure PCTCN2021139590-appb-000025
或者
Figure PCTCN2021139590-appb-000026
在一种实施方式中，通式(I)的化合物中的FAPI单元和C单元满足以下条件：
如果将FAPI单元和C单元进行连接(去掉中间的白蛋白结合单元)，则连接得到的新的化合物选自：
Figure PCTCN2021139590-appb-000027
Figure PCTCN2021139590-appb-000028
换言之，在该实施方式中，通式(I)的化合物可以看作是在化合物FAPI-02、FAPI-04、FAPI-21、FAPI-34、FAPI-42、FAPI-46、FAPI-52、FAPI-69、FAPI-70、FAPI-71、FAPI-72、FAPI-73、FAPI-74的分子结构中插入白蛋白结 合单元AB。化合物FAPI-02、FAPI-04、FAPI-21、FAPI-34、FAPI-42、FAPI-46、FAPI-52、FAPI-69、FAPI-70、FAPI-71、FAPI-72、FAPI-73、FAPI-74在WO2019154886A1中披露为一种FAP抑制剂。
在一种优选的实施方式中，通式(I)的化合物中的FAPI单元和C单元满足以下条件：如果将FAPI单元和C单元进行连接(去掉中间的白蛋白结合单元)，则连接得到的新的化合物选自：FAPI-04、FAPI-21或FAPI-46。在一种实施方式中，通式(I)的化合物中的FAPI单元和C单元满足以下条件：如果将FAPI单元和C单元进行连接(去掉中间的白蛋白结合单元)，则连接得到的新的化合物为FAPI-04。
在一种实施方式中，AB单元包含4-碘-苯基末端基团。
在一种实施方式中，AB单元选自
Figure PCTCN2021139590-appb-000029
其中R选自
Figure PCTCN2021139590-appb-000030
Figure PCTCN2021139590-appb-000031
其中n＝1、2或3。
在一种实施方式中，AB单元通过与FAPI单元中的末端
Figure PCTCN2021139590-appb-000032
Figure PCTCN2021139590-appb-000033
形成酰胺键将其与FAPI单元相连，AB单元通过与C单元中的末端羰基形成酰胺键将其与C单元相连。
在一种实施方式中，通式(I)的化合物选自：
Figure PCTCN2021139590-appb-000034
本公开还提供了一种螯合物，其包含：
上述通式(I)的化合物或者其药学可接受的盐、异构体或溶剂合物，和
放射性核素。
在所述螯合物中，螯合剂单元与放射性核素直接螯合(例如， 68Ga与衍生自DOTA的螯合剂单元螯合)，或者通过与其它金属螯合间接地引入放射性核素(例如，Al 3+与衍生自DOTA的螯合剂单元螯合，放射性核素 18F以反离子形式引入螯合物中)。
在一种实施方式中，放射性核素选自： 18F、 51Cr、 67Ga、 68Ga、 111In、 99mTc、 186Re、 188Re、 139La、 140La、 175Yb、 153Sm、 166Ho、 86Y、 88Y、 90Y、 149Pm、 165Dy、 169Er、 177Lu、 47Sc、 142Pr、 159Gd、 212Bi、 213Bi、 72As、 72Se、 97Ru、 109Pd、 105Rh、 101mRh、 119Sb、 128Ba、 123I、 124I、 131I、 197Hg、 211At、 151Eu、 153Eu、 169Eu、 201Tl、 203Pb、 212Pb、 64Cu、 67Cu、 188Re、 186Re、 198Au、 225Ac、 227Th和 199Ag。例如，所述放射性核素为 68Ga。
本公开还提供了一种药物组合物，其包含或组成为：
至少一种上述螯合物，
任选地，和药学上可接受的辅料。
在一种实施方式中，药物组合物包含或组成为至少一种上述螯合物。在另一种实施方式中，药物组合物包含或组成为至少一种上述螯合物和药学上可接受的辅料。
本公开的组合物必须或视需要还可包含将螯合物配制成用于预期的给药途径的药学上可接受的辅料。辅料包括但不限于稀释剂、崩解剂、沉淀抑制剂、表面活性剂、助流剂、粘合剂、润滑剂、包衣材料等。辅料在E.W.Martin的“Remington's Pharmaceutical Sciences”中被一般性描述。辅料的实例包括但不限于单硬脂酸铝、硬脂酸铝、羧甲基纤维素、羧甲基纤维素钠、交聚维酮、异硬脂酸甘油酯、单硬脂酸甘油酯、羟基乙基纤维素、羟基甲基纤维素、羟基硬脂酸羟基二十八酯、羟基丙基纤维素、羟基丙基甲基纤维素、乳糖、乳糖一水合物、硬脂酸镁、甘露醇、微晶纤维素等。
适当时可用于将所述组合物配制成用于预期的给药途径的试剂包括：
酸化剂(实例包括但不限于乙酸、柠檬酸、富马酸、盐酸、硝酸)；
碱化剂(实例包括但不限于氨水溶液、碳酸铵、二乙醇胺、单乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺(triethanolamine)、三乙醇胺(trolamine))；
缓冲剂(实例包括但不限于偏磷酸钾、磷酸氢二钾、乙酸钠、无水柠檬酸钠以及柠檬酸钠二水合物)；等等。
