Compound for dual targeting of fibroblast activating protein and integrin subtype as well as preparation and application of compound

Abstract

The invention relates to a compound for dual targeting of fibroblast activating protein and integrin subtype as well as a preparation method and application of the compound, and belongs to the field of nuclear medicine and molecular imaging. The present invention provides a compound or a pharmaceutically acceptable salt, tautomer, raceme, hydrate, solvate thereof, comprising: (i) a chelating ligand moiety (CL); (ii) a first targeting moiety (BT); (iii) a second targeting moiety (CY); wherein (i), (ii) and (iii) are fixed, combined or connected through any L; bT is a fibroblast activation protein (FAP) specific binding ligand structure; cY is an integrin subunit alpha v beta 3 or alpha v beta 6 specific binding ligand structure; l is selected from one or a combination of more joints of L1, L2, L3, L4, L5, L6 and L7; l1, L2, L3, L4, L5, L6, and L7 are each independently a bond, a monovalent linker, a divalent linker, or a trivalent linker. By adopting a multi-target diagnosis or treatment mode, the sensitivity of diagnosis imaging is improved, and the treatment success rate is increased.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of nuclear medicine and molecular imaging technology, and specifically provides a compound for double targeting fibroblast activation protein and integrin subtypes, and a preparation method and application thereof. BACKGROUND

[0002] Tumor mass is composed of tumor cells and tumor stroma, and in highly desmoplastic tumors such as breast cancer, colon cancer and pancreatic cancer, tumor stroma accounts for more than 90% of tumor mass. Cancer-associated fibroblasts (CAFs), also known as tumor-associated fibroblasts (TAFs) or activated fibroblasts, are an important component of tumor stroma and are involved in tumor growth, migration and development. CAFs express different markers such as fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA) and vimentin. FAP is highly specifically expressed in activated fibroblasts and is not expressed in benign tumors or normal adult tissues, so FAP is the most potential molecular marker for CAFs. In addition, FAP is also an essential factor for promoting tumor cell proliferation and metastasis, remodeling extracellular matrix, inducing neovascularization, mediating immunosuppression, and participating in tumor cell energy metabolism. It can be seen that FAP has become a potential target for tumor imaging and treatment, and further research on FAP is of great significance for the diagnosis, treatment and prognosis of malignant tumors.

[0003] Integrins are heterodimeric receptors that are important for cell-cell and cell-extracellular matrix (ECM) interactions and are composed of an alpha subunit and a beta subunit. So far, 18 alpha subunits and 8 beta subunits have been found in mammals, which can form 24 different integrin molecules in combination. As a member of the integrin family, integrin αvβ6 is found to be highly expressed in various types of tumors, but not expressed or lowly expressed in normal tissues. The expression of integrin αvβ6 is closely related to the malignant properties of tumor invasion, progression, angiogenesis, metastasis and poor prognosis of patients. Integrins αvβ3 and αvβ5 are also involved in angiogenesis and metastasis of solid tumors, making them potential candidates for cancer treatment. Increasing evidence shows that the interaction between integrin receptors and TGF-β is a key factor in the pathogenesis and development of fibrosis. Integrins α3β1, αvβ5, especially αvβ6, control the activation and signaling of TGF-β in fibrosis. It is necessary to develop new targeting molecules for integrins αvβ3 and αvβ6 to improve the stability of tumor imaging in vivo.

[0004] The existing patent CN117105912A constructs a dimeric MR molecular probe Gd-DOTA-Suc-Lys-(FAPI 04)2 targeting fibroblast activation protein, which can be recognized and combined with FAP-positive tissue cells highly expressed in tumors, and endows the MR probe with tumor targeting property. CN117164557A discloses a radiopharmaceutical labeling precursor targeting fibroblast activation protein, which can be coupled and labeled with various radionuclides and applied to various clinical application scenarios of nuclear medicine. However, the reported FAP ligands have low uptake in tumor tissues and unsatisfactory retention effect, which greatly limits their treatment potential. SUMMARY

[0005] The present application aims to provide a compound doubly targeting fibroblast activation protein and integrin subtypes, and a preparation method and application thereof, to realize improved diagnostic imaging sensitivity and improved treatment success rate by adopting a multi-target point diagnosis or treatment method.

[0006] To achieve the above-mentioned purpose, the technical solutions of the present application are as follows:

[0007] On the one hand, the present application provides a multifunctional compound that can be used for medical imaging and treatment, which can be used for preoperative, in situ and postoperative medical imaging and treatment.

[0008] On the one hand, the present application provides a compound or a pharmaceutically acceptable salt, tautomer, racemate, hydrate, solvate or isotopically labeled material thereof, comprising:

[0009] (i) a chelating ligand moiety (CL); (ii) a first targeting moiety (BT); (iii) a second targeting moiety (CY);

[0010] wherein (i), (ii), (iii) are fixed, combined or connected by any L (for example, by a first covalent bond connecting L to CL and a second covalent bond connecting L to BT, etc.);

[0011] wherein the first targeting moiety is a fibroblast activation protein (FAP) specific binding ligand structure; the second targeting moiety is an integrin subunit specific binding ligand structure, preferably an integrin αvβ3 or αvβ6 specific binding ligand structure;

[0012] the L is selected from one or more of L a , L b , L c .

[0013] the L a , L b , L c are each independently selected from L 1 , L2 , L 3 , L 4 , L 5 , L 6 , L 7 , L

[0014] L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently is a bond, a monovalent linker, a divalent linker, or a trivalent linker.

[0015] Further, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently is a bond, -Z(R 3 ), -Z-, -N(R 1 ) n -, -N(R 1 )4, -C(=Z)-, -((C(R 2 ) p ) q -, -S(=O) m -, -NR 1 -C(=O)-, -NR 1 -C(=O)-NR 1 -, -C(=O)-NR 1 -, -((C(R 2 ) p ) q -Z) x -(C(R 2 ) p ) q -, -(C(R 2 ) p ) q -(Z-(C(R 2 ) p ) q ) x -, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; one or more L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L7 Each of them can be combined with each other to form L a , L b or L c Then connect with (i), (ii) and (iii) arbitrarily; in this application, a reasonable situation refers to one or more L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 They can be combined with each other as stable chemical bonds;

[0016] Each Z is independently selected from O or S; each n is independently selected from 0, or 1; each p is independently selected from 0, 1 or 2; each m is independently selected from 0 or 1;

[0017] q and x are each independently selected from an integer of 0-30, for example, selected from 0-20 or 0-10 or 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

[0018] Each R 1 and R 3 are independently H, cycloalkyl or alkyl;

[0019] Each R 2 is independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, alkyl-COOH, -SO3H, alkyl-SO3H, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkyl;

[0020] L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 、R 2 、R 1 and R 3each independently of one another hydrogen, -F, -CI, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, alkyl-COOH, -SO3H, alkyl-SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl.

[0021] Further, each independently of one another the substituents are hydrogen, -F, -CI, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-6 alkyl-COOH, -SO3H, C 1-6 alkyl-SO3H, C 1-6 alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, C 2-6 heterocyclyl, C 6-12 aryl, C 1-6 heteroaryl or C 1-6 alkyl.

[0022] Further, each independently of one another L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 is independently of one another a bond, -Z(R 3 ), -Z-, -N(R 1 ) n - , -N(R 1 )4, -C(=Z)-, -((C(R 2 ) p ) q -, -S(=O) m -, -NR 1 -C(=O)-, -NR 1 -C(=O)-NR 1 -, -C(=O)-NR 1 -, -((C(R 2 ) p ) q -Z) x -(C(R 2 ) p )q -(C(R 2 ) p ) q -(Z-(C(R 2 ) p ) q ) x - C(R 1-6 )2- C(R 1-12 )2- C(R 3-12 )2- C(R 4-12 )2- C(R 6-12 )2- C(R 5-12 )2- C(R 1 )2- C(R 2 )2- C(R 3 )2- C(R 4 )2- C(R 5 )2- C(R 6 )2- C(R 7 )2- C(R

[0023] each L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently is a bond, -Z(R 3 ), -Z-, -N(R 1 ) n - , -N(R 1 )4, -C(=Z)-, -((C(R 2 ) p ) q -, -S(=O) m -, -NR 1 -C(=O)-, -NR 1 -C(=O)-NR 1 -, -C(=O)-NR 1 -, -((C(R 2 ) p ) q -Z) x -(C(R 2 ) p ) q -, -(C(R 2 ) p ) q -(Z-(C(R 2 ) p ) q ) x -, C1-6 Heteroalkylene, C 1-12 Alkylene, C 3-12 Cycloalkylene, C 4-12 Heterocyclic alkylene, phenylene, pyridylene or C 5-12 Heteroarylene, optionally, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 Each independently may be further mono- or poly-substituted by the same or different substituents described herein.

[0024] Furthermore, each R 1 and R 3 Independently H, C 3-12 Cycloalkyl or C 1-6 The alkyl group may be further substituted or polysubstituted by the same or different substituents described in the present invention.

[0025] Furthermore, each R 2 are independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6 Alkyl-SO3H, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-12 Cycloalkyl, C 4-12 Heterocycloalkyl, C 6-12 Aryl, C 5-12 Heteroaryl or C 1-6 The alkyl group may be further substituted or polysubstituted by the same or different substituents described in the present invention.

[0026] Furthermore, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 Each independently selected from a bond, -O-, -S-, -NH-, -C(=O)-, -NH-C(=O)-, -NR 1 -C(=O)-NR 1 -、-C(=O)-NH-、-(CH2) q -、-(CHR 2 ) q -、-((CH2) q -O) x -、-((CH2)q -O) x -(CH2) q -、-(CH2) q -(O-(CH2) q ) x -、 (For example ), (For example cyclohexylene, cyclopentylene), (For example wherein each A is independently selected from CR 2 or N; each B is independently selected from -C(R 2 )2-、O、-S(=O) m -、-N(R 1 ) n - In the present invention, the values ​​of q, A or B in the same structural formula may be the same or different and do not affect each other.

[0027] Furthermore, the L a , L b , L c Each independently selected from -(CH2) q -((CH2) q -O) x -NH-C(=O)-(CH2) q -、-(CH2) q -((CH2) q -O) x -NH-C(=O)-(CH2) q -((CH2) q -O) x -、-NH-C(=O)-(CH2) q -((CH2) q -O) x -、-NR 1 -C(=O)-NR 1 -、-C(=O)-((CH2) q -O) x -(CH2) q -NH-C(=O)-(CH2) q -、-C(=O)-((CH2) q -O) x -(CH2) q -、-C(=O)-NH-、-(CHR 2 ) q -C(=O)-NH-, -(CH2)q -C(=O)-NH-, -C(=O)-NH-(CH2) q -, q -, q -O) x -, q -O) x -(CH2) q -, q -(O-(CH2) q ) x -, In the present application, the values of q, x, A or B in the same structural formula can be the same or different, and are not affected by each other.

[0028] For example, the L a , L b , L c are each independently selected from phenylmethyl, methylenepyridyl (e.g., 2-methylen-4-pyridyl), methylenecyclohexyl-, and the like.

[0029] Further, the chelating ligand moiety (CL) is including but not limited to AAZTA, BAT, CDTA, DTA, DTPA, CY-DTA, DTCBP, CTA, cyclam, cyclen, TETA, Sarcophagine, CPTA, TEAMA, Cyclen, DO3A, DO2A, TRITA, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H4octapa, H2dedpa, H5decapa, H2azapa, H2CHX DEDPA, DFO-Chx-MAL, DFO-p-SCN, DFO-1AC, DFO-BAC, p-SCN-Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, Diphosphine, DOTA, DOTAGA, DOTA-MFCO, DOTAM-monoacid, Nitro-DOTA, Nitro-PA-DOTA, p-NCS-Bz-DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-DOTA, DOTMA, NB-DOTA, H4NB-DOTA, H4TCE-DOTA, 3,4,3-(Li-1,2-HOPO), TREN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOXP, p-NCS-DOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-monoamide-DOTA, BCN-DOTA, acetylene-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2A (trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)acetamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA, maleimidyl-mono-amide-DOTA, maleimide-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone-benzothiazole, thiosemicarbazone-styrylpyridine tetradentate ligand H2L2-4, HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, Deferiprone, THP, HYNIC (2-hydrazinonicotinamide), NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIM A, IAM B, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, Macropa, Macropaquin, Macroquin-SO3, N, x S 4-x, N2S2, N3S, N4, MAG3B, NOTA, NODAGA, SCN-Bz-NOTA-R, NOT-P(NOTMP), NOTAM, p-NCS-NOTA, TACN, TACN-TM, NETA, NETA-monoamine, p-SCN-PhPr-NE3TA, C-NE3TA-NCS, C-NETA-NCS, 3p-C-NETA, NODASA, NOPO, NODA, NO2A, N-Benzyl-NODA, C-NOTA, BCNOT-monoamine, maleimido-mono-amide-NOTA, NO2A-azide, NO2A-yne, NO2AP, NO3AP, N-NOTA, oxo-DO3A, p-NH2-Bn-NOTA, p-NH2-Bn-oxo-DO3A, p-NO2-Bn-Cyclen, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, TRAP, PEPA, BF-PEPA, Pycup, Pycup2A, pycup1A1Bn, pycup2Bn, SarAr-R, Diamsar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me), TAM A, TAM B, TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, TE2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ-HTCPP, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 1,4,7-triazacyclononane-N-glutaric acid-N',N"-diacetic acid (NODAGA), 1,4,7-triazacyclononane-1,4-diacetic acid-methylphenylacetic acid (NODA-MPAA), bis(2-hydroxybenzyl)ethylenediamine diacetic acid (HBED), 4,11-bis-(carboxymethylmethyl)-1,4,8,11-tetraazabicyclo[6.6.2) one or more of hexadecane (CB-TE2A), DFO, hexaazatriphenylchlorin (THP), dodecanetetraacetic acid, nitro-DOTA, 4-aminophenethyl-1,4,7,10-tetraazacyclodecane- N,N',N",N"' -tetraacetic acid (PA-DOTA), diethylenetriaminepentaacetic acid (DTPA), (2-[4,7-bis(carboxymethyl)-1,4,7-triazol-1 -yl] moiety of acetic acid)-NOTA, (triethylenetetraamine)-TETA, desferrioxamine, (ethylenediaminetetraacetic acid)-EDTA, and penicillamine.

[0030] HYNIC, DTPA, EDTA, DOTA, TETA, bisamino bithiol (BAT) based chelators are disclosed in US 5,720,934; deferoxamine (DFO) is disclosed in (Doulias, et al., Free Radic Biol Med, 2003, 35:719), tetraazacyclododecane and N3S, N2S2 and N4 chelators are disclosed in US 5,367,080A, US 5,364,613 A, US 5,021,556A, US 5,075,099A, US 5,886,142A, all of which references are incorporated by reference in their entirety. 6-amino-6-methylperhydro-l,4-diazepane-N,N',N",N"-tetraacetic acid (AAZTA) is disclosed in Pfister et al. (Pfister, et al., EJNMMI Res, 2015, 5:74), deferitrone, i.e. 1,2-dimethyl-3,4-hydroxypyridinone, and hexadentate tris(3,4-hydroxypyridinone) THP) are disclosed in Cusnir et al. (Cusnir, et al., Int J Mol Sci, 2017, 18), monamine-monamide dithiol (MAMA) based chelators are disclosed in Demoin et al. (Demoin, et al., Nucl Med Biol, 2016, 43:802), MACROPA and analogs are disclosed in Thiele et al. (Thiele, et al., Angew Chem Int Ed Engl, 2017, 56:14712), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N'",N"",N""'-hexaacetic acid (HEHA) and PEPA analogs are disclosed in Price and Orvig (Price, et al., Chem Soc Rev, 2014, 43:260), Pycup and analogs are disclosed in Boros et al. (Boros, et al., Mol Pharm, 2014, 11:617), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetrakis(carbamoylmethyl)-l,4,7,10-tetraazacyclododecane (TCM), 2-[(carboxymethyl)]-[5-(4-nitrophenyl-l-[4,7,10-tris-(carboxymethyl)-l,4,7,10-tetraazacyclododecan-l-yl]pentan-2-yl)-amino]acetic acid (3p-C-DEPA), CB-TE2A, TE2A, TE1A1P, Diamsar, 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6] - eicosane-1,8-diamine (SarAr), NETA, N,N0,N00 tris(2-mercaptoethyl)-1,4,7- triazacyclononane (TACN-TM), {4-[2-(bis-carboxymethyl-amino)-ethyl]-7- carboxymethyl-[1,4,7]triazacyclonon-1 -yl}-acetic acid (NETA), diethylenetriamine pentaacetic acid (DTPA), 3-({4,7-di-[(2-carboxy-ethyl)-hydroxy-phosphorylmethyl]- [1,4,7]triazacyclonon-1 -ylmethyl}-hydroxy-phosphoryl)-propanoic acid (TRAP), NOPO, H4octapa, SHBED, BPCA, 3,6,9,15-tetraazabicyclo[9.3.1]- pentadeca-1 (15),1 1,13-triene-3,6,9,-triacetic acid (PCTA) and 1,4,7,10,13- pentazacyclopentadecane-N,N',N",N'",N""-pentaacetic acid (PEPA) are disclosed in Price and Orvig (Price, et al., Chem Soc Rev, 2014, 43: 260), 1 -hydroxy-2- pyridinone ligands (HOPO) are disclosed in Allott et al. (Allott, et al., Chem Commun (Camb), 2017, 53: 8529), [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6- methyl-[1,4]diazepan-1 -yl]-acetic acid (DATA) is disclosed in Tornesello et al. (Tornesello, et al., Molecules, 2017, 22: 1282), tetra(aminomethyl)methane (TAM) and analogues are disclosed in McAuley 1988 (McAuley, et al., Canadian Journal of Chemistry, 1989, 67: 1657), hexadentate tris(3,4-hydroxypyridinone) (THP) and analogues are disclosed in Ma et al. (Ma, et al., Dalton Trans, 2015, 44: 4884).

