Compound for double targeting of fibroblast activation protein and integrin subtype, preparation therefor, and use thereof

Abstract

Provided is a compound for double targeting of a fibroblast activation protein and an integrin subtype, comprising: (i) a chelating ligand moiety (CL); (ii) a first targeting moiety (BT); and (iii) a second targeting moiety (CY), wherein (i), (ii), and (iii) are fixed, combined, or connected by means of any L; BT is a fibroblast activation protein (FAP)-specific binding ligand structure; CY is an integrin subunit αvβ3 or αvβ6-specific binding ligand structure; L is selected from one or a combination of L1, L2, L3, L4, L5, L6, and L7; L1, L2, L3, L4, L5, L6, and L7 are each independently a key, a monovalent joint, a divalent joint, or a trivalent joint. Also provided are a preparation method for the compound and use thereof.

Description

Compounds targeting both fibroblast activation protein and integrin subtypes and preparation and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of nuclear medicine and molecular imaging technology, and specifically provides a compound targeting both 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 functional integrin molecules by combining with each other. As a member of the integrin family, integrin αvβ6 is found to be highly expressed in many different types of tumors, while 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 to the onset 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, C

[0021] each independently of one another 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] each independently of one another hydrogen, -F, -CI, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 each independently 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 cyclohexylidene, cyclopentylidene), (for example phenylene) ; wherein each A is independently selected from CR 2 or N; and each B is selected from -C(R 2 )2-, O, -S(=O) m -, -N(R 1 ) n - , or -C(=Z)-. In the present invention, the values of q, A or B in the same structural formula can be the same or different, and are independent of each other.

[0027] Further, each of L a , L b , L c is 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 -, q -, q -, 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 do not affect each other.

[0028] For example, the L a , L b , L c are each independently selected from the group consisting of phenylmethylene, 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, bis-aminothiol (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), tetra-pyridine and N3S, N2S2and N4chelators are disclosed in US 5,367,080 A, US 5,364,613 A, US 5,021,556 A, US 5,075,099 A, US 5,886,142 A, 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,N00tris(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),11,13-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 complexing111 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 chelating trivalent isotopic metals are described by Eisenwiener et al. (Eisenwiener, et al., Bioconjug Chem, 2002, 13: 530); N4-chelators such as 99m Tc-N4-chelators have been used for peptide labeling in the case of minigastrin targeting CCK-2 receptors (Nock, et al., J Nucl Med, 2005, 46: 1727).

[0032] Further, the chelating ligand moiety (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-chelators 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] 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.

[0036] Further, the chelating ligand moiety (CL) is selected from the group consisting of DOTA, DOTAGA, NOTA, N4Ac, and NODAGA, and analogs thereof.

[0037] 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.

[0038] Further, the first targeting moiety (BT) is R4 R 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;

[0039] y is selected from an integer from 0 to 8, for example from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0040] Further, the R 4 is hydrogen, C 1-12 1-4 alkyl or C 3-12 3-8 cycloalkyl. Further, the R 4 is hydrogen, C 1-4 1-4 alkyl or C 3-6 3-8 cycloalkyl. Further, the R 4 is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl or the like.

[0041] Further, the R 5 and R 6 are each independently hydrogen, C 1-12 1-4 alkyl, C 3-12 3-8 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.

[0042] Further, the first targeting moiety (BT) is Preferably

[0043] 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).

[0044] Further, the second targeting moiety (CY) is:

[0045] 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.

[0046] 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.

[0047] Further, the second targeting moiety (CY) is selected from one or more of the following structural formulae:

[0048] Further, the compound structure is

[0049] wherein CL, BT, CY, L a , L b , L c , R 1 and R 2 have the meaning as described herein.

[0050] Further, the compound structure is

[0051] wherein CL, CY, each L have the meaning as described herein.

[0052] Further, the compound according to the present application is selected from one of the following structures:

[0053] Further, 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 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, 151Eu, 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, 224Raor 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, 32P. 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.