本公开的另一方面涉及上述的螯合物或组合物用于诊断或治疗在哺乳动物或人类中以成纤维细胞激活蛋白过度表达为特征的疾病。例如以成纤维细胞激活蛋白(FAP)过度表达为特征的疾病选自癌症、慢性炎症、动脉粥样硬化、纤维化、组织重塑和瘢痕病，优选地，其中癌症选自乳腺癌、胰腺癌、小肠癌、结肠癌、直肠癌、肺癌、头颈癌、卵巢癌、肝细胞癌、食道癌、下咽癌、鼻咽癌、喉癌、骨髓瘤细胞、膀胱癌、胆管细胞癌、透明细胞肾癌、神经内分泌肿瘤、致癌性骨软化症、肉瘤、CUP(原发性未知癌)、胸腺癌、胶质瘤、神经胶质瘤、星形细胞瘤、子宫颈癌和前列腺癌。
本公开的又一方面涉及一种试剂盒，其包含或组成为上述螯合物或上述药物组合物，以及用于诊断或治疗疾病的说明书。在一种优选的实施方式中，所述疾病为成纤维细胞激活蛋白过度表达为特征的上述疾病。
实施例
实施例的起始材料是市售可得的和/或可以以有机合成领域技术人员熟知的多种方法进行制备。有机合成领域的技术人员会在下述合成方法的中适当地选择反应条件(包括溶剂、反应气氛、反应温度、实验的持续时间和后处理)。有机合成领域的技术人员会理解，存在于分子各部分上的官能团应当与所提出的试剂和反应相容。
以下缩写分别表示：
一、TEFAPI-01/02/03/04的合成
Figure PCTCN2021139590-appb-000035
合成的试剂和起始物料均可在中国通过一般商业渠道购得，供应商包括国药集团化学试剂有限公司、萨恩化学技术(上海)有限公司、九鼎化学(上海)科技有限公司、北京百灵威科技有限公司、北京市通广精细化工公司、上海毕得医药科技有限公司、北京伊诺凯科技有限公司、上海麦克林生化科技有限公司、西格玛奥德里奇(上海)贸易有限公司。其中的关键起始物料均在线路图上标示出CAS号。
TEFAPI-01、TEFAPI-02、TEFAPI-03、TEFAPI-04通过以上化学线路合成。具体可以分解为砌块7a合成、砌块7b-d合成、砌块12合成、砌块13合成、砌块20合成及砌块连接6部分，相互之间具有一定的前置性要求。
砌块7a合成：
a)向Trt-Cl树脂(3.85g,76.3mmol,1eq)/二氯甲烷(500mL)溶液中加入71989-26-9(42.90g,91.56mmol,1.2eq)、N,N-二异丙基乙胺(29.58g,228.90mmol,39.87mL,3eq)，室温搅拌，并氮气鼓泡48小时。随后，混合物依次用二氯甲烷(5*500mL)、CH 3OH(5*500mL)和二甲基甲酰胺(5*500mL)洗涤，得到化合物1(35.75g,76.30mmol,100.00％产率)。
b)向上述树脂中加入哌啶/二甲基甲酰胺(v/v＝1:5,400mL)溶液，氮气鼓泡20分钟，随后用二甲基甲酰胺(5*300mL)洗涤，获得化合物2(14.19g,54.51mmol,100.00％产率)。
c)在0℃下加入化合物27913-58-2(5.35g,18.44mmol,1.2eq)/二甲基甲酰胺(200mL)溶液中加入6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯HCTU(12.71g,30.73mmol,2eq)、HOBt(1.04g,7.68mmol,0.5eq)和N,N-二异丙基乙胺(5.96g,46.10mmol,8.03mL,3eq)，随后在0摄氏度继续搅拌1小时。随后向体系中加入化合物2(4g,15.37mmol,1eq)树脂，随后在25℃氮气鼓泡3小时。树脂应用二甲基甲酰胺(4*100mL)和二氯甲烷(6*200mL)洗涤，获得化合物3(8.18g,15.36mmol,100.00％产率)。
d)向上述树脂中加入二氯甲烷/三氟乙酸(v/v＝100:1,600mL)溶液，氮气鼓泡20 分钟，随后过滤。滤液使用NaHCO 3(aq)调至中性，并用二氯甲烷(200mL*3)和水(200mL*3)分液萃取，合并的有机相用柠檬酸(200mL*3)洗涤，随后减压蒸干，获得黄色固体化合物7a(2.1g,3.97mmol,25.84％产率,98.0％纯度)。MS(ESI +):m/z419.0(M+H) +
砌块7b-d合成：
Figure PCTCN2021139590-appb-000036
b、c和d具有相似的实验步骤，现以b作为实施例。
a)在0℃下，向化合物71989-14-5(4.95g,19mmol,1eq)的二甲基甲酰胺(100mL)溶液中加入6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯HCTU(15.72g,38.00mmol,2eq)、HOBt(1.28g,9.50mmol,0.5eq)和N,N-二异丙基乙胺(7.37g,57.00mmol,9.93mL,3eq)，并在0℃反应1小时。随后加入化合物2(9.38g,22.80mmol,1.2eq)树脂，在25℃下氮气鼓泡反应2小时。树脂用二甲基甲酰胺(4*100mL)洗涤，获得化合物4b(12.42g,17.10mmol,89.99％产率,90％纯度)。
b)化合物4b(9.17g,19mmol,1eq)树脂中加入哌啶/二甲基甲酰胺(v/v＝1:5,400mL)溶液，氮气鼓泡30分钟，随后用二甲基甲酰胺(5*300mL)洗涤，获得化合物5b(4.95g,17.11mmol,90.07％产率,90％纯度)。