[0031] Diagnostic and / or therapeutic applications of some of the above chelators are described in the prior art. For example, 2-hydrazinonicotinic acid (HYNIC) has been widely used for incorporation of 99m Tc and 186,188 Re (Schwartz, et al., Bioconjug Chem, 1991, 2: 333; Babich, et al., J Nucl Med, 1993, 34: 1964; Babich, et al., Nucl Med Biol, 1995, 22: 25); DTPA for Octreoscan to complex111 In, and some modifications are described in the literature (Li, et al., Nucl Med Biol, 2001, 28:145; Brechbiel, et al., Bioconjug Chem, 1991, 2:187); the use of DOTA-type chelators in radiotherapy is described by Tweedle et al. (US Pat 4,885,363); other polyaza macrocycles that chelate trivalent isotopes of metals are described by Eisenwiener et al. (Eisenwiener, et al., Bioconjug Chem, 2002, 13:530); N4-chelators such as 99m Tc-N4-chelates have been used for peptide labeling in the case of minigastrin targeting the CCK-2 receptor (Nock, et al., J Nucl Med, 2005, 46: 1727).

[0032] Further, the chelating ligand portion (CL) is selected from but not limited to DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic, 99m Tc(CO)3-chelating agents and analogs thereof, wherein:

[0033] DOTA denotes 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTAGA denotes 1,4,7,10-tetraazacyclododecane,1-(pentanedioyl)-4,7,10- triacetic acid; NOTA denotes 1,4,7-triazacyclononane triacetic acid; NODAGA denotes 1,4,7-triazacyclononane-N-pentanedioyl-N',N"-diacetic acid; NODA-MPAA denotes 1,4,7-triazacyclononane-1,4-diacetic acid-methylphenylacetic acid; HBED denotes bis(2-hydroxybenzyl)ethylenediamine diacetic acid; TETA denotes 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid; CB-TE2A denotes 4,11-bis-(carboxymethylmethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane; DTPA denotes diethylenetriaminepentaacetic acid; DFO denotes Desferal or Desferrioxamine type chelator group, a non-limiting example of the chemical name is N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide; Macropa denotes N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown; HOPO denotes Octadentate hydroxypyridinone type chelator group, a non-limiting example of the structure is shown below; TRAP denotes 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy-phosphorylmethyl]-[1,4,7]triazonan-1-ylmethyl}-hydroxy-phosphoryl)-propanoic acid; THP denotes hexadentate tris(3,4-hydroxypyridinone); DATA denotes [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid; NOTP denotes 1,4,7-triazacyclononane-N,N'N"-tris(methylene phosphonic acid); Sarcophagine denotes 3,6,10,13,16,19-hexaazabicyclo[6.6.6] Eicosane; FSC represents 3, 15, 27-triamino-7, 19, 31-trihydroxy-10, 22, 34- trimethyl-1, 13, 25-trioxa-7, 19, 31-triaza-cyclohexatriaconta-9, 21, 33-triene-2, 8, 14, 20, 26, 32-hexone; NETA, {4-[2-(bis-carboxymethyl-amino)-ethyl]-7- carboxymethyl-[1, 4, 7] triazacyclonon-1-yl}-acetic acid; H4octapa, N, N'-(6-carboxy-2- pyridinylmethyl)-N, N'-diacetic acid-1, 2-ethanediamine; Pycup represents 1, 8-(2, 6- pyridinedimethylene)-1, 4, 8, 11-tetraazacyclotetradecane; NxS4-x (N4, N2S2, N3S) represents a group of tetradentate chelators with N atoms (basic amines or non-basic amides) and thiols as donors that stabilize Tc-complexes, especially Tc(V)-oxo complexes. A representative non-limiting example of MAG3 is shown below; and MAG3 represents {2-[2-(3-mercapto-propionylamido)-acetylamino]- acetylamino}-acetic acid; HYNIC represents 6-hydrazinonicotinic acid;. 99m Tc(CO)3-chelator represents a bidentate or tridentate chelator that is capable of forming stable complexes with the technetium tricarbonyl fragment;

[0034] The chemical structure is shown below:

[0035]

[0036]

[0037] Further, the chelating ligand moiety (CL) is selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, and analogs thereof.

[0038] Further, the chelating ligand moiety (CL) is selected from the group consisting of DOTA, DOTAGA, NOTA, N4Ac, and NODAGA, and analogs thereof.

[0039] Further, the first targeting moiety (BT) is selected from the group consisting of a blood cell, a peptide, a polyethylene glycol (e.g., (PEG)n, where n is an integer from 0 to 32), a small molecule, a prodrug, a nucleic acid, an aptamer, an oligosaccharide, and an antibody or antigen binding fragment thereof thereof. Further, the first targeting moiety (BT) is selected from one or more of a prostate specific membrane antigen (PSMA) targeting agent, a fibroblast activation protein (FAP) inhibitor, an arginine-glycine- glutamic acid fibronectin or integrin targeting peptide, a somatostatin targeting peptide, a pentixafor chemokine receptor targeting agent, and heparin.

[0040] Further, the first targeting moiety (BT) is R 4 is hydrogen, deuterium, alkyl or cycloalkyl; R 5 and R 6 are each independently hydrogen, deuterium, alkyl, cycloalkyl, hydroxyl, cyano, -F, -Cl, -Br, -I, -NH2, nitro, -COOH or -B(-Y 1 )(-Y 2 ); Y 1 and Y 2 are independently -OH, or together with the boron atom to which they are attached represent a group hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring hydrolysable to a boronic acid;

[0041] y is selected from an integer from 0 to 8, for example from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0042] Further, the R 4 is hydrogen, C 1-12 alkyl or C 3-12 cycloalkyl. Further, the R 4 is hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl. Further, the R 4 is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl or the like.

[0043] Further, the R 5 and R 6 are each independently hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, hydroxyl, cyano, -F, -Cl, -Br, -I, -NH2, nitro, -COOH or -B(-Y 1 )(-Y 2 ); Y 1 and Y 2 are independently -OH, or together with the boron atom to which they are attached represent a group hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring hydrolysable to a boronic acid. Further, the R 5 and R 6 are each independently hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, hydroxyl, cyano, -F, -Cl, -Br, -I, -NH2, nitro, -COOH or -B(-Y 1 )(-Y 2 ); Y 1 and Y 2are independently -OH, or together with the boron atom to which they are attached represent a group that can be hydrolyzed to form a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring that can be hydrolyzed to form a boronic acid.

[0044] Further, the first targeting moiety (BT) is Preferably

[0045] Furthermore, the second targeting moiety (CY) is selected from one or more of a photodynamic therapy agent, an integrin subtype inhibitor, a peptide compound (polypeptide compound, such as a cyclic peptide compound), a radioimaging agent, a radiotherapy agent, a chemotherapy agent, an anti-fibrotic agent or an anti-cancer agent (for example, an anti-cancer agent that is effective against cancer cells or cancer-associated fibroblasts, myofibroblasts or other tumor microenvironment factors).

[0046] Further, the second targeting moiety (CY) is:

[0047]

[0048] Among them, R 7 and R 8 are each independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; said R, R 7 and R 8 Each independently further optionally substituted by the same or different substituents R 9 Single or multiple substitutions; the R 9 It is hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxy, -SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio or alkyl.

[0049] Furthermore, R, R 7 and R 8 Each independently selected from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl, C 5-12 Heterocycloalkyl, C 6-12 Aryl and C 5-12 Heteroaryl. The R, R 7 and R 8 Each independently further optionally replaced by the same or different R 9 Monosubstituted or polysubstituted. Further, R, R 7 and R 8 Each independently selected from phenyl, naphthyl, pyridyl, pyrimidinyl and C 5-12 Heteroaryl, said R, R 7 and R 8each independently further optionally substituted with the same or different R 9 monosubstituted or polysubstituted.

[0050] Further, the second targeting moiety (CY) is selected from one or more of the following structural formulae:

[0051]

[0052]

[0053] Further, the compound has the structure wherein CL, BT, CY, L a , L b , L c , R 1 and R 2 have the meaning as described herein.

[0054] Further, the compound has the structure wherein CL, CY, each L have the meaning as described herein.

[0055] Further, the compound according to the present application is selected from one of the following structures:

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Further, the compound further comprises a diagnostically active nuclide or a therapeutically active nuclide, wherein preferably the diagnostically active nuclide is a diagnostically active radionuclide, more preferably selected from 18 F, 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P, 44 Sc, 47 Sc, 165 Dy, 169 Er, 177 Lu, 142 Pr, 159 Gd, 72 As,72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 203 Pb, 212 Pb, 175 Yb, 139 La, 140 La, 166 Ho, 51 Cr, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 55 Co, 64 Cu, 67 Ga, 68 Ga, 152 Tb, 155 Tb, 161 Tb, 86 Y, 90 Y, 89 Sr, 89 Zr, 94m Tc, 99m Tc, 111 In, 114m In, 117m Sn, 153 Sm, 149 Pm, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 32 P, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 186 Re,188 Re, 225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th, and wherein the therapeutically active nuclide is a therapeutically active radionuclide, more preferably selected from 18 F, 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P, 44 Sc, 47 Sc, 165 Dy, 169 Er, 177 Lu, 142 Pr, 159 Gd, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 203 Pb, 212 Pb, 175 Yb, 139 La, 140 La, 166 Ho, 51 Cr, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 55 Co, 64 Cu, 67 Ga, 68 Ga, 152 Tb, 155 Tb, 161 Tb, 86 Y, 90 Y, 89 Sr, 89 Zr, 94m Tc, 99m Tc,111 In, 114m In, 117m Sn, 153 Sm, 149 Pm, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 32 P. 18 F. 76 Br, 77 Br, 123 I. 124 I. 125 I. 169 Second, 177 Lu, 186 Re、 188 Re、 211 At 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 186 Re、 188 Re、 225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th.

[0063] In another aspect, the present invention provides a probe comprising the compound of the present invention, comprising: dissolving the compound of the present invention in a radiolabeled buffer, and then adding a diagnostic radionuclide or a therapeutic radionuclide for reaction to obtain the probe.

[0064] Furthermore, the metal ions in the radiolabeled buffer are selected from 18 F. 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P. 44 Sc, 47 Sc, 165 Dy, 169 Second, 177 Lu, 142 Pr, 159 Gd, 72 As、 72 Se,97 Ru 109 pd 105 Rh、 101m Rh、 119 Sb 128 Ba 197 Hg、 211 And 151 Me、 153 Me、 169 Me、 203 Pb、 212 Pb、 175 Yb、 139 Day, 140 Day, 166 Ho 51 Cr、 43 sc、 44 sc、 51 Mn 52 Mn 55 Co. 64 Cu、 67 Ga 68 Ga 152 Tb 155 Tb 161 Tb 86 Y、 90 Y、 89 Mr. 89 Zr、 94m Tc 99m Tc 111 in 114m in 117m Sn 153 Sm、 149 PM 152 Tb 155 Tb 201 Tl 203 Pb、 32 Q 18 F、 76 Bro 77 Bro 123 I 124 I 125 I 169 Err 177 sun 186 Re 188 Re 211 And 212 Pb、 212 Hello 213 Hello 223 Ra 224 Ra 186 Re 188 Re225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th cation.

[0065] Furthermore, the metal ion is bound to the chelating ligand portion (CL) of the compound.

[0066] In another aspect, the present invention provides a method for preparing the compound of the present invention, comprising the following steps:

[0067] The structural substance of the second targeting part (CY) after reacting with the linker is reacted with the structural substance of the chelating ligand part (CL), and then further condensed with the structural substance of the first targeting part (BT) to prepare the compound of the present invention.

[0068] In another aspect, the present invention provides a pharmaceutical composition comprising any compound described herein. For example, such a pharmaceutical composition may comprise any compound of the present invention and a pharmaceutically acceptable carrier and / or excipient.

[0069] .On the other hand, the present invention provides a use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament for diagnosing or treating a disease characterized by overexpression of fibroblast activation protein and integrin family subtypes (such as integrin αvβ3 or αvβ6) in an animal or human individual.

[0070] Furthermore, the disease includes but is not limited to breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, glioma, glioma, astrocytoma, cervical cancer or prostate cancer.

[0071] Furthermore, the use includes use in preparing tumor imaging agents or radionuclide targeted therapy agents.

[0072] In another aspect, the present invention provides a method for diagnosing or treating a disease in an animal or human subject characterized by overexpression of fibroblast activation protein and an integrin family subtype (e.g., integrin αvβ3 or αvβ6), comprising administering to a patient in need thereof a compound or pharmaceutical composition of the present invention.

[0073] In another aspect, the present application provides a method of diagnosing or treating a disease characterized by overexpression of fibroblast activation protein and an integrin family subtypes (e.g., integrin αvβ3 or αvβ6) in an animal or human subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition according to the present application.

[0074] In another aspect, the present application provides a kit comprising a compound according to the present application, one or more optional excipients and optionally one or more devices selected from a labeling device, a purification device, an administration device, a radiation protection device, an analysis device or an application device.

[0075] The term "alkyl" denotes a saturated straight or branched chain monovalent hydrocarbon radical containing one to twenty carbon atoms, wherein the alkyl group can be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; examples of alkyl groups include, but are not limited to, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl. When the alkyl group is a linking group, and "alkyl" is recited in the definition of the Markush group, then "alkyl" denotes the linking alkylene group. The term "alkylene" denotes a saturated divalent hydrocarbon radical derived from a saturated straight or branched chain hydrocarbon by removal of two hydrogen atoms. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0076] The term "heteroalkyl" denotes an alkyl group in which some of the carbon atoms are replaced by different heteroatoms (e.g., O, N, S, Si, or P), wherein the alkyl portion has the meaning as described herein. The heteroalkyl moiety can include four optionally different heteroatoms (e.g., O, N, S, Si, or P), such as alkoxy, alkylamino, and the like. The term "heteroalkylene" denotes a saturated divalent hydrocarbon radical derived from a saturated straight or branched chain hydrocarbon by removal of two hydrogen atoms.

[0077] The terms "heterocycle" or "heterocyclyl" are used interchangeably and mean a monovalent, nonaromatic, saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic ring system of 3-12 ring atoms, and at least one carbon atom, containing one, two, or three heteroatoms selected from O, N, S, including mono-, bridge-, peri-, and spiro-heterocyclic groups. Unless otherwise indicated, a heterocyclyl group can be carbocyclic or nitrogen-containing and -CH2- groups can optionally be replaced by -C(=O)- groups. Sulfur atoms of the ring can optionally be oxidized to the S-oxide or S-oxide. The heterocyclic ring can be monocyclic or bicyclic; specifically, the bicyclic ring system can be peri-, spiro-, or bridged. In some embodiments, a heterocyclyl group contains 4-7 ring atoms, i.e., represents a 4-7 membered heterocyclyl group; examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. Examples of heterocyclyl groups include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidinyl, dihydropyranyl, oxasulfuranyl, dithiolanyl, oxothienyl, thiomorpholinyl, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl, oxepinyl, oxazepinyl, oxazinanyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl. "Cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent, mean divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

[0078] Aryl can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form biaryls. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl groups having methylene linking groups. The term "arylene" means a divalent aryl group, wherein aryl has the definition as described herein.

[0079] Heteroaryl can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), benzopyrrole, e.g., indol and isoindol, benzopyridine, e.g., quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), and the like. The term "heteroarylene" means a divalent heteroaryl group, wherein heteroaryl has the definition as described herein.

[0080] Cycloalkyl refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from the group consisting of: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. 4-7 Cycloalkyl refers to a cycloalkyl group having 4 to 7 ring atoms. 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. The term "cycloalkylene" refers to a divalent saturated monocyclic carbon ring system. The -CH2- group in the cycloalkylene group may optionally be replaced by -C(=O)-. In some embodiments, the cycloalkylene group contains 3 to 7 ring carbon atoms, i.e., C 3-7 In one embodiment, the cycloalkylene group contains 3 to 6 carbon atoms, i.e., C 3-6 In another embodiment, the cycloalkyl group contains 3-5 carbon atoms, i.e., C 3-5 Examples of cycloalkylene include, but are not limited to, 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclopentylene, 1,1-cyclohexylene, 1,3-cyclopentylene, etc. The cycloalkylene group may be independently optionally substituted with one or more substituents described herein.

[0081] In this article, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 Each is independently a bond, a monovalent linker, a divalent linker, or a trivalent linker, for example, -N(R 1 ) n -, when n is 0, -N(R 1 ) n -N is a trivalent linker, when n is 1, -N(R 1 )n - N is a divalent linker; and the like; and the like. The position of the bond can be combined at any reasonable position on the ring and can be represented as and the like; and the like.

[0082] The elements involved in the structures of the present application are elements including all their isotopes. Exemplary isotopes that can be included in the compounds of the present application include isotopes of hydrogen (H), carbon (C), nitrogen (N), oxygen (O), phosphorus (P), sulfur (S), fluorine (F), chlorine (Cl), and bromine (Br), such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F, 37 Cl, Br 81 . That is, hydrogen (H) includes 1 H, 2 H, 3 H; carbon (C) includes 12 C, 13 C, 14 C; nitrogen (N) includes 14 N, 15 N; oxygen (O) includes 16 O, 17 O; phosphorus (P) includes 30 P, 31 P, 32 P; sulfur (S) includes 32 S, 33 S, 34 S, 36 S; fluorine (F) includes 18 F, 17 F; chlorine (Cl) includes 35 Cl, 37 Cl; and bromine (Br) includes 79 Br, 81 Br.

[0083] The term "isotopically-labeled compound" refers to a compound of the present application that is labeled with an isotope. It is the same as those compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can be incorporated into a compound of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H,13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0084] Compounds of the present application comprising additional isotopic substitutions as described above and pharmaceutically acceptable salts of said compounds are within the scope of the present application. Isotopically-labeled compounds of the application, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated into the compounds of the present application can be used in the preparation of pharmaceuticals and / or in substrate tissue distribution assays. Because of ease of preparation and detectability, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. Further, substitution with heavier isotopes such as deuterium, i.e. 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Thus, in some circumstances, it can be preferred.

[0085] In the present application, the similar terms "j-k", "j-k membered" or "C j -C k " are used, wherein said j and k each independently are any non-zero natural number, and k>j; for example "1-4" means 1, 2, 3 or 4, "4-6 membered" means 4, 5 or 6 membered; "C3-C6" means C3, C4, C5 or C6. By analogy.

[0086] Compared with the prior art, the present application has the following advantages:

[0087] The present application provides a compound which can simultaneously specifically recognize FAP and one of αVβ3 or αVβ6, and targets fibroblast activation protein and integrin family subtypes (one of αVβ3 or αVβ6). The compound of the present application can be further linked to a radionuclide (for example, a diagnostic nuclide, a therapeutic nuclide) to form a probe, which is used for preventing, treating, alleviating, and / or diagnosing cancer in a subject in need thereof, has high tumor uptake in the patient's body, good in vivo metabolic performance, good half-life, and has very good clinical application prospects.

[0088] The compounds of the present invention are complexes composed of heterodimeric ligands that simultaneously recognize FAP and αVβ3, or FAP and αVβ6, chelated with radionuclides. Their use offers significant advantages in both diagnosis and treatment, overcoming the lack of targeting of single chelators (e.g., DOTA) and enabling the construction of novel compounds that impart tumor targeting. Compared to single targets, compounds prepared with heterodimeric ligands that simultaneously recognize FAP and αVβ3, or FAP and αVβ6, can enhance specific targeted therapy.

[0089] The present invention uses polypeptide compounds, especially cyclic peptides as the active drug portion (CY) combined with heterodimeric ligands that can simultaneously recognize FAP and αVβ3, or FAP and αVβ6, and a complex composed of radionuclide chelation, so that the prepared compound has the advantages of strong structural stability, enzymatic stability, good pharmacokinetic characteristics, rapid tissue clearance and effective tumor penetration.

[0090] The peptide-based radiopharmaceuticals prepared by this invention are promising clinical diagnostic agents. These bispecific heterodimers possess the advantages of peptide compounds, including excellent in vivo biodistribution, high tumor uptake, and prolonged retention. Furthermore, compared to small-molecule FAP ligands and their radionuclide complexes, these compounds offer enhanced specificity, more accurately targeting tumor cells, and reduced adverse reactions associated with off-target toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 For Example 2[ 68 Figure 1 shows the results of in vitro stability testing of [Ga]-cRGD-FAPI-01.

[0092] Figure 2 For Example 8[ 68 Figure 1 shows the results of in vitro stability testing of [Ga]-cRGD-FAPI-03.

[0093] Figure 3 For Example 11[ 68 Figure 1 shows the results of in vitro stability testing of [Ga]-cRGD-FAPI-04.

[0094] Figure 4 For Example 2[ 68 Figure 1 shows the results of small animal Micro-PET-CT imaging experiments using [Ga]-cRGD-FAPI-01.

[0095] Figure 5 For Example 5[ 68 Figure 1. Results of small animal Micro-PET-CT imaging experiments using [Ga]-cRGD-FAPI-02.

[0096] Figure 6 For Example 8[ 68 Ga]-cRGD-FAPI-03 in the small animal Micro-PET-CT imaging experiment results figure.

[0097] Figure 7 For Example 11[ 68 Ga]-cRGD-FAPI-04 in the small animal (U87MG tumor-bearing mice) Micro-PET-CT imaging experiment results figure.

[0098] Figure 8 For Example 11[ 68 Ga]-cRGD-FAPI-04 in the small animal (A549-FAP tumor-bearing mice) Micro-PET-CT imaging experiment results figure.

[0099] Figure 9 For tumor and organ radioactivity as a function of time figure.

[0100] Figure 10 For 177 Lu-labeled molecules in the tissue distribution of U87MG tumor-bearing mice figure.

[0101] Figure 11 For 177 Lu-labeled compounds in tumor-bearing mice treatment effect figure.

[0102] Figure 12 For in vivo stability test results figure.

[0103] Figure 13 For cell efflux experiment results figure.

[0104] Figure 14 For in vitro cell internalization experiment results figure. DETAILED DESCRIPTION

[0105] The present application will be further described below in conjunction with specific examples. These examples are only used to illustrate the present application and not used to limit the scope of the present application.

[0106] A preparation process of the compound of the present application is as follows:

[0107]

[0108] wherein R 10 is a protecting group known to those skilled in the art, for example, Boc; wherein, CY, CL, BT, L a , L b all have the meanings described in the present application; -C(=O)-X 1 has the same meaning as L cConsistent with the meaning;

[0109] Step 1) Synthesis of compound A (e.g. RGD series cyclic peptide) by solid phase peptide synthesis (SPPS); alternatively, the resulting compound A (e.g. RGD series cyclic peptide) is condensed with a linker (Linker-PG) compound B with a protecting group to obtain compound C: CY-Linker-PG (e.g. cRGD-Linker-PG);

[0110] Step 2) Removal of the protecting group of the resulting compound C under acidic or catalytic hydrogenation conditions to obtain compound D: CY-Linker (e.g. cRGD-Linker);

[0111] Step 3) Reaction of compound D with compound E to obtain compound F, and further condensation with compound G (e.g. small molecule ligand targeting FAP) to obtain a bispecific heterodimer compound H (compound of the present application) targeting fibroblast activation protein (FAP) and one of the two subtypes of the integrin family, ανβ3 or ανβ6.

[0112] Example 1 DOTA-cRGD-FAPI-01

[0113] Synthesis of compound 2

[0114]

[0115] Resin pretreatment: 2-chlorotrityl resin (10 g, 0.4-3.0 mmol / g) was washed with CH2Cl2three times, each time for 30 min of shaking bed, and the resin was reserved.

[0116] Compound 1 (8.92 g, 30 mmol) and DIPEA (5.82 g, 45 mmol) were added in CH2Cl2(50 mL) and shaken for 4 h. Filtration and removal of solvent. The solid was washed with DMF (50 mL x 3) to obtain compound 2.

[0117] Synthesis of compound 3

[0118]

[0119] A 20% piperidine solution in N,N-dimethylformamide (50 mL) was added to compound 2 (the product obtained in the previous step was directly used), and shaken for 1.5 h at room temperature. Filtration and removal of solvent. The solid was washed with DMF (50 mL x 3) to obtain compound 3.

[0120] Synthesis of compound 5

[0121]

[0122] After adding solvent DMF (50 mL) to compound 3 (the product of the previous step was directly used as the raw material), compound 4 (6.94 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (2.58 g, 20 mmol) were sequentially added, the pH of the reaction system was about 7-8, and the reaction was shaken for 3 h. Filtration was performed, and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of resin solid was used to elute the compound loaded on the resin with V (1,1,1,3,3,3-hexachloropropan-2-ol) / V (dichloromethane) = 1 / 4 to obtain compound 5, and the filtrate was subjected to LC-MS. LC-Ms (ESI + )m / z: 706.26 ([M+H] + ).

[0123] Synthesis of compound 6

[0124]

[0125] After adding 20% piperidine in N,N-dimethylformamide (50 mL) to compound 5 (the product of the previous step was directly used as the raw material), the reaction was shaken at room temperature for 1.5 h. Filtration was performed, and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of resin solid was used to elute the compound loaded on the resin with V (1,1,1,3,3,3-hexachloropropan-2-ol) / V (dichloromethane) = 1 / 4 to obtain compound 6, and the filtrate was subjected to LC-MS. LC-Ms (ESI + )m / z: 484.17 ([M+H] + ).

[0126] Synthesis of compound 8

[0127]

[0128] After adding solvent DMF (50 mL) to compound 6 (the product of the previous step was directly used as the raw material), compound 7 (5.02 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (2.58 g, 20 mmol) were sequentially added, the pH of the reaction system was about 7-8, and the reaction was shaken for 3 h. Filtration was performed, and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of resin solid was used to elute the compound loaded on the resin with V (1,1,1,3,3,3-hexachloropropan-2-ol) / V (dichloromethane) = 1 / 4 to obtain compound 8, and the filtrate was subjected to LC-MS. LC-Ms (ESI + )m / z: 968.43 ([M+H] + ).

[0129] Synthesis of compound 9

[0130]

[0131] A solution of 20% piperidine in N,N-dimethylformamide (50 mL) was added to compound 8 (the product from the previous step was used directly) and shaken on a shaker at room temperature for 1.5 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of the resin solid was eluted with V(1,1,1,3,3,3-hexachloropropan-2-ol) / V(dichloromethane) = 1 / 4 to give compound 9, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 746.44 ([M+H] + ).

[0132] Synthesis of compound 11

[0133]

[0134] A solution of 20% piperidine in N,N-dimethylformamide (50 mL) was added to compound 11 (the product from the previous step was used directly) and shaken on a shaker at room temperature for 1.5 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of the resin solid was eluted with V(1,1,1,3,3,3-hexachloropropan-2-ol) / V(dichloromethane) = 1 / 4 to give compound 12, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 893.53 ([M+H] + ).

[0135] Synthesis of compound 12

[0136]

[0137] A solution of 20% piperidine in N,N-dimethylformamide (50 mL) was added to compound 11 (the product from the previous step was used directly) and shaken on a shaker at room temperature for 1.5 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of the resin solid was eluted with V(1,1,1,3,3,3-hexachloropropan-2-ol) / V(dichloromethane) = 1 / 4 to give compound 12, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 893.53 ([M+H] + ).

[0138] Synthesis of compound 14

[0139]

[0140] To compound 12 (the product from the previous step was used directly), solvent DMF (50 mL) was added, followed by compound 13 (4.12 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (2.58 g, 20 mmol). The pH of the reaction system was about 7-8, and the reaction was shaken for 3 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of resin solid was used to elute the compound loaded on the resin with V(1,1,1,3,3,3-hexachloropropan-2-ol) / V(dichloromethane) = 1 / 4 to obtain compound 14, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 1286.71 ([M+H] + ).

[0141] Synthesis of compound 15

[0142]

[0143] To compound 14 (the product from the previous step was used directly), 20% piperidine in N,N-dimethylformamide (50 mL) was added, and the reaction was shaken at room temperature for 1.5 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of resin solid was used to elute the compound loaded on the resin with V(1,1,1,3,3,3-hexachloropropan-2-ol) / V(dichloromethane) = 1 / 4 to obtain compound 15, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 1064.65 ([M+H] + ).

[0144] Synthesis of compound 16

[0145] N 2 -(N 2 -((S)-2-amino-4-(tert-butoxy)-4-oxobutanoyl)-D-phenylalanyl)-N 6 -((benzyloxy)carbonyl)-L-lysyl)-N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-L-arginyl)glycine (16)

[0146]

[0147] The resin solid compound 15 (the product obtained in the above step was directly charged), was eluted with V (1,1,1,3,3,3-hexachloropropan-2-ol) / V (dichloromethane) = 1 / 4 to load the compound on the resin to obtain crude compound 16, 11.2 g, without purification, directly used in the next step.

[0148] Synthesis of compound 17

[0149] tert-Butyl 2-((2S,5R,8S,11S)-5-benzyl-8-(4-(((benzyloxy)carbonyl)amino)butyl)- 3,6,9,12,15-pentaoxo-11-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenofuran-5-yl)sulfonyl) guanidino)propyl)-1,4,7,10,13-pentazacyclopentadec-2-yl)acetate (17)

[0150]

[0151] Compound 16 (11.2 g, 10.53 mmol, theoretical amount) was dissolved in DMF (120 mL), HATU (6.0 g, 15.78 mmol) and DIPEA (4.08 g, 31.59 mmol) were added and stirred at room temperature overnight. After the reaction was completed, H2O (360 mL) was added, and the separation was carried out after the layering was observed. The water phase and the organic phase were separated, and the organic phase was washed with saturated aqueous sodium chloride solution (180 mL). The organic phase was concentrated to obtain compound 17, white solid, 2.97 g; LC-Ms (ESI + )m / z: 1046.69 ([M+H] + ).

[0152] Synthesis of compound 18

[0153] tert-Butyl 2-((2S,5R,8S,11S)-8-(4-aminobutyl)-5-benzyl-3,6,9,12,15-pentaoxo-11-(3- ((2,2,4,6,7-pentamethyl-2,3,4,6,7-pentamethyl-2,3-dihydrobenofuran-5-yl)sulfonyl) guanidino)propyl)-1,4,7,10,13-pentazacyclopentadec-2-yl)acetate (18)

[0154]

[0155] Compound 17 (2.87g, 2.74mmol) was dissolved in MeOH (100mL), 10% Pd / C (292mg, 0.27mmol) was added, the reaction atmosphere was replaced with H2, and the reaction was stirred at room temperature overnight. After the reaction was completed, the Pd / C was removed by filtration with diatomite, and the filtrate was concentrated to obtain crude compound 18, a milky white solid, 1.51g; LC-Ms (ESI + )m / z: 912.83 ([M+H] + ).

[0156] Synthesis of compound 20

[0157] tert-Butyl 2-((2S,5R,8S,11S)-8-(1-(9H-fluoren-9-yl)-3,13-dioxo-2,7,10-trioxa-4,14-diazaoctadecan-18-yl)-5-benzyl-3,6,9,12,15-pentaoxo-11-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenofuran-5-yl)sulfonyl)guanidino)propyl)-1,4,7,10,13-pentazacyclopentadecyl)acetate (20)

[0158]

[0159] Compound 19 (399.44mg, 0.82mmol) was dissolved in DMF (6mL) and stirred and cooled in an ice water bath, HATU (404mg, 1.06mmol) and DIPEA (211.3mg, 1.63mmol) were added, and after stirring for 30min, compound 18 (745.5mg, 0.82mmol) was added, and the reaction temperature was naturally transitioned to room temperature as the ice water melted. After TLC detection showed that the reaction was complete, H2O (70mL) was added to the reaction system, and CH2Cl2 (15mL x 3) was used for extraction, the organic phase was combined, and saturated aqueous sodium chloride was used for washing, a large amount of sticky white flocculent precipitate was separated out, and the water phase and the organic phase were separated, the organic phase (CH2Cl2 and white flocculent precipitate) was concentrated under reduced pressure. After being slurried with [v(CH2Cl2) / v(MeOH)] = 1 / 0, the highly polar impurities were removed to obtain compound 20, a yellow solid, 983.8mg; without further purification, it was directly used in the next reaction. LC-Ms (ESI + )m / z: 1293.97 ([M+H] + ).

[0160] Synthesis of compound 21

[0161] 2-((2S,5R,8S,11S)-8-(4-(3-(2-(2-aminoethoxy)ethoxy)propanamido)butyl)-5- benzyl-3,6,9,12,15-pentaoxo-11-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5- yl)sulfonyl)guanidino)propyl)-1,4,7,10,13-pentazacyclopentadec-2-yl)ethyl acetate tert-butyl (21)

[0162]

[0163] Compound 20 (590 mg, 0.45 mmol) was dissolved in CH2Cl2(20 mL), piperidine (4 mL) was added, and the mixture was stirred at room temperature. After the reaction was completed (about 4-5 h) as determined by TLC, the bulk of the solvent was removed by concentration under reduced pressure with a septum pump, and then the bulk of the piperidine was removed by concentration under reduced pressure with an oil pump. Purification by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 5 / 1 gave the target compound 21 as a white solid, 290 mg; LC-Ms (ESI + )m / z: 1071.79 ([M+H] + ).