c)0℃下，向化合物27913-58-2(6.61g,22.80mmol,1.2eq)的二甲基甲酰胺(100mL)溶液中加入6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯HCTU(15.72g,38.00mmol,2eq)、N,N-二异丙基乙胺(7.37g,57.00mmol,9.93mL,3eq)和HOBt(1.28g,9.50mmol,0.5eq)at 0℃，随后在0摄氏度继续搅拌1小时。随后向体系中加入化合物5b(7.93g,19mmol,1eq)树脂，并在25℃反应2h，树脂用二甲基甲酰胺(4*100mL)和二氯甲烷(6*200mL)洗涤，获得化合物6b(3.5g,5.08mmol,26.71％产率)。
d)向上述树脂中加入二氯甲烷/三氟乙酸(v/v＝100:1,600mL)溶液，氮气鼓泡20分钟，随后过滤。滤液使用NaHCO 3(aq)调至中性，并用二氯甲烷(200mL*3)和水(200mL*3)分液萃取，合并的有机相用柠檬酸(200mL*3)洗涤，随后减压蒸干，获得黄色 固体化合物7b(3.2g,7.11mmol,74.99％产率,93.20％纯度)。 1H NMR(CDCl 3-d 6,400MHz):δppm 1.43-1.51(m,23H),1.71-1.88(m,6H),1.91-1.93(m,3H),2.23-2.26(m,2H),2.57-2.61(m,3H),3.07-3.11(m,3H),4.48-4.50(m,1H),4.57-4.60(m,1H),4.34-4.37(m,1H),4.76(br s,1H),6.99-7.09(m,2H),7.58-7.61(m,2H),8.09-8.12(m,1H)
砌块12合成：
Figure PCTCN2021139590-appb-000037
a)0℃下，20分钟内缓慢地向化合物203866-15-3(10g,37.70mmol,1eq)的MeOH(25mL)溶液中加入NH 3的(28.89g,1.70mol,45eq)的MeOH(125mL)溶液。随后温度恢复至室温，在N 2(15psi)气氛下搅拌反应18小时。反应结束后，减压蒸发浓缩，使用PE/MTBE打浆，得到黄色固体化合物8(8.9g,35.57mmol,94.34％产率)。 1H NMR(400MHz DMSO)：δ1.28-1.45(m,9H),2.16-2.38(m,1H),2.59-2.87(m,1H),3.55-3.84(m,2H),4.08-4.36(m,1H),6.97-7.19(m,1H),7.36-7.61(m,1H)
b)0℃下，20分钟内缓慢地向化合物8(8.9g,35.57mmol,1eq)的二氯甲烷(100mL)溶液中加入吡啶(3.38g,42.68mmol,3.44mL,1.2eq)。保持0℃，加入三氟乙酸酐(8.96g,42.68mmol,5.94mL,1.2eq)，随后反应恢复至室温并搅拌18小时，随后减压浓缩。使用PE/MTBE打浆，得到黄色固体化合物9(7.5g,32.30mmol,90.81％产率)。 1H NMR(400MHz氯仿-d)：δ1.33-1.66(m,9H),2.71(br t,J＝9.04Hz,2H),3.80(br s,2H),4.52-4.90(m,1H)
c)向化合物9(7.0g,30.14mmol,1eq)的乙腈(200mL)溶液中加入HCl/二氧杂环已烷(4M,14.00mL,1.86eq)，随后反应18小时。固体过滤并用甲基叔丁基醚(100mL)洗涤，得到白色固体化合物10(2.2g,13.05mmol,43.30％产率,HCl)。 1H NMR(400MHz DMSO)δ2.64-3.13(m,2H),3.48-3.89(m,2H),4.99(br t,J＝6.95Hz,1H),9.80(br s,2H)
d)向10mL的二甲基甲酰胺中依次加入2-(叔丁氧基羰基氨基)乙酸(779.41mg,4.45mmol,1.5eq)、HOBt(80.16mg,593.22μmol,0.2eq)、HBTU(2.25g,5.93mmol,2eq)和化合物10(500mg,2.97mmol,1eq,HCl)，随后反应搅拌30分钟。随后加入DIPEA(1.15g,8.90mmol,1.55mL,3eq)并搅拌16小时。反应结束后，加入水(20mL)，并用EtOAc(50mL)萃取，有机相浓缩后，使用硅胶柱层析法(PE:EtOAc＝1:1)纯化，得到化合物11(0.625g,2.13mmol,71.68％产率)。 1H NMR(400MHz DMSO):δ1.38(m,9H),2.78(m,2H),3.77(m,2H),4.06(m,1H),4.23(m,1H),5.07(d,J＝5.2Hz,1H),7.14(m,1H)
e)向化合物11(0.4g,1.38mmol,1eq)的乙腈(13.5mL)溶液中，在0摄氏度下，加入HCl/二氧杂环已烷(4M,2.67mL,7.71eq)，随后反应恢复至室温反应16小时。浓缩得到灰白色固体化合物12(322mg,1.28mmol,92.89％产率,90％纯度,HCl)。 1H NMR(400MHz DMSO):δ2.81-3.01(m,2H),3.57(s,2H),3.69(br d,J＝5.01Hz,1H),3.78-3.89(m,1H),3.91-4.14(m,2H),4.24(ddd,J＝15.59,11.41,4.11Hz,1H),5.19(dd,J＝8.70,3.34Hz,1H),8.38(br s,3H)
砌块13合成：
Figure PCTCN2021139590-appb-000038
a)化合物137076-54-1(150mg,261.90umol,1eq)溶解于乙腈(15mL)中，并依次加入1-羟基吡咯烷-2,5-二酮(33.16mg,288.09umol,1.1eq)、2-(IH-苯并三唑-1-基)-N,N,N’,N’-四甲基异脲六氟化磷HBTU(109.26mg,288.09umol,1.1eq)，随后搅拌12小时，混合物减压干燥后，使用prep-TLC(EA:CAN＝7:1)纯化，得到浅黄色固体化合物13(115mg,171.69μmol,65.56％产率)直接用于下步。
砌块20合成：
Figure PCTCN2021139590-appb-000039
a)化合物52351-75-4(20g,112.89mmol,1eq)和KOH(69.68g,1.24mol,11eq)溶解于H 2O(200mL)中，随后加入PYRUVIC ACID(10.94g,124.18mmol,8.75mL,1.1eq)，反应混合物在40℃下反应15小时。随后将反应冷却至15℃，并用盐酸酸化至pH 3，将固体过滤并用去离子水洗涤，得到灰白色固体化合物14(24g,92.23mmol, 81.70％产率,95％纯度) 1H NMR(400MHz DMSO):δ3.70-4.24(m,3H),7.58(dd,J＝9.24,2.80Hz,1H),8.15(d,J＝9.30Hz,1H),8.26(d,J＝2.74Hz,1H),8.53(s,1H),13.75(br s,2H),MS(ESI+):m/z 248.1(M+H) +
b)向化合物14(24g,97.09mmol,1eq)中加入硝基苯(150mL)并在220℃下搅拌1.5小时。随后将反应冷却至15℃，并加入PE(150mL)，析出的固体用PE(100mL)洗涤，得到灰白色固体化合物15(16.8g,82.68mmol,85.16％产率)。 1H NMR(400MHz DMSO)δ3.72-4.14(m,3H),7.49(dd,J＝9.23,2.75Hz,1H),7.93(d,J＝4.40Hz,1H),8.02(d,J＝9.17Hz,1H),8.18(d,J＝2.69Hz,1H),8.87(d,J＝4.40Hz,1H),13.76(br s,1H)。MS(ESI+):m/z 202.1(M-H) -
c)向化合物15(40g,196.86mmol,1eq)加入氢溴酸(1L,48％于水溶液)，并在130℃下搅拌12小时。随后，反应使用350ml 30％氢氧化钠溶液碱化至pH＝6，大量沉淀析出，沉淀过滤后，使用甲醇洗涤沉淀，并抽干得到粗产物，并用甲醇多次洗涤得到产品褐色固体化合物16(30g,128.93mmol,65.50％产率,81.3％纯度)。 1H NMR(400MHz,DMSO-d 6)δppm 13.66(br s,1H),10.24(s,1H),8.77(d,J＝4.5Hz,1H),8.06(d,J＝2.6Hz,1H),7.95(d,J＝9.1Hz,1H),7.84(d,J＝4.4Hz,1H),7.36(dd,J＝2.7,9.1Hz,1H)。MS(ESI -):m/z 377.0(2M-H) -
d)向化合物16(30g,158.59mmol,1eq)的二甲基甲酰胺(300mL)溶液中加入碳酸钾(87.67g,634.36mmol,4eq)和1-溴-3-氯-丙烷(24.97g,158.59mmol,15.60mL,1eq)，随后反应在60℃搅拌12小时。蒸发浓缩后，向体系加入200mL水，大量固体析出，随后反应混合物在25℃搅拌15分钟，抽滤。使用乙酸乙酯研磨，并过滤，获得棕色固体化合物17(37.58g,130.13mmol,86.15％产率,92％纯度)。 1H NMR(400MHz,DMSO-d 6)δppm 2.26-2.98(m,2H),3.83-3.88(m,2H),4.22-4.25(m,2H),7.54(dd,J＝9.19,2.69Hz,1H),7.96(d,J＝4.38Hz,1H),8.03-8.11(m,1H),8.19(d,J＝2.63Hz,1H),8.90(d,J＝4.38Hz,1H)。MS(ESI +):m/z 266.1(M+H) +,
e)将化合物17(30g,112.91mmol,1eq)加入N–甲基-吡咯烷酮(300mL)中，并加入哌嗪-1-甲酸叔丁酯(105.15g,564.56mmol,5eq)和碘化钾(9.37g,56.46mmol,0.5eq)，随后60℃搅拌12小时。反应混合物冷却至室温并过滤，粗产品由Prep-HPLC(0.1％FA)纯化得到黄色固体化合物18(42.96g,96.16mmol,85.16％产率,93％纯度)。 1H NMR(400MHz,DMSO-d 6)δppm 8.82(d,J＝4.4Hz,1H),8.19-8.16(m,1H),7.99(d,J＝9.3Hz,1H),7.85(d,J＝4.4Hz,1H),7.45(dd,J＝2.8,9.1Hz,1H),4.15(br t,J＝6.2Hz,2H),2.62-2.50(m,6H),2.42(br t,J＝4.6Hz,4H),1.99(br d,J＝6.6Hz,2H),1.39(s,9H)。MS(ESI +):m/z 416.1(M+H) +