[0164] Synthesis of compound 24: tris tert-butyl 2,2',2"-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2- oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (24)

[0165]

[0166] Compound 22 (800 mg, 1.40 mmol) was dissolved in MeCN (2 mL), HBTU (582.7 mg, 1.54 mmol) and compound 23 (176.8 mg, 1.54 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed as determined by TLC, dilution was performed by adding H2O (50 mL), extraction was performed by using CH2Cl2(40 mL x 3), the combined organic phases were dried over Na2SO4, suction filtration was performed, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by trituration with [v(EtOAc) / v(PE)] = 5 / 1 to give compound 24 as a white solid, 809 mg;

[0167] Synthesis of compound 26

[0168] (S)-5-(benzyloxy)-5-oxo-4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10- tetraazacyclododecan-1-yl)acetamido)pentanoic acid (26)

[0169]

[0170] Compound 24 (1.17 g, 1.75 mmol) and compound 25 (415.2 mg, 1.75 mmol) were dissolved in THF (20 mL) and stirred at room temperature overnight. After TLC detection of the reaction, THF was removed under reduced pressure. H2O (10 mL) was added for dilution, and EtOAc (10 mL x 3) was extracted. The organic phase was combined, dried over Na2SO4, filtered, and purified by silica gel column chromatography [v(CH2Cl2) / v(MeOH)] = 50 / 1 to obtain compound 26 as a white foam, 685 mg; LC-Ms (ESI + )m / z: 792.60 ([M+H] + ).

[0171] Synthesis of compound 27: 2,2',2"-(10-((R)-20-((2S,5S,11S,14R)-14-benzyl-11-(2-(tert-butoxy)-2-oxoethyl)-3,6,9,12,15-pentaoxo-5-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenofuran-5-yl)sulfonyl)guanidino)propyl)-1,4,7,10,13-pentazacyclopentadec-2-yl)-4-(3-(benzyloxy)-3-oxopropyl)-2,5,15-trioxo-9,12-dioxa-3,6,16-triazadocosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (27)

[0172]

[0173] Compound 26 (214.4 mg, 0.27 mmol) was dissolved in DMF (5 mL) and stirred and cooled in an ice water bath. HATU (133.8 mg, 0.35 mmol) and DIPEA (70 mg, 0.54 mmol) were added, and the reaction was stirred for 30 min. Compound 21 (290 mg, 0.27 mmol) was added, and the reaction temperature was naturally transitioned to room temperature as the ice water melted. After TLC detection of the reaction, H2O (50 mL) was added to the reaction system, CH2Cl2 (15 mL x 3) was extracted, the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification by silica gel column chromatography [v(CH2Cl2) / v(MeOH)] = 30 / 1-10 / 1 yielded the target compound 27 as a colorless transparent gel, 154 mg; LC-Ms (ESI + )m / z: 923.49 ([M / 2+H] + ), 1846.16 ([M+H] + ).

[0174] Synthesis of compound 28: (R)-1-((2S,5S,11S,14R)-14-benzyl-11-(2-(tert-butoxy)-2- oxoethyl)-3,6,9,12,15-pentaoxo-5-(3-(3-((2,2,4,6,7-pentamethyl-2,3,3-dihydrobenofuran-5- yl)sulfonyl)guanidino)propyl)-1,4,7,10,13-pentazacyclopentadec-2-yl)-6,16-dioxo-17-(2-(4,7,10- tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)-9,12-dioxa-5,15- diazicosa-20-oic acid (28)

[0175]

[0176] Compound 27 (72.4 mg, 0.039 mmol) was dissolved in MeOH (3 mL), 10% Pd / C (4.2 mg, 0.0039 mmol) was added, the atmosphere was replaced with H2, and the reaction was stirred at room temperature overnight. After the reaction was completed, the Pd / C was removed by filtration with celite, and the filtrate was concentrated to give the crude compound 28 as a colorless transparent gel; LC-Ms (ESI + m / z: 878.50 ([M / 2+H] + ), 1755.77 ([M+H] + ).

[0177] Synthesis of compound 31: tert-butyl 2-(3a,5,5-trimethylhexahydro-4,6-methano- benzo[d][1,3,2]dioxol-2-yl)pyrrolidine-1-carboxylate (31)

[0178]

[0179] Compound 29 (10 g, 46.50 mmol) was dissolved in THF, and compound 30 (7.92 g, 46.50 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the reaction system was directly placed under reduced pressure in a rotary evaporator to remove the solvent. Purification by silica gel column chromatography [v(PE) / v(EtOAc)] = 1 / 0-10 / 1 gave the target compound 31, 13.85 g.

[0180] Synthesis of compound 32: (2R)-2-(3a,5,5-trimethylhexahydro-4,6-methano- benzo[d][1,3,2]dioxol-2-yl)pyrrolidine hydrochloride (32)

[0181]

[0182] HCl / EtOAc (2N, 60 mL) was added dropwise to compound 31 (13.85 g, 39.66 mmol) and left to react at room temperature. A large amount of white solid was produced during the process. After suction filtration, the white solid was washed with EtOAc and the solid was dried on an oil pump (yield 8.17 g, 82.69%); this solid compound (8.17 g, 32.79 mmol) was dissolved in 63 ml of CH2Cl2to form a white suspension and left to stir in an oil bath at 40°C for 8 h. The white solid was filtered and 3.67 g was obtained. This solid was dissolved in 12 ml of isopropanol and left to stir in an oil bath at 40°C overnight. The white solid was filtered and this was the desired compound 32 in the desired configuration, 3.29 g; white solid; 1 H-NMR (CDC13, 500 MHz) δ: 4.44 (d, J = 8.60 Hz, 1H), 3.43 (d, J = 6.90 Hz, 1H), 3.22 (t, J = 7.75 Hz, 1H), 2.35-2.30 (m, 1H), 2.27-2.21 (m, 1H), 2.07-1.93 (m, 7H), 1.45 (s, 3H), 1.27 (s, 3H), 1.12 (d, J = 11.10 Hz, 1H), 0.83 (s, 3H).

[0183] Synthesis of compound 34: tert-butyl ((2R)-1-oxo-1-((2R)-2-(3a,5,5-trimethylhexahydro- 4,6-methano-benzo[d][1,3,2]dioxol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamate (34)

[0184]

[0185] Compound 32 (3.29 g, 11.52 mmol) was dissolved in CH2Cl2and DIPEA (5.96 g, 46.08 mmol), 33 (2.18 g, 11.52 mmol), EDCI (2.65 g, 13.82 mmol) and HOBT (1.71 g, 12.70 mmol) were added sequentially and left to react at room temperature. Purification by column chromatography on silica gel [v(PE) / v(EtOAc)] = 10 / 1-5 / 1 gave compound 34, 2.69 g (containing a small amount of DIPEA).

[0186] Synthesis of compound 35: (2R)-2-amino-1-((2R)-2-(3a,5,5-trimethylhexahydro-4,6- methano-benzo[d][1,3,2]dioxol-2-yl)pyrrolidin-1-yl)propan-1-one (35)

[0187]

[0188] Compound 34 (500 mg, 1.19 mmol) was dissolved in 2 mL CH2Cl2, 2 mL TFA was added, and stirring was performed at room temperature. After the reaction was completed by TLC detection, the reaction system was concentrated under reduced pressure to obtain crude compound 35. Without purification and characterization, it was directly used in the next step; LC-Ms (ESI + )m / z: 321.15 ([M+H] + )..

[0189] Synthesis of compound 37: tert-butyl (4-((((2R)-1-oxo-1-((2R)-2-(3a,5,5-trimethylhexahydro-4,6-methano-benzo[d][1,3,2]dioxol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)benzyl)carbamate (37)

[0190]

[0191] Compound 35 (517 mg, 1.19 mmol) was dissolved in DMF, DIPEA (461 mg, 3.57 mmol) was added, and after adjusting the pH to about 7-8, compound 36 (299 mg, 1.19 mmol) and HATU (678 mg, 1.78 mmol) were added. After the reaction was completed by TLC detection, the reaction system was diluted with 10 mL EtOAc, and the organic phase was washed with 40 mL H2O. Extraction was performed with EtOAc (50 mL), the organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride solution, dried, filtered under suction, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography [v(PE) / v(EtOAc)] = 1 / 0-5 / 1-3 / 1 to obtain compound 37, 260 mg of white foam solid; LC-Ms (ESI + )m / z: 554.34 ([M+H] + )..

[0192] Synthesis of compound 38: 4-(aminomethyl)-N-((2R)-1-oxo-1-((2R)-2-(3a,5,5-trimethylhexahydro-4,6-methano-benzo[d][1,3,2]dioxol-2-yl)pyrrolidin-1-yl)propan-2-yl)benzamide (38)

[0193]

[0194] Compound 37 (260 mg, 0.47 mmol) was dissolved in 2 mL CH2Cl2, 2.5 mL TFA was added, and stirring was performed at room temperature. After the reaction was completed by TLC detection, the reaction system was concentrated under reduced pressure, and without purification, it was directly used in the next step; LC-Ms (ESI +m / z: 454.10 ([M+H] + ).

[0195] Synthesis of compound 39: 2,2',2"-(10-((4R)-20-((2S,5S,11S,14R)-14-benzyl-11-(2-(tert- butoxy)-2-oxoethyl)-3,3,2"-2-tert-butyltris tert-butyl ester-6,9,12,15-pentaoxo-5-(3-((2,2,4,6,7- pentamethyl-2,3,6,-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-1,4,7,10,13- pentaazacyclopentadec-2-yl)-2,5,15-trioxo-4-(3-oxo-3-((4-((2R)-1-oxo-1-((2R)-2-(3a,5,5- trimethylhexahydro-4,6-methylenedioxybenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)prop-2-yl)carbamoyl) benzyl)amino)propyl)-9,12-dioxa-3,6,16-triazacyclododecane-1,4,7-trisyl)triacetate (39)

[0196]

[0197] Compound 28 (147 mg, 0.084 mmol) was dissolved in DMF (5 mL) and stirred in an ice water bath, HATU (41.4 mg, 0.11 mmol) and DIPEA (21.7 mg, 0.17 mmol) were added, and the stirring was continued for 30 min, then compound 38 (38 mg, 0.084 mmol, theoretical amount) was added, and the reaction temperature was naturally transitioned to room temperature as the ice water melted. After TLC detection showed that the reaction was complete, H2O (50 mL) was added to the reaction system, and CH2Cl2(15 mL x 3) was used for extraction, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to obtain the crude target compound 39. LC-Ms (ESI + m / z: 1096.35 ([M / 2+H] + ).

[0198] Synthesis of compound DOTA-cRGD-FAPI-01: 2,2',2"-(10-((R)-20-((2S,5S,11S,14R)-14-benzyl-11-(carboxymethyl)-5-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentazacyclopentadec-2-yl)-4-(((4-(R)-1-((R)-2-borylpiperidin-1-yl)-1-oxopropan-2-yl)amino)-3-oxopropyl)-2,5,15-trioxo-9,12-dioxa-3,6,16-triazadocosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trisyl)triacetic acid

[0199]

[0200] Compound 39 was dissolved in H2O, after stirring for 1 h, benzeneboronic acid (15.4 mg, 0.13 mmol) and a solution of MeCN / TBME = 1 / 6 were added, after stirring for 3 h, the solution was allowed to stand and the organic and aqueous phases were separated, the aqueous phase was taken and dried in a vacuum drying box, finally, 134 mg of crude product was obtained, which was purified by reverse phase preparative column to obtain DOTA-cRGD-FAPI-01, white solid 2.9 mg. LC-Ms (ESI + m / z: 1581.57 ([M+H] + ), 1562.44 ([M-H2O+H] + ), 781.87 ([(M-H2O) / 2+H] + ).

[0201] [ 68 Ga]-cRGD-FAPI-01 and [ 177 Lu]-cRGD-FAPI-01 are complexes prepared by labeling DOTA-cRGD-FAPI-01 with radionuclides, after labeling, the compounds are subjected to quality control and purification by analytical radio-HPLC, the radiochemical purity of all the complexes is greater than 95%, and the obtained complexes will be used for in vitro and in vivo experiments.

[0202] Example 2 68 Preparation of [

[0203] 68Ga: The ligand compound DOTA-cRGD-FAPI-01 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.25 M), and then the germanium-gallium generator eluted with dilute hydrochloric acid (4 mL, 0.05 mol / L) was added to the above mixture. After oscillation, the resulting mixture was reacted at 90-100 °C for 10-15 min. Then, it was diluted with sterilized water for injection and separated and purified by purification through a C18 column (ethanol / water (1 / 1, v / v), 2 mL) to obtain [Ga]-cRGD-FAPI-01. 68 Ga]-cRGD-FAPI-01.

[0204] Example 3 177 Preparation of [Lu]-cRGD-FAPI-01

[0205] 177 Lu: The ligand compound DOTA-cRGD-FAPI-01 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.4 M), and then 185 MBq of commercially available 177 LuCl3solution was added, and gentisic acid (2.0 mg) was added. The reaction mixture was reacted at 95 °C for 30-60 min, cooled to room temperature, and then diluted with physiological saline to obtain [Lu]-cRGD-FAPI-01. 177 Lu]-cRGD-FAPI-01 was directly used after dilution with physiological saline.

[0206] Example 4 Synthesis of DOTA-cRGD-FAPI-02

[0207] Compound 46

[0208]

[0209] To a solid-phase synthesis tube containing the resin (10.0 g) was added compound 40 (2.99 g, 8.0 mmol), CH2Cl2(50 mL) and DIPEA (3.10 g, 24 mmol, 3 eq), and shaken on a shaker for 4 h. Filtration under suction and removal of the solvent were performed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), and then dried under suction and the solvent was removed to obtain compound 41 (13.9 g).

[0210] A 20% piperidine DMF solution (piperidine / DMF = 1 / 4, 50 mL) was added to compound 41 (the product obtained in the previous step was directly used), and shaken on a shaker at room temperature for 1 h. Filtration under suction and removal of the solvent were performed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), and then dried under suction and the solvent was removed to obtain compound 42.

[0211] DMF (50 mL) was added to compound 42 (the product from the previous step was used directly), followed by the addition of compound 43 (3.19 g, 8.0 mmol), HATU (4.56 g, 12 mmol, 1.5 eq) and DIPEA (3.10 g, 24 mmol, 3 eq), and the mixture was shaken for 2 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), and the solid was dried and the solvent was removed to give compound 44.

[0212] A 20% piperidine solution in DMF (50 mL) was added to compound 44 (the product from the previous step was used directly), and the mixture was shaken for 1 h at room temperature. The solid was filtered off and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), and the solid was dried and the solvent was removed to give compound 45.

[0213] DMF (50 mL) was added to compound 45 (the product from the previous step was used directly), followed by the addition of compound 26 (1.20 g, 1.5 mmol), HATU (0.68 g, 1.8 mmol, 1.2 eq) and DIPEA (0.58 g, 4.5 mmol, 3 eq), and the mixture was shaken for 2 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), and the solid was dried and the solvent was removed to give compound 46. A small amount of the resin solid was eluted with 1,1,1,3,3,3-hexachloropropan-2-ol / CH2Cl2(v / v) = 1 / 4 to elute the compound loaded on the resin, and the filtrate was subjected to LC-MS. LC-MS (ESI + )m / z: 1084.85 ([M+H] + ).

[0214] Compound 48: Tris-tert-butyl 2,2',2"-(10-((14S)-14-(3-(benzyloxy)-3-oxopropyl)- 3,13,16-trioxo-1-(4-(((2R)-1-oxo-1-((2R)-2-(3a,5,5-trimethylhexahydro-4,6- methanobenzo[d][1,3,2]dioxaboran-2-yl)pyrrolidin-1-yl)prop-2-yl)carbamoyl)phenyl)- 6,9-dioxa-2,12,15-triazahexadecyl-17-yl)-1,4,7,10-tetraazadodecane-1,4,7-trisyl)triacetate (48)

[0215]

[0216] Compound 46 (the product from the previous step was used directly) was washed with 20% hexafluoroisopropanol (hexafluoroisopropanol / DCM = 1 / 4) three times (50 mL x 3), and filtered under suction. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil, which was purified by column chromatography [V(MeOH) / V(DCM) = 1 / 30-1 / 20] to give the target product - 4-(3,13,17-trioxo-19-phenyl-14-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetylamino)-6,9,18-trioxa-2,12-diazanonadecyl)benzoic acid (47). Yellowish oil; 0.35 g.