f)向化合物18(12.00g,26.57mmol,92％纯度,1.02eq)的二甲基甲酰胺(120mL)溶液中加入O-苯并三唑-1-基-四甲基脲鎓六氟磷酸盐(19.76g,52.10mmol,2eq)、1-羟基苯并三唑(7.04g,52.10mmol,2eq)、N,N-二异丙基乙基胺(10.10g,78.15mmol,13.61mL,3eq)，随后加入化合物12(5.88g,26.05mmol,1.00eq,HCl)，反应在25℃搅拌12小时。过滤，滤液使用prep-HPLC(HCl)纯化，得到黄色固体化合物19(11.27g,17.29mmol,66.37％产率,90％纯度)。 1H NMR(400MHz,DMSO-d 6)δppm 1.41(s,9H),2.27-2.33(m,2H),3.27-3.29(m,5H),3.43-3.55(m,2H),3.93-4.21(m,10H),5.19(dd,J＝9.26,2.75Hz,1H),7.59(dd,J＝9.26,2.63Hz,1H),7.69(d,J＝4.63Hz,1H)7.87-8.00(m,1H),8.14(d,J＝9.26Hz,1H),8.95(d,J＝4.63Hz,1H),9.24(br t,J＝5.82Hz,1H),11.00(br s,1H)。MS(ESI +):m/z 587.2(M+H) +。
g)将化合物19(2g,3.41mmol,1eq)溶解于乙酸乙酯中(40mL)，加入盐酸/乙酸乙酯溶液(4M,4mL,4.69eq)，随后反应在25℃下反应6小时。反应混合物蒸发浓缩，并直接使用，获得黄色固体化合物20(1.5g,粗品,HCl)。MS(ESI -):m/z 485.1(M+H) +
砌块连接：
Figure PCTCN2021139590-appb-000040
a、b、c和d具有相似的实验步骤，现以b作为实施例。
a)将化合物7b(200mg,333.04umol,1eq,TFA)溶解于二甲基甲酰胺(1mL)中，加入HBTU(157.88mg,416.29umol,1.25eq)、HOBt(58.50mg,432.95umol,1.3eq)、N,N-二异丙基乙胺(215.21mg,1.67mmol,290.04uL,5eq)和化合物20(229.65mg,333.04umol,1eq)，混合物搅拌4小时。反应产物浓缩后，使用prep-HPLC(TFA)纯化得到浅黄色固体化合物21b(200mg,产率51.86％)。MS(ESI +):m/z 1158.5(M+H) +
b)将化合物21b(100mg,86.35umol,1eq)溶解于二氯甲烷(2mL)中，加入TFA(616.00mg,5.40mmol,0.4mL,62.56eq)，反应搅拌3小时，随后蒸发浓缩，直接得到粗产物黄色油状液体化合物22b(96.36mg,产率100.00％,TFA salt)。MS(ESI +):m/z 1002.3(M+H) +
c)将化合物22b(69.41mg,103.62umol,1.2eq)溶解于二甲基甲酰胺(0.5mL)中，依次加入N,N-二异丙基乙胺(55.80mg,431.77umol,75.21uL,5eq)和化合物(96.36mg,86.35umol,1eq,TFA)，反应搅拌12h，随后真空浓缩除去溶剂。得到粗产品黄色油状化合物23b(130mg,产率96.72％)。MS(ESI +):m/z 779.0(M/2+H) +
d)化合物23b(130mg,83.52umol,1eq)加入TFA(3.08g,27.01mmol,2mL,323.43eq)并搅拌4小时。随后减压浓缩，使用prep-HPLC(TFA)纯化，得到浅黄色固体化合物24b(TEFAPI-02)(15mg,产率12.69％,98.1％纯度). 1H NMR(400MHz,DMSO-d 6)δ＝1.26(br d,J＝8.13Hz,2H),1.34-1.57(m,3H),1.58-1.70(m,1H),1.71-1.82(m,2H),2.08-2.16(m,2H),2.19-2.29(m,2H),2.62-2.72(m,2H),2.78-2.99(m,6H),3.09(br s,12H),3.55-3.72(m,16H),3.80-3.86(m,2H),3.91-3.98(m,2H),4.07-4.43 (m,7H),4.52-4.61(m,1H),4.67(br dd,J＝8.76,4.63Hz,1H),5.16(dd,J＝9.88,2.50Hz,1H),6.99-7.05(m,J＝8.13Hz,2H),7.48(dd,J＝9.26,2.63Hz,1H),7.56(d,J＝4.38Hz,1H),7.61-7.66(m,J＝8.00Hz,2H),7.90(brs,1H),7.99-8.11(m,2H),8.18(br d,J＝7.13Hz,1H),8.41(br d,J＝2.25Hz,1H),8.85(d,J＝4.38Hz,1H),9.13(br t,J＝5.75Hz,1H).MS(ESI +):m/z 779.0(M/2+H) +
TEFAPI-01、TEFAPI-02、TEFAPI-03、TEFAPI-04的合成表征结果如下：
化合物TEFAPI-01
Figure PCTCN2021139590-appb-000041
白色固体
LCMS(ESI +):m/z 637.5(M+Na) +Rt:0.588min.
LC条件：Kinetex C18 50*2.1mm柱(5um粒径)1.0ml/min
梯度：A相0.04％TFA/水，B相0.02％TFA/乙腈。0.00-1.00min 5-95％B，1.00-1.80min95-100％B。
HPLC:Rt:3.224min
LC条件：Luna-C18 2.0*50mm柱(5um粒径)，A相0.04％TFA/水，B相0.02％TFA/乙腈。
LC梯度：0.00-2.80min：0-60％B 0.5mL/min，2.80-5.00min：60％B 0.5mL/min。
1H NMR(400MHz,DMSO-d 6)
δppm 9.11(br t,J＝5.8Hz,1H),8.83(d,J＝4.3Hz,1H),8.41(br s,1H),8.15(br d,J＝7.9Hz,1H),8.01(d,J＝9.3Hz,1H),7.88(br s,1H),7.63(d,J＝8.1Hz,2H),7.54(d,J＝4.3Hz,1H),7.46(dd,J＝2.3,9.3Hz,1H),7.01(d,J＝8.0Hz,2H),5.21-5.09(m,1H),4.73-4.64(m,1H),4.27-4.19(m,8H),3.88-3.67(m,2H),3.66-3.52(m,2H),3.28-3.12(m,16H),3.12-2.99(m,12H),2.92-2.79(m,6H),2.27-2.18(m,2H),2.16-2.04(m,2H),1.79-1.72(m,2H),1.62(br s,1H),1.51-1.39(m,3H),1.28-1.21(m,2H)。
19F NMR(400MHz,DMSO-d 6)-73.641
化合物TEFAPI-02
Figure PCTCN2021139590-appb-000042
淡黄色固体
LCMS(ESI +):m/z 779.0(M/2+H) +,Rt:1.403min
LC条件：Kinetex C18 50*2.1mm柱(5um粒径)1.0ml/min
梯度：A相0.037％TFA/水，B相0.018％TFA/乙腈。0.00-0.40min 5％B,0.40-3.00min5-95％B，3.00-4.00min 95％B。
1H NMR(400MHz,DMSO-d 6)
δ＝1.26(br d,J＝8.13Hz,2H),1.34-1.57(m,3H),1.58-1.70(m,1H),1.71-1.82(m,2H),2.08-2.16(m,2H),2.19-2.29(m,2H),2.62-2.72(m,2H),2.78-2.99(m,6H),3.09(br s,12H),3.55-3.72(m,16H),3.80-3.86(m,2H),3.91-3.98(m,2H),4.07-4.43(m,7H),4.52-4.61(m,1H),4.67(br dd,J＝8.76,4.63Hz,1H),5.16(dd,J＝9.88,2.50Hz,1H),6.99-7.05(m,J＝8.13Hz,2H),7.48(dd,J＝9.26,2.63Hz,1H),7.56(d,J＝4.38Hz,1H),7.61-7.66(m,J＝8.00Hz,2H),7.90(brs,1H),7.99-8.11(m,2H),8.18(br d,J＝7.13Hz,1H),8.41(br d,J＝2.25Hz,1H),8.85(d,J＝4.38Hz,1H),9.13(br t,J＝5.75Hz,1H)
19F NMR(400MHz,DMSO-d 6)-73.764
化合物TEFAPI-03
Figure PCTCN2021139590-appb-000043
白色固体
LCMS(ESI +):702.0[(M+2H)/2] +,RT:1.13min
LC条件：ZORBAX Eclipse XDB-C18 2.1*30mm柱(3.5um粒径)1.0ml/min
梯度：A相0.037％TFA/水，B相0.018％TFA/乙腈。0.00-1.00min 5-95％B，1.00-1.80min 95-100％B。
1H NMR(400MHz,DMSO-d 6)
δ＝1.24(br d,J＝8.12Hz,2H),1.41(m,3H),1.75(br s,1H),1.95(br s,4H),2.03-2.09(m,3H),2.18-2.26(m,3H),2.28-2.38(m,1H),2.48(br s,4H),2.56-2.68(m,4H),2.80-2.91(m,2H),3.08(br s,2H),3.51(br s,2H),3.63(br s,2H),3.77(s,1H),3.99-4.14(m,2H),4.22(br t,J＝5.90Hz,2H),4.27-4.35(m,1H),4.37-4.49(m,2H),4.75-4.93(m,2H),5.04(t,J＝6.62Hz,1H),6.53(br d,J＝15.74Hz,1H),6.92-7.09(m,4H),7.44(dd,J＝9.36,2.09Hz,1H),7.56(d,J＝4.38Hz,1H),7.61-7.66(m,J＝8.00Hz,2H),7.64(brs,1H),7.90(m,2H),8.02(br d,J＝7.13Hz,1H),8.45(br d,J＝2.25Hz,1H),8.84(d,J＝4.38Hz,1H),9.19(br t,J＝5.75Hz,1H)
化合物TEFAPI-04
Figure PCTCN2021139590-appb-000044
淡黄色固体
LCMS(ESI +):m/z 1416.2(M+H) +,Rt:1.900min
LC条件：Kinetex C18 50*2.1mm柱(5um粒径)1.0ml/min
梯度：A相0.037％TFA/水，B相0.018％TFA/乙腈。0.00-0.40min 5％B,0.40-3.00min5-95％B，3.00-4.00min 95％B。
1H NMR(400MHz,DMSO-d 6)
δ＝1.21-1.33(m,2H),1.35-1.58(m,6H),1.60-1.69(m,2H),1.73-1.81(m,2H),2.09-2.18(m,2H),2.18-2.30(m,4H),2.78-3.00(m,6H),3.04-3.14(m,9H),3.56-3.69(m,16H),3.84(br s,2H),3.93-4.00(m,2H),4.08-4.42(m,8H),4.62-4.76(m,1H),5.13-5.18(m,1H),6.99-7.05(m,2H),7.47(dd,J＝9.26,2.63Hz,1H),7.56(d,J＝4.25Hz,1H),7.63(d,J＝8.00Hz,2H),7.89(d,J＝2.25Hz,1H),7.99(br d,J＝7.38Hz,1H),8.03(d,J＝9.26Hz,1H),8.13(br d,J＝7.50Hz,1H),8.44(br d,J＝1.88Hz,1H),8.85(d,J＝4.38Hz,1H),9.13(br t,J＝6.02Hz,1H)