[0217] Compound 47 (0.35 g, 0.32 mmol) was dissolved in DMF (1.5 mL), and HATU (0.15 g, 0.39 mmol, 1.2 eq), compound 35 (0.17 g, 0.39 mmol, 1.2 eq) and DIPEA (0.08 g, 0.65 mmol, 2 eq) were added successively. The reaction was stirred at room temperature for 2 h. TLC (MeOH:DCM = 1:10) was used to monitor the completion of the reaction. The reaction was worked up by adding water (7 mL) to the reaction mixture and washing. A yellowish sticky semi-solid was obtained. The crude product was dried and purified by column chromatography [V(MeOH) / V(DCM) = 1 / 50→1 / 30] to give the target product 48. Yellowish oil; 0.19 g; LC-MS (ESI + )m / z: 1387.25 ([M+H] + ).

[0218] Compound 49: (14S)-3,13-dioxo-1-(4-((2R)-1-oxo-1-((2R)-2-(3a,5,5-trimethylhexahydro-4,6-methanoben[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)phenyl)-14-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetylamino)-6,9-dioxa-2,12-diazheptadecyl-17-oxoacetic acid)-14-(2-(4,7,10-tetraazacyclododec-1-yl)acetylamino phenyl)-6,9-dioxa-2,12-diazheptadecan-17-carboxylic acid (49)

[0219]

[0220] Compound 48 (0.19 g, 0.14 mmol) was dissolved in methanol (3 mL), 10% Pd / C (23.0 mg, 0.02 mmol, 0.14 eq) was added, hydrogen was replaced, and the reaction was stirred at room temperature for 2 h. TLC (MeOH:DCM = 1:10) was used to monitor the completion of the reaction, and the reaction was post-treated by filtration and concentration of the filtrate to obtain the target product 49. Light yellow oil 0.15 g; the compound was directly used in the next reaction without further purification. LC-MS (ESI + )m / z: 1297.08 ([M+H] + .

[0221] Compound 51: (R)-2-((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((benzyloxy)carbonyl)amino)pentanoic acid

[0222]

[0223] Compound 50 (10.00 g, 37.6 mmol), Na2CO3(3.98 g, 37.6 mmol) were mixed into a suspension with water / 1,4-dioxane mixed solvent (v / v = 2.5 / 1, 175 mL), and then 100 mL of FmocOSu (12.67 g, 37.6 mmol) in 1,4-dioxane was added dropwise, and the reaction was stirred at room temperature for 22 h. MS was detected by sampling, and the [M+Na + ] value of compound 51 was detected. The reaction was concentrated under reduced pressure to half of the original volume, 600 mL of water was added, 1M HCl was used to adjust the pH to 3-4, at this time a large amount of white solid was precipitated, most of the water was filtered off, and the wet filter cake was dissolved in 400 mL of DCM, extracted and separated, the organic phase was retained, and the aqueous phase was back-extracted with 300 mL of DCM once, the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 51 as a white solid, 17.15 g. 1 H NMR (DMSO-d6, 500 MHz) δ: 7.88 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.5 Hz, 2H), 7.45-7.19 (m, 9H), 6.71 (d, J = 7.0 Hz, 1H), 4.98 (s, 2H), 4.22 (dq, J = 10.2, 5.5, 4.3 Hz, 3H), 3.67 (q, J = 6.6 Hz, 1H), 2.95 (q, J = 6.7 Hz, 2H), 1.67 (dq, J = 15.3, 5.7 Hz, 1H), 1.53 (ddd, J = 15.8, 13.3, 7.4 Hz, 1H), 1.38 (tt, J = 12.4, 6.6 Hz, 2H). LC-Ms (ESI + )m / z: 525.3 ([M+Na +]).

[0224] Compound 53: (R)-2-((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(((benzyloxy)carbonyl)amino)pentanoic acid)pentanoic acid

[0225]

[0226] Compound 51 (15.12 g, 31 mmol) was dissolved in 120 mL of chlorobenzene, and then paraformaldehyde (9.29 g, 0.3 mol, 10 eq) and TsOH·H2O (0.59 g, 3.1 mmol, 0.1 eq) were added in sequence. The temperature was raised to 60°C and stirred for 1 h. TLC (V(MeOH):V(DCM)=1:10, Rf=0.4) showed that the reaction was complete. A sample was taken for MS analysis, which showed [M+Na + ] value, and the reaction of the raw material compound 7 was complete. Stop heating, post-treatment: add 250 mL of saturated NaHCO3 solution to the reaction solution under ice bath and stir for 5 min, then add 200 mL of EtOAc for extraction, retain the organic phase, and back-extract the aqueous phase with 200 mL of EtOAc once, combine the organic phases, dry over anhydrous Na2SO4, filter, and concentrate at 45°C to obtain the crude product 52, which was purified by column chromatography [MeOH:DCM=1:30-1:10] to obtain (9H-fluoren-9-yl)methyl (R)-4-(3-((benzyloxy)carbonyl)amino)propyl)-5-oxooxazolidine-3-carboxylate (52) as a white foamy solid, 5.60 g. LC-Ms(ESI + )m / z:537.2([M+Na + ]).

[0227] Intermediate 52 (2.5 g, 4.9 mmol) was dissolved in 20 mL of DCE, and then TFA (8.50 g, 75 mmol, 15 eq) and triethylsilane (2.90 g, 25 mmol, 5 eq) were added in sequence. The temperature was raised to 60°C and refluxed with stirring for 4 h. TLC (MeOH:DCM=1:10, Rf=0.4) showed that the reaction of the starting material was complete. A sample was taken for MS analysis, which showed the presence of compound 53 [M+Na + ] value, and the reaction of the raw material intermediate 52 was complete. Stop heating and post-treatment: under ice bath, add 100 mL of saturated NaHCO3 solution to the reaction solution and stir for 5 minutes, then add 100 mL of EtOAc for extraction, retain the organic phase, and back-extract the aqueous phase with 50 mL of EtOAc once. The organic phases are combined, dried over anhydrous Na2SO4, filtered, and concentrated at 45°C to obtain the crude product 53, which is purified by column chromatography [MeOH:DCM=1:0→1:50] to obtain 53 as a light yellow oil, 2.40 g. LC-Ms(ESI +m / z: 539.2 ([M+Na + ]).

[0228] Compound 61

[0229]

[0230] To compound 61 (the product from the previous step was used directly) was added DMF (200 mL) followed by compound 53 (2.40 g, 4.8 mmol), HATU (2.74 g, 7.2 mmol) and DIPEA (1.24 g, 9.6 mmol) sequentially. The mixture was shaken for 2 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (150 mL x 3) and then with EtOAc (150 mL x 3). The solid was dried and the solvent was removed to give compound 62.

[0231] To compound 60 (the product from the previous step was used directly) was added 200 mL of 20% diethylamine in DMF and the mixture was shaken for 2 h at room temperature. The solid was filtered off and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then with EtOAc (200 mL x 3). The solid was dried and the solvent was removed to give compound 61 (14.8 g). A small amount of the resin solid was used to elute the compound loaded on the resin with 1,1,1,3,3,3-hexachloropropan-2-ol / CH2Cl2(v / v) = 1 / 4. The filtrate was subjected to LC-MS. LC-Ms (ESI + m / z: 703.4 ([M+H] + ).

[0232] Compound 63

[0233]

[0234] To compound 61 (the product from the previous step was used directly) was added DMF (200 mL) followed by compound 53 (2.40 g, 4.8 mmol), HATU (2.74 g, 7.2 mmol) and DIPEA (1.24 g, 9.6 mmol) sequentially. The mixture was shaken for 2 h. The solid was filtered off and the solvent was removed. The solid was washed with DMF (150 mL x 3) and then with EtOAc (150 mL x 3). The solid was dried and the solvent was removed to give compound 62.

[0235] To compound 62 (the product from the previous step was used directly), 150 mL of 20% diethylamine in DMF was added and shaken at room temperature for 1 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (150 mL x 3) and then with EtOAc (150 mL x 3), and was dried and the solvent was removed to give compound 63. A small amount of the resin solid was used to elute the compound loaded on the resin with 1,1,1,3,3,3-hexachloropropan-2-ol / CH2Cl2(v / v) = 1 / 4, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 979.6 ([M+H] + .

[0236] Compound 66

[0237]

[0238] To compound 63 (the product from the previous step was used directly), compound 64 (2.21 g, 4.8 mmol), HATU (2.74 g, 7.2 mmol) and DIPEA (1.24 g, 9.6 mmol) were added sequentially and shaken at room temperature for 2 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (150 mL x 3) and then with EtOAc (150 mL x 3), and was dried and the solvent was removed to give compound 65 (14.1 g).

[0239] To compound 65 (the product from the previous step was used directly), 150 mL of 20% diethylamine in DMF was added and shaken at room temperature for 1 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (150 mL x 3) and then with EtOAc (150 mL x 3), and was dried and the solvent was removed to give compound 66 (12.9 g). A small amount of the resin solid was used to elute the compound loaded on the resin with 1,1,1,3,3,3-hexachloropropan-2-ol / CH2Cl2(v / v) = 1 / 4, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 1076.91 ([M+H] + .

[0240] Compound 80

[0241]

[0242] To compound 68 (the product from the previous step was used directly) was added solvent DMF (200 mL) followed by compound 69 (8.75 g, 20 mmol), HATU (9.13 g, 24 mmol) and DIPEA (5.17 g, 40 mmol) and shaken for 2 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then EtOAc (200 mL x 3), and then dried and the solvent was removed to give compound 70.

[0243] To compound 70 (the product from the previous step was used directly) was added 200 mL of 20% diethylamine in DMF and shaken for 2 h at room temperature. The solid was filtered and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then EtOAc (200 mL x 3), and then dried and the solvent was removed to give compound 71.

[0244] To compound 71 (the product from the previous step was used directly) was added solvent DMF (200 mL) followed by compound 72 (8.75 g, 20 mmol), HATU (9.13 g, 24 mmol) and DIPEA (5.17 g, 40 mmol) and shaken for 2 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then EtOAc (200 mL x 3), and then dried and the solvent was removed to give compound 73.

[0245] To compound 73 (the product from the previous step was used directly) was added 200 mL of 20% diethylamine in DMF and shaken for 2 h at room temperature. The solid was filtered and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then EtOAc (200 mL x 3), and then dried and the solvent was removed to give compound 74.

[0246] To compound 71 (the product from the previous step was used directly) was added solvent DMF (200 mL) followed by compound 72 (8.75 g, 20 mmol), HATU (9.13 g, 24 mmol) and DIPEA (5.17 g, 40 mmol) and shaken for 2 h. The solid was filtered and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then EtOAc (200 mL x 3), and then dried and the solvent was removed to give compound 73.

[0247] To compound 73 (the product from the previous step was used directly) was added 200 mL of 20% diethylamine in DMF and shaken for 2 h at room temperature. The solid was filtered and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then EtOAc (200 mL x 3), and then dried and the solvent was removed to give compound 74.

[0248] To compound 74 (the product from the previous step was used directly) was added solvent DMF (200 mL), followed by compound 13 (8.75 g, 20 mmol), HATU (9.13 g, 24 mmol) and DIPEA (5.17 g, 40 mmol), and the mixture was shaken for 2 h. The mixture was filtered, and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then with EtOAc (200 mL x 3), and the mixture was filtered and the solvent was removed to give compound 76.

[0249] To compound 76 (the product from the previous step was used directly) was added 200 mL of a 20% diethylamine solution in DMF, and the mixture was shaken for 2 h at room temperature. The mixture was filtered, and the solvent was removed. The solid was washed with DMF (200 mL x 3) and then with EtOAc (200 mL x 3), and the mixture was filtered and the solvent was removed to give compound 77.

[0250] Compound 77 (the product from the previous step was used directly) was eluted from the resin with 1,1,1,3,3,3-hexachloropropan-2-ol / CH2Cl2(v / v) = 1 / 4 (150 mL x 3), and the crude compound was obtained after concentration. Compound 78 was obtained as a yellow solid after purification by column chromatography [MeOH:DCM = 1:20-1:8], 3.10 g.

[0251] Compound 78 (3.00 g, 2.6 mmol) was dissolved in DMF (30 mL), and HATU (1.47 g, 3.9 mmol, 1.5 eq) and DIPEA (0.67 g, 5.2 mmol, 2 eq) were added, and the mixture was stirred at room temperature for 1.5 h. LC (MeOH:DCM = 1:10, Rf = 0.6) monitoring showed that the starting material was completely reacted, and MS monitoring showed that the starting material was completely reacted and that the MS value of the target compound 80 was obtained. The reaction mixture was washed with H2O (100 mL), and a large amount of yellow sticky solid was precipitated. The mixture was filtered, and the filter cake was dried and then purified by column chromatography [V(MeOH) / V(DCM) = 1 / 30→1 / 15] to give the target product 80. Yellow solid; 1.10 g; LC-Ms (ESI + )m / z: 1632.88 ([M+H] + ).

[0252] Compound 81

[0253]

[0254] Compound 80 (1.01 g, 0.83 mmol) was dissolved in MeOH (30 mL), 10% Pd / C (0.18 g, 0.17 mmol, 0.2 eq) was added, hydrogen was replaced, and the mixture was stirred at 50 °C for 16 h. MS detection showed that the reaction was complete, and there was the MS value of the target molecule 81. Work-up: filtration, concentration of the filtrate to give compound 81, which was directly used in the next reaction without purification. Yellow oil, 345.8 mg; LC-Ms (ESI + )m / z: 1498.88 ([M+H] + ).

[0255] Compound 82

[0256]

[0257] Compound 81 (3.5 g, 2.8 mmol,) was dissolved in DMF (10 mL), compound 19 (1.1 g, 2.8 mmol,) was added, HATU (2.1 g, 3.7 mmol) and DIPEA (4.08 g, 14 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was complete, H2O (360 mL) was added, and the mixture was allowed to stand to separate into an aqueous phase and an organic phase. The aqueous phase and the organic phase were separated, and the organic phase was washed with saturated aqueous sodium chloride solution (180 mL). The organic phase was concentrated, and column chromatography (DCM / MeOH = 50 / 1-10 / 1) was performed to give compound 82, which was a white solid, 2.0 g. LC-Ms (ESI + )m / z: 1880.69 ([M+H] + )。

[0258] Compound 83

[0259]

[0260] Compound 82 (2.0 g, 1.1 mmol) was added to a 20% piperidine solution in dichloromethane, and the mixture was stirred at room temperature for 1.5 h. After the reaction was complete, water was added to dilute the mixture, 1M HCl was added to adjust the pH to 7, and the mixture was filtered to give compound 83, which was a white solid, 800 mg. LC-Ms (ESI + )m / z: 1657.69 ([M+H] + )。

[0261] Compound 84

[0262]

[0263] Compound 83 (800 mg, 0.48 mmol, 1 eq) was dissolved in DMF (5 mL) and compound 49 (622 mg, 0.48 mmol, 1 eq), HATU (202 mg, 0.53 mmol, 1.1 eq) and DIPEA (155 mg, 1.2 mmol, 2.5 eq) were added thereto. The mixture was reacted at room temperature for 3 hours and extracted with EtOAc (10 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried, filtered, and concentrated under reduced pressure. Vacuum drying gave a light yellow colloid, compound 84, 350 mg. LC-Ms (ESI + )m / z:1469.87([M / 2+H] + ).

[0264] Compound 86: DOTA-cRGD-FAPI-02: 2,2',2'-(10-(S)-4-(2-(3-(4-(((R)-1-(((R)-2-boropyrrolidin-1-yl)-1-oxopropyl-2-yl)carbamoyl)benzyl)amino)-3-oxopropyloxy)ethoxy)ethyl)carbamoyl)-2,2-((3S,6S,9S,15S,18S,21S,24S,29aR)-15-(carboxymethyl)-9-(3-guanidinopropyl) -6,24-bis(4-hydroxybenzyl)-18-isobutyl-2,21-dimethyl-1,4,7,10,13,16,19,22,25-nonaoxacosanehydro-1H-pyrrolo[1,2-a][1,4,7,10,13,16,19,22,25]nonaazacycloheptan-3-yl)-2,7,17-trioxo-11,14-dioxo-3,8,18-triazapolysaccharide-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0265]

[0266] Compound 84 (350 mg, 0.0359 mmol, 1 eq) was dissolved in DCM (3 mL), and TFA (3 mL) was added and reacted at room temperature for 1 hour. The reaction solution was dried in vacuo to obtain a light yellow solid 2,2',2'-(10-(4S)-22-(3S,6S,9S,15S,18S,21S,24S,29aR)-15-(carboxymethyl)-9-(3-guanidinopropyl)-6,24-bis(4-hydroxybenzyl)-18-isobutyl-2,21-dimethyl-1,4,7,10,13,16,19,22,25-nonaoxoctacosanehydro-1H-pyrrolo[1,2a][1,4,7,10,13,16,19,22]nonaazacycloheptane-3-yl)- 2,7,17-Trioxo-4-(2-(3-oxo-3-(4-(((2R)-1-oxo-1-(2R)-2-(3a,5,5-trimethylhexahydro-4,6-methylbenzo[d][1,3,2]dioxol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)benzyl)amino)propoxy)ethoxy)ethyl)carbamoyl)-11,14-dioxa-3,8,18-triazapolysaccharide-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (85), 350 mg.

[0267] Compound 85 (350 mg) was dissolved in H2O and stirred for 1 h. Phenylboronic acid (67.4 mg, 0.56 mmol) and a solution of MeCN / TBME (V / V) = 1 / 6 (3 mL) were added. Stirring was continued for 3 h. The solution was allowed to stand for separation. The organic phase and the aqueous phase were separated. The aqueous phase was taken and dried in a vacuum drying oven to obtain 100 mg of a crude product. 3.5 mg of a white solid was obtained by reverse phase preparative column separation. LC-MS (ESI + )m / z:1089.66([(M-2H2O) / 2+H] + ).

[0268] Example 5 68 Preparation of [Ga]-cRGD-FAPI-02

[0269] 68 Ga: The ligand compound DOTA-cRGD-FAPI-02 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.25 M); the germanium gallium generator was then eluted with dilute hydrochloric acid (4 mL, 0.05 mol / L) and added to the above mixture. After shaking, the new mixture was reacted at 90-100°C for 10-15 minutes. Then, it was diluted with sterile water for injection and purified by C18 column purification (ethanol / water (1 / 1, v / v), 2 mL) to obtain [ 68 Ga]-cRGD-FAPI-02.

[0270] Example 6 177 Preparation of [Lu]-cRGD-FAPI-02

[0271] 177 Lu: The ligand compound DOTA-cRGD-FAPI-02 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.4 M), and 185 MBq of the purchased 177 LuCl3 solution, and add gentisic acid (2.0 mg), the reaction mixture is reacted at 95 ° C for 30-60 min, cooled to room temperature, [ 177 Lu]-cRGD-FAPI-02 was diluted with saline and used directly.

[0272] Example 7 DOTA-cRGD-FAPI-03

[0273] Compound 87

[0274]

[0275] Compound 9 (prepared from compound 1 according to the procedures of Example 1, compound 9 was added directly to the mixture in DMF (50 mL). Compound 59 (3.87 g, 10 mmol), HATU (5.7 g, 15 mmol), and DIPEA (2.58 g, 20 mmol) were then added sequentially. The reaction system had a pH of approximately 7-8 and was shaken for 3 h. Filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3), drained, and the solvent removed to yield compound 87. A small amount of the resin solid was removed and the compound loaded on the resin was eluted with 1,1,1,3,3,3-hexachloropropane-2-ol / dichloromethane (v / v) = 1 / 4. The filtrate was then submitted to LC-MS. LC-MS (ESI+) m / z: 1115.53 ([M+H]+).

[0276] Compound 88

[0277]

[0278] A 20% piperidine solution in DMF was added to compound 87 (the product from the previous step was added directly) and shaken at room temperature for 1.5 h. Filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3). A small amount of the resin solid was removed and the resin-loaded compound was eluted with 1,1,1,3,3,3-hexachloropropane-2-ol / dichloromethane (1 / 4) to obtain compound 88. The filtrate was submitted to LC-MS. LC-MS (ESI+) m / z: 893.53 ([M+H]+).

[0279]

[0280] To compound 88 (the product of the previous step was used directly), solvent DMF (50 mL) was added, followed by compound 13 (4.12 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (2.58 g, 20 mmol). The pH of the reaction system was about 7-8, and the reaction was shaken for 3 h. Filtration was performed, and the solvent was removed. The solid was washed with DMF (50 mL x 3) to obtain compound 89. A small amount of resin solid was used to elute the compound loaded on the resin with V (1,1,1,3,3,3-hexachloropropan-2-ol) / V (dichloromethane) = 1 / 4, and the filtrate was subjected to LC-MS. LC-Ms (ESI+) m / z: 1286.71 ([M+H]+).

[0281] Compound 91

[0282]

[0283] To compound 89 (the product of the previous step was used directly), a 20% piperidine solution in DMF was added, and the reaction was shaken at room temperature for 1.5 h. Filtration was performed, and the solvent was removed. The solid was washed with DMF (50 mL x 3), and the solvent was removed by drying to obtain compound 91. A small amount of resin solid was used to elute the compound loaded on the resin with 1,1,1,3,3,3-hexachloropropan-2-ol / dichloromethane (V / V) = 1 / 4, and the filtrate was subjected to LC-MS. LC-Ms (ESI+) m / z: 1064.65 ([M+H]+).

[0284] Compound 93

[0285]

[0286] The resin solid compound 91 (the product of the previous step was used directly) was eluted with 1,1,1,3,3,3-hexachloropropan-2-ol / dichloromethane = 1 / 4 to obtain crude compound 92, 11.2 g, which was used directly in the next step without purification.

[0287] Compound 92 (11.2 g, 10.53 mmol) was dissolved in DMF (120 mL), and HATU (6.0 g, 15.78 mmol) and DIPEA (4.08 g, 31.59 mmol) were added and stirred at room temperature overnight. After the reaction was completed, H2O (360 mL) was added, and the aqueous and organic phases were separated by standing. The organic phase was washed with saturated aqueous sodium chloride solution (180 mL). The organic phase was concentrated to obtain compound 93, a white solid, 2.97 g; LC-Ms (ESI + )m / z: 1118.69 ([M+H] + ).

[0288] Compound 94

[0289]

[0290] Compound 93 (2.87 g, 2.74 mmol) was dissolved in MeOH (100 mL), 10% Pd / C (280 mg) was added, stirred at room temperature under hydrogen atmosphere overnight. After the reaction was completed, filtered, concentrated under vacuum to get the crude compound 94 as a milky white solid, 2.8 g; LC-Ms (ESI+) m / z: 984.83 ([M+H]+). + + .

[0291] Compound 95

[0292]

[0293] Compound 94 (2.8 g, 2.8 mmol,) was dissolved in DMF (10 mL), compound 19 (1.1 g, 2.8 mmol,) was added, HATU (1.4 g, 3.7 mmol) and DIPEA (1.8 g, 14 mmol) were added, stirred at room temperature overnight. After the reaction was completed, H2O (360 mL) was added, the separation of the water phase and the organic phase was carried out after standing, then the organic phase was washed with saturated aqueous sodium chloride solution (180 mL). The organic phase was concentrated, and column chromatography (DCM / MeOH (V / V) = 50 / 1-10 / 1) was used to obtain compound 95, white solid 2.0 g; LC-Ms (ESI+) m / z: 1365.69 ([M+H]+).

[0294]

[0295] Compound 95 (2.0 g, 1.46 mmol) was added to a 20% piperidine DMF solution, stirred at room temperature for 1.5 h. After the reaction was completed, water was added to dilute it, 1M HCl was added to adjust pH = 7, and then filtered to obtain white solid compound 96; LC-Ms (ESI+) m / z: 1143.69 ([M+H]+). +

[0296] ​​Compound 97: 2,2',2'-tris-tert-butyl (10-((4S)-22-((2S,5S,11S,14R)-11-(2-(tert- butoxy)-2-oxoethyl)-14-(4-(tert-butoxy)benzyl)-3,6,9,12,15-pentaoxo-5-(3-(((2,2,4,6,7- pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-1,4,7,10,13- pentaazacyclopentadecyl-2-yl)-2,7,17-trioxo-4-((2-(3-oxo-3-((4-((2R)-1-oxo-1-((2R)-2-(3a,5,5- trimethylhexahydro-4,6-methanoben[d][1,3,2]dioxol-2-yl)pyrrolidin-1-yl)prop-2-yl)carbamoyl) benzyl)amino)propoxy)ethoxy)ethyl)carbamoyl)-11,14-dioxo-3,8,18-triazadodecyl)-1,4,7,10- tetraazacyclododecane-1,4,7-trisyl)triacetate

[0297]

[0298] Compound 96 (800 mg, 0.618 mmol, 1 eq) was dissolved in DMF (5 mL), to which compound 49 (700 mg, 0.618 mmol, 1 eq), HATU (78 mg, 0.680 mmol, 1.1 eq) and DIPEA (140 mg, 0.680 mmol, 1.1 eq) were added, and reacted at room temperature for 3 hours, extracted with EtOAc (10 mL), the organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride solution, dried, filtered under suction, and concentrated under reduced pressure. Compound 97 was obtained as a yellowish gel 350 mg by drying under vacuum; LC-Ms (ESI + m / z: 1212.87 ([M+2H] + / 2).

[0299] Compound DOTA-cRGD-FAPI-03: 2,2',2'-(10-((S)-4-((2-(2-(3-(4-((((R)-1-(((R)-2-bromopyrrolidin-1-yl)-1- oxoprop-2-yl)carbamoyl)-3-oxopropoxy)ethoxy)ethyl)carbamoyl)-2,2-((2S,5S,11S,14R)-11- (carboxymethyl)-5-(3-guanidinopropyl)-14-(4-hydroxybenzyl)-3,6,9,12,5-pentaoxo-1,4,7,10,13- pentaazacyclopentadecyl-2-yl)-2,7,17-trioxo-11,14-dioxo-3,8,18-triazadodecyl)-1,4,7,10- tetraazacyclododecane-1,4,7-trisyl)triacetic acid

[0300]

[0301] Compound 97 (350 mg, 0.0359 mmol, 1 eq) was dissolved in CH2Cl2(3 mL), and TFA (3 mL) was added. The reaction was allowed to react at room temperature for 1 h. The reaction solution was dried in vacuum to obtain a light yellow solid 350 mg; the light yellow solid was added with H2O, and after stirring for 1 h, phenylboronic acid (67.4 mg, 0.56 mmol) and a solution of MeCN / TBME (V / V) = 1 / 6 were added. After continuing to stir for 3 h, the solution was allowed to stand to separate into organic and aqueous phases. The aqueous phase was taken and dried in a vacuum drying box. Finally, 80 mg of a crude product was obtained, which was separated by a reversed-phase preparative column to obtain DOTA-cRGD-FAPI-03, a white solid 1.5 mg; LC-Ms (ESI + )m / z: 1754.87 ([M+H] + ).

[0302] Example 8 68 Preparation of

[0303] 68 Ga: The ligand compound DOTA-cRGD-FAPI-03 (50 μg) was dissolved in a sodium acetate solution (1 mL, 0.25 M); then a germanium gallium generator was eluted with dilute hydrochloric acid (4 mL, 0.05 mol / L) into the above mixture, which was shaken. The resulting mixture was allowed to react at 90-100 °C for 10-15 min. Then, it was diluted with sterile water for injection and separated and purified by purification on a C18 column (ethanol / water (1 / 1, v / v), 2 mL) to obtain 68 Ga]-cRGD-FAPI-03.

[0304] Example 9 177 Preparation of

[0305] 177 Lu: The ligand compound DOTA-cRGD-FAPI-03 (50 μg) was dissolved in a sodium acetate solution (1 mL, 0.4 M), and then 185 MBq of a purchased 177 LuCl3solution was added, and gentisic acid (2.0 mg) was added. The reaction mixture was allowed to react at 95 °C for 30-60 min, and then cooled to room temperature to obtain 177 Lu]-cRGD-FAPI-03, which was further diluted with physiological saline and used directly.

[0306] Example 10

[0307] Compound 98

[0308]

[0309] Compound 38 (0.47 mmol, theoretical amount) was dissolved in DMF (0.5 mL), and DIPEA was slowly added dropwise to adjust the solution pH to about 7-8, and it was ready for use. In addition, compound 19 (Fmoc-PEG2-COOH) (146 mmol, 0.53 mmol) was dissolved in DMF (4 mL) and cooled in an ice water bath, and HATU (273 mg, 0.72 mmol) and DIPEA (124 mg, 0.96 mmol) were added, and after stirring for 30 min, the above-mentioned ready-to-use solution was added, and the reaction system temperature was naturally transitioned to room temperature, and it was stirred overnight. After TLC detection of the completion of the reaction, H2O (50 mL) was added to the reaction system, and EtOAc (15 mL x 3) was extracted, and the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 20 / 1 gave the target compound 98, 112 mg; LC-Ms (ESI + m / z: 713.76 [M+H] + .

[0310] Compound 100

[0311]

[0312] Compound 98 (112 mg, 0.16 mmol) was dissolved in 1 mL of CH2Cl2, 1 mL of TFA was added, and it was stirred at room temperature. After TLC detection of the completion of the reaction, the reaction system was concentrated under reduced pressure to obtain 4-((3-(2-(2-aminoethoxy)ethoxy)propanamido)methyl)-N-((2R)-1-oxo-1-((2R)-2-(3a,5,5-trimethylhexahydro-4,6-methanoben[d][1,3,2]dioxaborolan-2-yl)pyrrolidin-1-yl)propan-2-yl)benzamide trifluoroacetate (99), which was directly used in the next step without purification;

[0313] Compound 28 (112 mg, 0.064 mmol) was dissolved in DMF (5 mL) and stirred in an ice water bath, HATU (31.5 mg, 0.83 mmol) and DIPEA (16.5 mg, 0.13 mmol) were added, and stirring was continued for 30 min. Compound 99 (43 mg, 0.070 mmol) was then added, and the reaction temperature was naturally transitioned to room temperature as the ice water melted. After TLC detection showed that the reaction was complete, H2O (50 mL) was added to the reaction system, and CH2Cl2(15 mL x 3) was used for extraction. The combined organic phase was washed with saturated aqueous NaCl solution, dried, and concentrated under reduced pressure to obtain the crude product of compound 100, which was used directly in the next step without purification. LC-Ms (ESI + )m / z: 1175.66 [(M+2H) + / 2], 784.30 [(M+3H) + / 3].

[0314] Compound cRGD-FAPI-04: 2,2',2"-(10-((S)-22-((2S)5S,11S,14R)-14-benzyl-11- (carboxymethyl)-5-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13- pentaazacyclopentadecane-2-yl)-4-((2-(2-(3-((4-(R)-1-((R)-2-borolanyl-1-yl)-1- oxopropan-2-yl)carbamoyl)benzyl)amino)-3-oxopropoxy)ethyl)carbamoyl)- 2,7,17-trioxo-11,14-dioxa-3,8,18-triazadocosyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-trisyl)triacetic acid

[0315]

[0316] Compound 100 obtained in the previous step was dissolved in CH2Cl2(1 mL), and CF3COOH (1 mL) was added. The reaction was stirred at room temperature for 1 h. LC-Ms detection showed that compound 100 was consumed completely. The reaction was concentrated under reduced pressure to obtain a crude intermediate, which was dissolved in H2O and stirred for 1 h. Then, phenylboronic acid (14.2 mg, 0.12 mmol) and a solution of MeCN / TBME = 1 / 6 = 3.5 mL were added, and the reaction was stirred for another 3 h. The solution was allowed to stand to separate the organic phase and the aqueous phase. The aqueous phase was separated and dried in a vacuum drying oven. Finally, 190 mg of a crude product was obtained, and cRGD-FAPI-04, 3.6 mg, was obtained by reverse phase preparative separation. LC-Ms (ESI + )m / z: 1739.91 [M+H] + , 1722.80 [M-H2O+H] +,861.43[(M-H2O+2H) + / 2],852.49[(M-2H2O+2H) + / 2].

[0317] Example 11 68 Preparation of [Ga]-cRGD-FAPI-04

[0318] 68 Ga: The ligand compound DOTA-cRGD-FAPI-04 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.25 M); the germanium gallium generator was then eluted with dilute hydrochloric acid (4 mL, 0.05 mol / L) and added to the above mixture. After shaking, the new mixture was reacted at 90-100°C for 10-15 minutes. Then, it was diluted with sterile water for injection and purified by C18 column purification (ethanol / water (1 / 1, v / v), 2 mL) to obtain [ 68 Ga]-cRGD-FAPI-04.

[0319] Example 12 177 Preparation of [Lu]-cRGD-FAPI-05

[0320] 177 Lu: The ligand compound DOTA-cRGD-FAPI-03 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.4 M), and 185 MBq of the purchased 177 LuCl3 solution, and add gentisic acid (2.0 mg), the reaction mixture is reacted at 95 ° C for 30-60 minutes, cooled to room temperature, [ 177 Lu]-cRGD-FAPI-05 was diluted with saline and used directly.

[0321] Example 13 Preparation of cRGD-FAPI-05

[0322] Compound 102

[0323]

[0324] Compound 24 (15.58 g, 23.26 mmol) and compound 101 (5.52 g, 23.26 mmol) were dissolved in MeCN (150 mL) and stirred at room temperature overnight. After the reaction was completed by TLC detection, MeCN was removed under reduced pressure. H2O (10 mL) was added for dilution, and EtOAc (10 mL x 3) was extracted. The organic phase was combined, dried over Na2SO4, filtered, and purified by silica gel column chromatography [v(CH2Cl2) / v(MeOH)] = 30 / 1 to obtain compound 102 as a white foam, 9.28 g; LC-Ms (ESI+) m / z: 792.60 [M+H]+.