19F NMR(400MHz,DMSO-d 6)-73.775
二、利用 68Ga-TEFAPI-01、02、03及04对健康鼠成像测定体内半衰期
用5mL的0.6M高纯盐酸淋洗锗镓发生器，得到Ga-68盐酸溶液。取淋洗的Ga-68溶液1mL，加入100微升3M氢氧化钠、130微升3M醋酸钠调节酸度，最终pH为4.0，加入50微克TEFAPI-06前体，将反应混合物加热至90℃，保持10分钟。将反应溶液通过C18小柱，将游离离子去除，然后用乙醇溶液洗脱C18柱。得到标记好的 68Ga-TEFAPI系列分子。
取37MBq标记产物，加入200微升生理盐水进行稀释并用胰岛素注射器抽取好药 物备用，其中药物的乙醇含量不高于5％。将健康的小鼠事先麻醉放入PET/CT的采集床上，在尾静脉处放置留置针。将注射器连在留置针上，在推针的零时刻便开始进行PET数据的采集。采集时间点分别为0-60分钟，2小时，3小时，4小时，5小时。采集完毕后用专业软件进行数据重建，重建条件为前5分钟每分钟间隔均重建数据，5-60分钟每5分钟重建一次数据，其余时间点重建一次数据。采集的数据经过PET重建软件进行处理，得到连续图像,如图1A。在PET处理软件中，在小鼠的心脏处描绘固定区域，得到具心脏处的SUV-Mean和SUV-Max值。将得到的SUV在数据处理软件进行模拟。得到对应的血液半衰期，
据得出TEFAPI-01、02、03及04的半衰期分别117.5min、289.3min、359.3min及320min，均明显高于FAPI-04(t1/2为19min)。
三、 68Ga/ 86Y-TEFAPI-01、02、03及04在胰腺癌PDX小鼠模型的PET成像
用5mL的0.6M高纯盐酸淋洗锗镓发生器，得到Ga-68盐酸溶液。取淋洗的Ga-68溶液1mL，加入100微升3M氢氧化钠、130微升3M醋酸钠调节酸度，最终pH为4.0，加入50微克TEFAPI系列的前体，将反应混合物加热至90℃，保持10分钟。将反应溶液通过C18小柱，将游离离子去除，然后用乙醇溶液洗脱C18柱。得到标记好的 68Ga-TEFAPI分子。将标记好的 68Ga-TEFAPI分子用生理盐水稀释，每只小鼠注射3.7MBq。在0.5小时，1小时，2小时进行PET扫描成像，用PET图像处理软件进行重建。得到的显像图如下所示，可以看到该探针在肿瘤部位有明显的摄取。
Y-86是一种半衰期长达14.6小时的正电子核素，并且可以使用DOTA进行放射标记，因此非常适合用来长时间检测TEFAPI分子在活体内的分布情况。取1mL Y-86盐酸溶液，加入100微升3M氢氧化钠、130微升3M醋酸钠调节酸度，最终pH为4.0，加入50微克TEFAPI-前体，将反应混合物加热至90℃，保持10分钟。将反应溶液通过C18小柱，将游离离子去除，然后用乙醇溶液洗脱C18柱。得到标记好的 86Y-TEFAPI分子。将标记好的 86Y-TEFAPI分子用生理盐水稀释，每只小鼠注射7.4MBq。我们对PDX小鼠进行了长达12小时的成像。结果表明药物注射1小时后， 68Ga-FAPI-04已基本从体内中排出，肿瘤组织中未见明显 68Ga-FAPI-04滞留。TEFAPI-01、02、03及04四种分子的PET成像显示在PDX模型的肿瘤中都有摄取且摄取相对FAPI-04高。其中TEFAPI-03的肿瘤SUVmax、Tumor/blood Ratio、Tumor/muscle Ratio最高。
四、TEFAPI-03在PDX胰腺癌小鼠中的抑制实验
为了验证TEFAPI系列分子的针对FAP靶点的特异性，我们选择TEFAPI-03作为代表性分子在竞争抑制实验中我们对同一批小鼠进行了抑制前后的PET成像。根据Y-86长时间PET成像可以得知，注射药物6小时到12小时之间，肿瘤的摄取达到峰值。因此将荷瘤小鼠进行 68Ga-FAPI-04成像，确定小鼠具有肿瘤摄取。等待48小时确保 68Ga-FAPI-04代谢之后，对这两只小鼠注射300微克TEFAPI-03分子，12小时后对注射TEFAPI-06分子的小鼠进行 68Ga-FAPI-04的PET分子成像。注射后30分钟的成像结果显示，同一只小鼠的 68Ga-FAPI-04在未注射TEFAPI-03分子的成像显示，肿瘤处有明显摄取，注射之后的PET成像则显示在小鼠肿瘤处没有额外摄取。
结果表明TEFAPI-03的靶向部位为FAP。
本公开通过上述实施例示例说明了在FAPI分子中引入白蛋白结合单元后，TEFAPI等系列小分子的血液循环时间相比FAPI-04有非常大的提高，且肿瘤摄取情况也得到了有效改善。使用长半衰期的正电子核素Y-86，能够有效的检测小分子在活体内的分布情况，完整了解分子的代谢状况。在Y-86成像中可以观察到TEFAPI-03的滞留时间长， 代谢器官基本无核素残留，是非常好的运送治疗核素的小分子，有望成为核素治疗实验的靶向分子。
以上所述仅是本发明的示范性实施方式，而非用于限制本发明的保护范围，本发明的保护范围由所附的权利要求确定。

Claims (14)

  1. 一种通式(I)的化合物或者其药学可接受的盐、立体异构体或溶剂合物，
    C-AB-FAPI  (I)
    其中C为螯合剂单元；
    AB为白蛋白结合单元；
    FAPI为成纤维活化蛋白抑制剂单元。
  2. 根据权利要求1所述的化合物，其中C单元选自：
    Figure PCTCN2021139590-appb-100001
    Figure PCTCN2021139590-appb-100002
    或者
    Figure PCTCN2021139590-appb-100003
  3. 根据权利要求1或2所述的化合物，其中FAPI单元选自：
    Figure PCTCN2021139590-appb-100004
    Figure PCTCN2021139590-appb-100005
    或者
    Figure PCTCN2021139590-appb-100006
  4. 根据权利要求3所述的化合物，其中：
    C单元为
    Figure PCTCN2021139590-appb-100007