[0325] Compound 103

[0326]

[0327] Compound 38 (1.02 mmol, theoretical amount) was dissolved in DMF (0.5 mL), and DIPEA was slowly added dropwise to adjust the solution pH to about 7-8 for standby. In addition, compound 102 (807.8 mg, 1.02 mmol) was dissolved in DMF (5 mL) and cooled in an ice water bath. HATU (465.4 mg, 1.22 mmol) and DIPEA (395.5 mg, 3.06 mmol) were added and stirred for 30 min. The standby solution was then added, and the temperature of the reaction system was naturally transitioned to room temperature. After stirring overnight, the reaction was completed by TLC detection. H2O (50 mL) was added to the reaction system, and EtOAc (15 mL x 3) was extracted. The organic phase was combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 20 / 1 obtained the target compound 103, 626 mg; LC-Ms (ESI+) m / z: 1227.33 [M+H]+.

[0328] Compound 104

[0329]

[0330] Compound 103 (869 mg, 0.7080 mmol) was dissolved in MeOH (9 mL), and 10% Pd / C (150.7 mg, 1.416 mmol) was added to replace H2. After stirring at room temperature overnight, the Pd / C was removed by celite-assisted filtration, and the filtrate was concentrated to obtain the crude compound 104 as a colorless transparent gel; LC-Ms (ESI+) m / z: 569.3 [(M+2H)+ / 2], 1137.69 [M+H]+.

[0331] Compound 105

[0332]

[0333] Compound 104 (224.4 mg, 0.20 mmol) was dissolved in DMF (5 mL) and stirred in an ice water bath, HATU (90 mg, 0.24 mmol) and DIPEA (51 mg, 0.39 mmol) were added, after 30 min stirring, compound 18 (180 mg, 0.20 mmol) was added, the reaction temperature was naturally transferred to room temperature with the ice water melting. After TLC detection, the reaction was completed, H2O (50 mL) was added to the reaction system, CH2Cl2(15 mL x 3) was extracted, the organic phase was combined, washed with saturated sodium chloride aqueous solution, dried, concentrated under reduced pressure, and column chromatography on silica gel [v(CH2Cl2) / v(MeOH) = 50 / 1-20 / 1] was used to separate the target compound 105, which was a light yellow oil, 160 mg; LC-Ms (ESI+) m / z: 1016.70 [(M+2H)+ / 2], 678.22 [(M+3H)+ / 3].

[0334] Compound 106

[0335]

[0336] Compound 105 was dissolved in CH2Cl2(1 mL), CF3COOH (1 mL) was added, and stirring was performed at room temperature for 1 h. The reaction solution was detected by LC-Ms, and compound 105 was consumed completely. After concentration under reduced pressure, a crude intermediate was obtained. The intermediate was dissolved in H2O, stirred for 1 h, and then phenylboronic acid (14.2 mg, 0.12 mmol) and a solution of MeCN / TBME = 1 / 6 = 3.5 mL were added. After stirring for 3 h, the solution was allowed to stand and the organic phase and the aqueous phase were separated. The aqueous phase was taken and dried in a vacuum drying box. Finally, 130 mg of a crude product was obtained. After separation by a reversed-phase preparative column, 3.1 mg of white solid 106 (i.e., cRGD-FAPI-05) was obtained. LC-Ms (ESI + )m / z: 1421.05 [M+H] + .

[0337] Preparation of cRGD-FAPI-06

[0338] Compound 107

[0339]

[0340] Compound 102 (656.6 mg, 0.83 mmol) was dissolved in DMF (7 mL) and stirred in an ice water bath, HATU (378.3 mg, 0.99 mmol) and DIPEA (214.3 mg, 1.66 mmol) were added, and the stirring was continued for 30 min. Compound 18 (756 mg, 0.83 mmol) was added, and the temperature was naturally transferred to room temperature as the ice water melted. After the reaction was completed by TLC detection, H2O (50 mL) was added to the reaction system, and EtOAc (20 mL x 3) was used for extraction. The combined organic phase was washed with saturated NaCl aqueous solution, dried, concentrated under reduced pressure, and purified by silica gel column chromatography [v(CH2Cl2) / v(MeOH) = 30 / 1] to obtain the target compound 107, a yellowish oil, 775 mg; LC-Ms (ESI + )m / z: 562.64 [(M+3H) + / 3].

[0341] Compound 108

[0342]

[0343] Compound 107 (192 mg, 0.11 mmol) was dissolved in MeOH (5 mL), 10% Pd / C (24.2 mg, 0.23 mmol) was added, and H2 was replaced. After stirring at room temperature overnight, the Pd / C was removed by celite-assisted filtration, and the filtrate was concentrated to obtain the crude compound 108, a colorless transparent gel; LC-Ms (ESI + )m / z: 1595.36 [M+H] + .

[0344] Compound 109

[0345]

[0346] Compound 38 (0.59 mmol, theoretical amount) was dissolved in DMF (6 mL), and DIPEA was slowly added dropwise to adjust the pH of the solution to about 7-8, and it was ready for use. In addition, compound 108 (941.6 mg, 0.59 mmol) was dissolved in DMF (5 mL) and cooled in an ice water bath, and HATU (269.2 mg, 0.71 mmol) and DIPEA (152.5 mg, 1.18 mmol) were added, and after stirring for 30 min, the above-mentioned ready-to-use solution was added, and the temperature of the reaction system was naturally transitioned to room temperature, and it was stirred overnight. After TLC detection showed that the reaction was complete, H2O (50 mL) was added to the reaction system, and EtOAc (15 mL x 3) was extracted, the organic phase was combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 20 / 1 gave the target compound 109, 359.5 mg; LC-Ms (ESI + )m / z: 1017.1 [(M+2H) + / 2].

[0347] cRGD-FAPI-06: Compound 110

[0348]

[0349] Compound 109 was dissolved in CH2Cl2(1.5 mL), and CF3COOH (1.5 mL) was added, and it was stirred at room temperature for 1 h. The reaction solution was detected by LC-Ms, and compound 109 was completely consumed. After being concentrated under reduced pressure, a crude intermediate was obtained. The intermediate was dissolved in H2O, and after being stirred for 1 h, phenylboronic acid (15.6 mg, 0.13 mmol) and 4.0 mL of a solution of MeCN / TBME (V / V) = 1 / 6 were added, and the stirring was continued for 3 h. After the solution was allowed to stand and the organic phase and aqueous phase were separated, the aqueous phase was taken and dried in a vacuum drying oven. Finally, 110 mg of a crude product was obtained. Compound 110 was separated by a reversed-phase preparative column to obtain a white solid, 2.2 mg. LC-Ms (ESI + )m / z: 1421.06 [M+H] + .

[0350] Effect experiment 1: in vitro competitive binding test (IC 50 )

[0351] The cells are labeled with a radionuclide-labeled ligand (e.g. 68 Ga]-cRGD-FAPI-01) and a gradient dilution of 7 concentrations (10 -5 -10 -11IC 50 Values were calculated by non-linear fitting and SPSS algorithm.

[0352] IC 50 ) showed that the use of the compounds of the present application as radioligands in αvβ3-positive U87MG cells and FAP-positive A549-FAP cells was dose-dependent, the test results being shown in Table 1, where +: > 500 nM; ++: 100-500 nM; +++: 50-100 nM; ++++: < 50 nM.

[0353] Table 1

[0354]

[0355]

[0356] Note: " / " means not detected.

[0357] The test results show that the compounds of the present application have significant affinity for both αvβ3 and FAP targets. 177 The affinity of the compounds of the present application for FAP after labeling with Lu is superior to the affinity of PNT6555 and FAP-2286 for FAP.

[0358] PNT6555 structure reference: J Nucl Med 2024; 00: 1-9

[0359] FAP2286 structure reference: Eur J Nucl Med Mol Imaging 49, 3651-3667 (2022)

[0360] cRGDfK (DOTA-RGD) structure reference: Diagnostics 2021, 11(7), 1295

[0361] Effect experiment 2: in vitro stability test

[0362] The radiolabeled test compound was incubated in physiological saline and mouse serum at room temperature for 0.5 h, 1 h and 2 h, acetonitrile was added to precipitate the plasma proteins, after centrifugation, the supernatant was determined for radiochemical purity in radio-HPLC, and the nuclide complex slowly degraded.

[0363] Results: As shown in Table 2, Example 2 Figures 1-3 ​68 Ga]-cRGD-FAPI-01, Example 8 68 Ga]-cRGD-FAPI-03, and Example 11 68 Ga]-cRGD-FAPI-04 has good stability in PBS, human serum and rat serum.

[0364] Effect experiment 3: Small animal Micro-PET-CT imaging

[0365] The nude mice (n=3-4) carrying A549-FAP tumors were anesthetized and placed in a prone position in a Micro-PET imaging scanner, and injected with 68 Ga-labeled ligand (7.4-1.1 MBq) after 2h dynamic PET / CT images were collected. 10 min of scanning was performed every hour after injection. For data analysis, nude mouse images were reconstructed using Inevon Research Workplace 4.1 software, and the target region (ROI) was manually drawn on the tumor and major organs.

[0366] The nude mice (n=3-4) carrying U87MG tumors were anesthetized and placed in a prone position in a Micro-PET imaging scanner, and injected with 68 Ga-labeled ligand (7.4-1.1 MBq) after 2h dynamic PET / CT images were collected. 10 min of scanning was performed every hour after injection. For data analysis, nude mouse images were reconstructed using Inevon Research Workplace 4.1 software, and the target region (ROI) was manually drawn on the tumor and major organs.

[0367] Small animal Micro-PET-CT imaging:

[0368] As shown in Figure 4 Example 2 68 Ga]-cRGD-FAPI-01 has obvious radioactive concentration in the tumor site of U87MG tumor-bearing mice. PET-CT results show that after the compound is injected into the tail vein of tumor-bearing mice, it is rapidly distributed to the tumor and various organs, and is rapidly excreted from the body through the kidneys. Within 120 min, the radioactive concentration slowly increases, showing a higher uptake on the tumor. Within 30 min, the %ID / g has reached more than 10, and slowly increases.

[0369] As shown in Figure 5As shown in Example 5, the PET-CT results in the high αvβ6-expressing CAPAN-2 tumor model showed that the compound was rapidly distributed to the tumor and various organs after intravenous injection via the tail vein of tumor-bearing mice, and was rapidly excreted from the body through the kidneys; there was obvious radioactive concentration at the tumor site, and the %ID / g reached more than 2 within 60 min, and increased slowly.

[0370] As shown in Example 8, Figure 6 As shown in Example 11, 68 Ga]-cRGD-FAPI-03 had obvious radioactive concentration at the tumor site in U87MG tumor-bearing mice. The PET-CT results showed that the compound was rapidly distributed to the tumor and various organs after intravenous injection via the tail vein of tumor-bearing mice, and was rapidly excreted from the body through the kidneys. The radioactive concentration increased slowly within 120 min, showing higher uptake in the tumor and lower uptake in other organs. The %ID / g had reached more than 12 within 30 min, and increased slowly.

[0371] As shown in Example 8, Figure 7 As shown in Example 11, 68 Ga]-cRGD-FAPI-03 had obvious radioactive concentration at the tumor site in U87MG tumor-bearing mice. The PET-CT results showed that the compound was rapidly distributed to the tumor and various organs after intravenous injection via the tail vein of tumor-bearing mice, and was rapidly excreted from the body through the kidneys. The radioactive concentration increased slowly within 120 min, showing higher uptake in the tumor and lower uptake in other organs. The %ID / g had reached more than 12 within 30 min, and increased slowly.

[0372] The PET-CT results showed that Example 8 68 Ga]-cRGD-FAPI-03 and 68 Ga]PNT6555, 68 Ga]FAP-2286,

[0373] [ 68 Ga]cRGDfK and 68 Ga]FAP-04 could be more rapidly distributed to the tumor of the animal. At 60 min, the absorption value (%ID / g) of Example 8 in the tumor reached more than 16, which was 2.5 times that of 68 Ga]FAP-2286, 5 times that of 68 Ga]FAP-04, and 5.7 times that of 68 Ga]PNT6555. The specific results are shown in Table 2:

[0374] Table 2. Distribution of 68 Ga]-labeled compounds in mouse tumors

[0375] Compound No. Tumor distribution (60 min, %ID / g) Kidney distribution (60 min, %ID / g) <![CDATA[[ 68 Ga]-cRGD-FAPI-03]]> 16.6 1.6 <![CDATA[[ 68 Ga]cRGDfK]]> 0.9 1.2 <![CDATA[[ 68 For]PNT6555]]> 2.9 0.9 <![CDATA[[ 68 Ga]FAP-2286]]> 6.5 3.4 <![CDATA[[ 68 Ga]FAP-04]]> 3.2 5.0

[0376] As Figure 8 shown in Example 11[ 68 Ga]-cRGD-FAPI-04 showed significant radioactivity accumulation in the tumor site of A549-FAP tumor-bearing mice. The PET-CT results showed that after the compound was injected into the tail vein of tumor-bearing mice, it was rapidly distributed to the tumor and various organs, and was rapidly excreted out of the body through the kidneys. Within 120 min, the radioactivity accumulation slowly increased, showing higher uptake in the tumor and lower uptake in other organs. Within 60 min, the %ID / g reached more than 5, which was significantly better than the single FAP-targeting[ 68 Ga]PNT6555 and the single αvβ3-targeting[ 68 Ga]cRGDfK(DOTA-RGD).

[0377] Effect experiment 4: in vivo biodistribution

[0378] 50-150 uCi of radioactively labeled test compound was injected into the tail vein of A549-FAP or U87MG tumor-bearing mice, and 1 h after injection, the animals were sacrificed, the test organs were stained and weighed, the radioactivity was measured using a γ-counter, and the percentage of uptake per gram of tissue (%ID / g) was calculated; the calculation formula is: %ID / g = (radioactivity concentration of the region of interest (μCi / g)) / (total radioactivity administered (μCi)) x 100%

[0379] Tissue distribution of U87MG tumor-bearing mice: when the tumor grew to a certain size, 177 The Lu-labeled compound was injected into the tail vein of the mice (about 0.05 mCi per mouse), and 1 h, 4 h, 24 h, 72 h and 168 h after administration, the animals were euthanized using carbon dioxide inhalation, and the tumor, blood and viscera (liver, kidney, muscle, etc.) of the animals were collected. All samples were measured for radioactivity count using a gamma counter.

[0380] 177 Biodistribution of Lu-labeled compound in tumor-bearing mice

[0381] Tissue distribution of U87MG tumor-bearing mice: when the tumor grew to a certain size, 177 Example 9[ 177 Lu]-cRGD-FAPI-03 and Example 10[ 177Lu]PNT6555 was injected into the tail vein of mice (about 0.05 mCi per mouse), and the animals were euthanized by carbon dioxide inhalation at 1 h, 4 h, 24 h, 72 h and 168 h after administration. The tumor, blood and organs (liver, kidney, muscle, etc.) of the animals were collected. The radioactivity of all samples was measured by a gamma counter. The tumor and organ radioactivity-time curve showed that, as shown in Figure 9 Example 9 was obviously concentrated at the tumor site, and the radioactivity value (% I.A. / g) reached about 30 at 1 h, slowly decreased at 4 h, and was still about 5 at 72 h. Example 9 had lower uptake and rapid excretion in other organs. 177 The radioactivity value of Lu]PNT6555 at the tumor site was lower than that of Example 9, especially in the bone, intestine and blood.

[0382] The radioactivity ratio of each molecule in the tumor and the main organs: as shown in Table 3 and Figure 10 According to the tissue distribution data of Lu-labeled molecules in U87MG tumor-bearing mice, 177 The radioactivity ratio of each molecule in the tumor and the main organs: as shown in Table 3 and

[0383] Table 3

[0384]

[0385] 177 Therapeutic effect of Lu-labeled compounds on tumor-bearing mice

[0386] 6-8 week old nude mice were inoculated subcutaneously with 1 x 10 7 U87MG cells on the right side of the back, and when the tumor reached the desired size, the animals were randomly assigned to each experimental group according to the tumor size, with 6 animals in each group. The inclusion criteria: average tumor volume 150-200 mm 3 , CV < 30%. Radioactive labeled compounds were injected intravenously, about 0.5-1 mCi per mouse. Health and appearance observations were made every day after the start of the experiment, and animal body weight and tumor size were measured before the sampling time point.

[0387] The experimental results showed that Example 9[ 177 Lu]-cRGD-FAPI-03 had a significant inhibitory effect on tumor growth after being injected into tumor-bearing mice through the tail vein; Example 9[ 177 Lu]-cRGD-FAPI-03 and 177Lu]PNT6555 has more excellent effect of inhibiting tumor growth at the same dose, as shown in Figure 11

[0388] The compound developed by the application can double-target fibroblast activation protein and integrin family subtypes, has high affinity to FAP target and integrin αvβ3 or αvβ6, can simultaneously coordinate two types of targets, shows excellent metabolic kinetics, high tumor uptake and long tumor residence time, and is expected to be applied to diagnose or treat diseases characterized by overexpression of fibroblast activation protein and integrin family subotypes (for example, integrin αvβ3 or αvβ6).

[0389] Effect experiment 5: in vivo stability test

[0390] The radionuclide complex (Example 12, i.e. 177 The radionuclide complex (Example 12, i.e.

[0391] The experimental results are shown in Figure 12 It can be seen that Example 12 has good stability in mice for 1 h. It is proved that Example 12 has strong structural stability, enzymatic stability, etc.

[0392] Effect experiment 6: cell efflux experiment

[0393] FAP-high-expressing A549-FAP cells or U87MG cells capable of expressing FAP and αvβ3 were inoculated in 6-well plates or 24-well plates, and fresh culture medium without fetal bovine serum was used for culture. 0.5 uCi of radioactively labeled test compound (Examples 2, 8 and 11, respectively) was added to each well, and incubation was carried out at 37°C for 1 h. After incubation, the culture medium was removed and the cells were washed twice with ice PBS buffer. NaOH-SDS solution was added to lyse the cells and collect them. The radioactivity was determined by using a γ-counter.

[0394] The experimental results are shown in Figure 13 It can be seen that Examples 2 and 8 slowly efflux within 120 min, and Example 11 effluxes faster. It is proved that the compound of the application has a long residence time in vivo.

[0395] Effect experiment 7: in vitro cell internalization experiment

[0396] ​A549-FAP cells expressing high levels of FAP or U87MG cells expressing both FAP and αvβ3 were seeded into 6-well or 24-well plates and cultured in fresh culture medium without fetal bovine serum. 0.5 uCi of radiolabeled test compound (PNT6555, DOTA-RGD, Example 2, Example 8, and Example 11, respectively) was added to each well and incubated at 37°C for 1 hour. After incubation, the culture medium was removed and the cells were washed twice with ice-cold PBS buffer. A glycine hydrochloride solution (1 M, 1 mL, pH = 2.2) was added to the mixture and incubated at 37°C for 10 minutes. After incubation, the culture medium was removed and the cells were washed twice with ice-cold PBS buffer. The cells were lysed with a NaOH-SDS solution and collected. The radioactivity of the glycine hydrochloride solution and the lysed cell fluid was measured using a γ-counter.

[0397] The experimental results are as follows Figure 14 As shown, using U87MG cells for experiments, the total uptake (Uptake) and internalization (Internalization) of Examples 2, 8 and 11 were significantly higher than those of PNT6555 targeting FAP alone and [ 68 Ga]DOTA-cRGDfK (blue column, DOTA-RGD). This indicates that the dual-targeting compound provided by the present invention can simultaneously target FAP and αvβ3, significantly improving tumor cell uptake and internalization.

[0398] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound or its pharmaceutically acceptable salt, tautomer, racemate, hydrate, solvate or isotopically-labeled form thereof, characterized in that: (i) a chelating ligand moiety (CL); (ii) a first targeting moiety (BT); (iii) a second targeting moiety (CY); wherein (i), (ii), (iii) are fixed, bound or linked by any L; preferably, the first targeting moiety is a fibroblast activation protein (FAP)-specific binding ligand structure; the second targeting moiety is an integrin subunit-specific binding ligand structure, further preferably an integrin ανβ3 or ανβ6-specific binding ligand structure; each Z is independently selected from O or S; each n is independently selected from 0, or 1; The L is selected from one or more of L a , L b , L c ; the L a , L b , L c are each independently selected from one or more of a combination of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 ; L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are each independently a bond, a monovalent linker, a divalent linker, or a trivalent linker.

2. The compound of claim 1, wherein L 1 、L 2 、L 3 、L 4 、L 5 、L 6 、L 7 each independently is a bond, -Z(R 3 ), -Z-, -N(R 1 ) n -, 1 -, 2 -, p -, q -, m -, 1 -, 1 -, 1 -, 1 -, 2 -, p -, q -, x -, 2 -, p -, q -, 2 -, p -, q -, 2 -, p -, q -, x -, 1 alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; one or more L 2 , L 3 , L 4 , L 5 , L 6 , L 7 may be combined with each other to form L a , L b , or L c before any connection to (i), (ii), and (iii); each p is independently selected from 0, 1 or 2; each m is independently selected from 0 or 1; q and x are each independently selected from an integer from 0 to 30, for example from 0 to 20 or 0 to 10 or 0, 1, 2, 3, 4, 5, 6, 7 or 8; the alkoxy, alkylthio, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene are further optionally each independently mono- or poly-substituted with the same or different substituents; the substituents are hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, alkyl-COOH, alkyl-SO3H, -B(OH)2, hydroxyl, -SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl. the first targeting moiety (BT) is selected from a blood cell, a peptide, a polyethylene glycol, a small molecule, a prodrug, a nucleic acid, an aptamer, an oligosaccharide, and an antibody or antigen-binding fragment thereof thereof; further preferably, the first targeting moiety (BT) is selected from one or more of a prostate-specific membrane antigen (PSMA)-targeting agent, a fibroblast activation protein (FAP) inhibitor, an arginine-glycine-aspartate fibronectin or integrin-targeting peptide, a somatostatin-targeting peptide, a pentixafor chemokine receptor-targeting agent and heparin. each R is independently H, cycloalkyl, or alkyl; 1 and R is independently H, cycloalkyl, or alkyl; 3 each R is independently H, cycloalkyl, or alkyl; Each R 2 is independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, alkyl-COOH, -SO3H, alkyl-SO3H, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkyl; y is selected from an integer from 0 to 8 (for example, 0, 1, 2, 3, 4, 5, 6, 7 or 8); 3. The compound of claim 2, wherein L 1 、L 2 、L 3 、L 4 、L 5 、L 6 、L 7 each independently is a bond, -Z(R 3 ), -Z-, -N(R 1 ) n - , -N(R 1 )4, -C(=Z)-, -((C(R 2 ) p ) q -, -S(=O) m -, -NR 1 -C(=O)-, -NR 1 -C(=O)-NR 1 -, -C(=O)-NR 1 -, -((C(R 2 ) p ) q -Z) x -(C(R 2 ) p ) q -, -(C(R 2 ) p ) q -(Z-(C(R 2 ) p ) q ) x -, C 1-6 heteroalkylene, C 1-12 alkylene, C 3-12 cycloalkylene, C 4-12 heterocycloalkylene, C 6-12 arylene, or C 5-12 heteroarylene, optionally, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently can be further mono- or poly-substituted with the same or different substituents; L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently is a bond, -Z(R 3 ), -Z-, -N(R 1 ) n - , -N(R 1 )4, -C(=Z)-, -((C(R 2 ) p ) q -, -S(=O) m -, -NR 1 -C(=O)-, -NR 1 -C(=O)-NR 1 -, -C(=O)-NR 1 -, -((C(R 2 ) p ) q -Z) x -(C(R 2 ) p ) q -, -(C(R 2 ) p ) q -(Z-(C(R 2 ) p ) q ) x -, C 1-6 heteroalkylene, C 1-12 alkylene, C 3-12 cycloalkylene, C 4-12 heterocycloalkylene, phenylene, pyridinylene, or C 5-12 heteroarylene, optionally, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently can be further mono- or poly-substituted with the same or different substituents; Further preferably, each R 1 and R 3 is independently H, C 3-12 cycloalkyl, or C 1-6 alkyl; each R 2 is independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, C 1-6 alkyl-COOH, -SO3H, C 1-6 alkyl-SO3H, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, or C 1-6 alkyl; Further preferably, said L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently is selected from a bond, -O-, -S-, -NH-, -C(=O)-, -NH-C(=O)-, -NR 1 -C(=O)-NR 1 -, -C(=O)-NH-, -(CH2) q -, -(CHR 2 ) q -, -((CH2) q -O) x -, -((CH2) q -O) x -(CH2) q -, -(CH2) q -(O-(CH2) q ) x -, (eg ), (eg cyclohexylidene, cyclopentylidene), (eg phenylene); wherein each A is independently selected from CR 2 or N; each B is independently selected from -C(R 2 )2-, O, -S(=O) m -, -N(R 1 ) n - , or -C(=Z)-; Furthermore, the L a 、L b 、L c Each independently selected from -(CH2) q -((CH2) q -O) x -NH-C(=O)-(CH2) q -、-(CH2) q -((CH2) q -O) x -NH-C(=O)-(CH2) q -((CH2) q -O) x -、-NH-C(=O)-(CH2) q -((CH2) q -O) x -、-NR 1 -C(=O)-NR 1 -、-C(=O)-((CH2) q -O) x -(CH2) q -NH-C(=O)-(CH2) q -、-C(=O)-((CH2) q -O) x -(CH2) q -、-C(=O)-NH-、-(CHR 2 ) q -C(=O)-NH-, -C(=O)-NH-(CH2) q -、-(CH2) q -、-((CH2) q -O) x -、-((CH2) q -O) x -(CH2) q -、-(CH2) q -(O-(CH2) q ) x -、 Wherein, the values ​​of q, x, A or B in the same structural formula may be the same or different and do not affect each other; preferably, the L a 、L b 、L c Each independently selected from phenylenemethyl, methylenepyridinyl (e.g. 2-methylene-4-pyridinyl), methylene-cyclohexyl-, 4. The compound according to any one of claims 1 to 3, wherein The chelating ligand moiety (CL) is selected from AAZTA, BAT, CDTA, DTA, DTPA, CY-DTA, DTCBP, CTA, cyclam, cyclen, TETA, Sarcophagine, CPTA, TEAMA, Cyclen, DO3A, DO2A, TRITA, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H4octapa, H2dedpa, H5decapa, H2azapa, H2CHXD EDPA, DFO-Chx-MAL, DFO-p-SCN, DFO-1AC, DFO-BAC, p-SCN-Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, diphosphine, DOTA, DOTAGA, DOTA-MFCO, DOTAM-monoacid, nitro-DOTA, nitro-PA-DOTA, p-NCS-Bz-DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-DOTA, DOTMA, NB-DOTA, H4NB-DOTA, H4TCE-DOTA, 3,4,3-(Li-1,2-HOPO), TREN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOXP, p-NCS-DOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-monoamide-DOTA, BCN-DOTA, acetylene-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2A (trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)acetamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA, maleimidyl-mono-amide-DOTA, maleimide-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone-benzothiazole, thiosemicarbazone-styrylpyridine tetradentate ligand H2L2-4, HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, Deferiprone, THP, HYNIC (2-hydrazinonicotinamide), NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIM A, IAM B, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, Macropa, Macropaquin, Macroquin-SO3, N, x S 4-x , N2S2, N3S, N4, MAG3B, NOTA, NODAGA, SCN-Bz-NOTA-R, NOT-P(NOTMP), NOTAM, p-NCS-NOTA, TACN, TACN-TM, NETA, NETA-monoamine, p-SCN-PhPr-NE3TA, C-NE3TA-NCS, C-NETA-NCS, 3p-C-NETA, NODASA, NOPO, NODA, NO2A, N-Benzyl-NODA, C-NOTA, BCNOT-monoamine, maleimido-mono-amide-NOTA, NO2A-azide, NO2A-yne, NO2AP, NO3AP, N-NOTA, oxo-DO3A, p-NH2-Bn-NOTA, p-NH2-Bn-oxo-DO3A, p-NO2-Bn-Cyclen, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, TRAP, PEPA, BF-PEPA, Pycup, Pycup2A, pycup1A1Bn, pycup2Bn, SarAr-R, Diamsar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me), TAM A, TAM B, TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, TE2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ-HTCPP, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 1,4,7-triazacyclononane-N-glutaric acid-N',N"-diacetic acid (NODAGA), 1,4,7-triazacyclononane-1,4-diacetic acid-methylphenylacetic acid (NODA-MPAA), bis(2-hydroxybenzyl)ethylenediamine diacetic acid (HBED), 4,11-bis-(carboxymethylmethyl)-1,4,8,11-tetraazabicyclo[6.6.2) one or more of hexadecane (CB-TE2A), DFO, hexaazatriphenylhexaamine (HATMA), hexakis(3-hydroxy-4-pyridinone) (THP), dodecanetetraacetic acid, nitro-DOTA, 4-aminobenzyl-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (PA-DOTA), diethylenetriaminepentaacetic acid (DTPA), (2-[4,7-bis(carboxymethyl)-1,4,7-triazolane-1-yl] moiety of acetic acid)-NOTA, (triethylenetetramine)-TETA, desferrioxamine, (ethylenediaminetetraacetic acid)-EDTA, and penicillamine; and / or. the second targeting moiety (CY) is selected from one or more of a photodynamic therapy agent, an integrin subunit inhibitor, a peptide compound (a polypeptide compound, for example a cyclic peptide compound), a radioimaging agent, a radiotherapy agent, a chemotherapy agent, an anti-fibrotic agent or an anti-cancer agent (for example, an anti-cancer agent effective against cancer cells or cancer-associated fibroblasts, myofibroblasts or other tumor microenvironment factors); 5. The compound according to any one of claims 1 to 4, wherein The first targeting moiety (BT) is R 4 is hydrogen, deuterium, alkyl or cycloalkyl; R 5 and R 6 are each independently hydrogen, deuterium, alkyl, cycloalkyl, hydroxyl, cyano, -F, -Cl, -Br, -I, -NH2, nitro, -COOH or -B(-Y 1 )(-Y 2 ); Y 1 and Y 2 are independently -OH, or together with the boron atom to which they are attached represent a group hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring hydrolysable to a boronic acid; further preferably, the second targeting moiety (CY) is: Further preferably, R is hydrogen, C 4 alkyl or C 1-12 alkyl or C 3-12 cycloalkyl; Further preferably, R 5 and R 6 are each independently hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, hydroxy, cyano, -F, -Cl, -Br, -I, -NH2, nitro, -COOH or -B(-Y 1 )(-Y 2 ); Y 1 and Y 2 are independently -OH, or together with the boron atom to which they are attached represent a group hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring hydrolysable to a boronic acid; Further preferably, said first targeting moiety (BT) is Preferably is 6. The compound according to any one of claims 1 to 5, wherein further preferably, the second targeting moiety (CY) is selected from one or more of the following structural formulae: the compound structure is Among them, R 7 and R 8 are each independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; said R, R 7 and R 8 Each independently further optionally substituted by the same or different substituents R 9 Single or multiple substitutions; the R 9 is hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio or alkyl; further preferably, R, R 7 and R 8 Each independently selected from C 1-12 Alkyl, C 1-12 Heteroalkyl, C 3-12 Cycloalkyl, C 5-12 Heterocycloalkyl, C 6-12 Aryl and C 5-12 heteroaryl; said R, R 7 and R 8 Each independently further optionally replaced by the same or different R 9 monosubstituted or polysubstituted; the compound is selected from one of the following structures:

7. The compound of claim 1, wherein 10. A pharmaceutical composition comprising a compound of any one of claims 1-9 and a pharmaceutically acceptable excipient. Among them, CL, BT, CY, L a , L b , L c 、R 1 and R 2 It has the meaning as defined in any one of claims 1 to 6.

8. The compound of claim 2, wherein ​ 9. The compound of claim 1, wherein The compound further comprises a diagnostic active nuclide or a therapeutically active nuclide, wherein preferably the diagnostic active nuclide is a diagnostic active radionuclide, more preferably selected from the group consisting of 18 F, 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P, 44 Sc, 47 Sc, 165 Dy, 169 Er, 177 Lu, 142 Pr, 159 Gd, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 203 Pb, 212 Pb, 175 Yb, 139 La, 140 La, 166 Ho, 51 Cr, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 55 Co, 64 Cu, 67 Ga, 68 Ga, 152 Tb, 155 Tb, 161 Tb, 86 Y, 90 Y, 89 Sr, 89 Zr, 94m Tc, 99m Tc, 111 In, 114m In, 117m Sn, 153 Sm, 149 Pm, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 32 P, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 186 Re, 188 Re, 225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th, and wherein the therapeutically active nuclide is a therapeutically active radionuclide, more preferably selected from 18 F, 225 Ab, 225 Ac, 198 Au, 199 Ag, 32 P, 44 Sc, 47 Sc, 165 Dy, 169 Er, 177 Lu, 142 Pr, 159 Gd, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 203 Pb, 212 Pb, 175 Yb, 139 La, 140 La, 166 Ho, 51 Cr, 43 Sc, 44 Sc, 51 Mn, 52 Mn, 55 Co, 64 Cu, 67 Ga, 68 Ga, 152 Tb, 155 Tb, 161 Tb, 86 Y, 90 Y, 89 Sr, 89 Zr, 94m Tc, 99m Tc, 111 In, 114m In, 117m Sn, 153 Sm, 149 Pm, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 32 P, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 186 Re, 188 Re, 225 Ab, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 212 Bi, 213 Bi, 223 Ra, 224 Ra or 227 Th. ​ 11. Use of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 10 for the manufacture of a medicament for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein and an integrin family subunit (e.g., integrin αvβ3 or αvβ6) in an animal or human subject.

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