    FAPI单元为
    Figure PCTCN2021139590-appb-100008
  5. 根据前述权利要求中任一项所述的化合物，其中AB单元包含4-碘-苯基末端基团
    Figure PCTCN2021139590-appb-100009
    优选地，所述AB单元选自
    Figure PCTCN2021139590-appb-100010
    其中R选自
    Figure PCTCN2021139590-appb-100011
    其中n＝1、2或3。。
  6. 根据前述权利要求中任一项所述的化合物，其中AB单元通过与FAPI单元中的末端
    Figure PCTCN2021139590-appb-100012
    形成酰胺键将其与FAPI单元相连，AB单元通过与C单元中的末端羰基形成酰胺键将其与C单元相连。
  7. 根据权利要求1所述的化合物，选自：
    Figure PCTCN2021139590-appb-100013
    Figure PCTCN2021139590-appb-100014
    或者它们的药学可接受的盐、异构体或溶剂合物。
  8. 一种螯合物，其包含权利要求1-7中任一项的化合物和放射性核素。
  9. 根据权利要求8所述的螯合物，其中所述放射性核素选自： 18F、 51Cr、 67Ga、 68Ga、 111In、 99mTc、 186Re、 188Re、 139La、 140La、 175Yb、 153Sm、 166Ho、 86Y、 88Y、 90Y、 149Pm、 165Dy、 169Er、 177Lu、 47Sc、 142Pr、 159Gd、 212Bi、 213Bi、 72As、 72Se、 97Ru、 109Pd、 105Rh、 101mRh、 119Sb、 128Ba、 123I、 124I、 131I、 197Hg、 211At、 151Eu、 153Eu、 169Eu、 201Tl、 203Pb、 212Pb、 64Cu、 67Cu、 188Re、 186Re、 198Au、 225Ac、 227Th和 199Ag中的一种或多种。
  10. 根据权利要求9所述的螯合物，其中所述放射性核素为 68Ga。
  11. 一种药物组合物，其包含或组成为：
    至少一种根据权利要求8-10中任一项所述的螯合物，
    任选地，和药学上可接受的辅料。
  12. 根据权利要求8-10中任一项所述的螯合物或根据权利要求11所述的药物组合物在制备用于诊断或治疗在受试者中以成纤维细胞激活蛋白(FAP)过度表达为特征的疾病的试剂或试剂盒中的用途。
  13. 根据权利要求12所述的用途，其中以成纤维细胞激活蛋白(FAP)过度表达为特征的疾病选自癌症、慢性炎症、动脉粥样硬化、纤维化、组织重塑和瘢痕病，优选地，其中癌症选自乳腺癌、胰腺癌、小肠癌、结肠癌、直肠癌、肺癌、头颈癌、卵巢癌、肝细胞癌、食道癌、下咽癌、鼻咽癌、喉癌、骨髓瘤细胞、膀胱癌、胆管细胞癌、透明细胞肾癌、神经内分泌肿瘤、致癌性骨软化症、肉瘤、CUP(原发性未知癌)、胸腺癌、胶质瘤、神经胶质瘤、星形细胞瘤、子宫颈癌和前列腺癌的一种或多种。
  14. 一种试剂盒，其包含或组成为根据权利要求8-10中任一项所述的螯合物或根据权利要求11所述的药物组合物，以及用于诊断或治疗疾病的说明书。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024022332A1 (en) * 2022-07-26 2024-02-01 Shanghai Sinotau Biotech. Co., Ltd Fap inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024037635A1 (en) * 2022-08-19 2024-02-22 Boomray Pharmaceuticals (Beijing) Corporation Limited A trifunctional compound and use thereof
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018111989A1 (en) * 2016-12-14 2018-06-21 Purdue Research Foundation Fibroblast activation protein (fap)-targeted imaging and therapy
CN111699181A (zh) * 2018-02-06 2020-09-22 海德堡大学 Fap抑制剂
WO2020205948A1 (en) * 2019-04-03 2020-10-08 Tarveda Therapeutics, Inc. Hsp90-binding conjugates and formulations thereof
CN112105354A (zh) * 2017-12-15 2020-12-18 普拉西斯生物技术有限责任公司 成纤维细胞激活蛋白抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018111989A1 (en) * 2016-12-14 2018-06-21 Purdue Research Foundation Fibroblast activation protein (fap)-targeted imaging and therapy
CN112105354A (zh) * 2017-12-15 2020-12-18 普拉西斯生物技术有限责任公司 成纤维细胞激活蛋白抑制剂
CN111699181A (zh) * 2018-02-06 2020-09-22 海德堡大学 Fap抑制剂
WO2020205948A1 (en) * 2019-04-03 2020-10-08 Tarveda Therapeutics, Inc. Hsp90-binding conjugates and formulations thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024022332A1 (en) * 2022-07-26 2024-02-01 Shanghai Sinotau Biotech. Co., Ltd Fap inhibitors

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