[0054] 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.

[0055] 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 Such as 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 227a cation of Th.

[0056] Further, the metal ion binds to a chelating ligand portion (CL) of the compound.

[0057] In another aspect, the present application provides a method of preparing the compound of the present application, the specific steps of which are as follows:

[0058] The compound of the present application is prepared by reacting the structural material of the second targeting moiety (CY) after reacting with the linker, with the structural material of the chelating ligand portion (CL), and further condensing with the structural material of the first targeting moiety (BT).

[0059] In another aspect, the present application provides a pharmaceutical composition comprising any of the compounds of the present application. For example, such a pharmaceutical composition can comprise any of the compounds of the present application and a pharmaceutically acceptable carrier and / or excipient.

[0060] In another aspect, the present application provides use of a compound or a pharmaceutical composition of the present application in the manufacture of a medicament for the diagnosis or treatment of a disease characterized by overexpression of fibroblast activation protein and an integrin family subtype (e.g., integrin ανβ3 or ανβ6) in an animal or human subject.

[0061] Further, 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 cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocellular carcinoma, clear cell kidney cancer, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymus cancer, glioma, glioblastoma, astrocytoma, cervical cancer, or prostate cancer.

[0062] Further, the use includes use in the manufacture of a tumor imaging agent or a radionuclide targeted therapy agent.

[0063] 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 subtype (e.g., integrin ανβ3 or ανβ6) in an animal or human subject, the method comprising administering to a patient in need thereof a compound or a pharmaceutical composition of the present application.

[0064] 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 subtype (e.g., integrin ανβ3 or ανβ6) in an animal or human subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present application.

[0065] 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, wherein the device is selected from a labeling device, a purification device, an administration device, a radiation protection device, an analysis device or an application device.

[0066] 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 described herein. Unless otherwise specified, an alkyl group contains 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 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 radical by removal of two hydrogen atoms. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0067] 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 radical by removal of two hydrogen atoms.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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 other analogs. In this document The position of the bond can be combined at any reasonable position on the ring, which can be represented as and other analogs. In this document

[0073] The elements involved in the structure of the present invention are elements including all their isotopes. Exemplary isotopes that can be included in the compounds of the present invention 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 .

[0074] The term "isotopically-labeled compound" refers to a compound of the present invention that is labeled with an isotope. It is the same as those compounds described in the present invention 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 the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0075] 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 present 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.

[0076] 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.

[0077] Compared with the prior art, the present application has the following advantages:

[0078] The present application provides a compound which can simultaneously specifically recognize FAP and one of αVβ3 or αVβ6, and further links with a radionuclide (for example, a diagnostic radionuclide, a therapeutic radionuclide) to form a probe, which is used for preventing, treating, alleviating, and / or diagnosing cancer in a subject in need thereof, has a high tumor uptake in the patient, has a good in vivo metabolic performance, has a good half-life, and has a very good clinical application prospect.

[0079] 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.

[0080] 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.

[0081] 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

[0082] Figure 1 is a diagram of Example 2[ 68 Figure 1 shows the results of in vitro stability testing of [Ga]-cRGD-FAPI-01.

[0083] FIG2 is an example 8[ 68 Figure 1 shows the results of in vitro stability testing of [Ga]-cRGD-FAPI-03.

[0084] FIG3 is an example of embodiment 11[ 68 Figure 1 shows the results of in vitro stability testing of [Ga]-cRGD-FAPI-04.

[0085] Figure 4 is a diagram of Example 2[ 68 Figure 1 shows the results of small animal Micro-PET-CT imaging experiments using [Ga]-cRGD-FAPI-01.

[0086] Figure 5 is an example of embodiment 5[ 68 Figure 1. Results of small animal Micro-PET-CT imaging experiments using [Ga]-cRGD-FAPI-02.

[0087] FIG6 is an example 8[ 68Figure 1 shows the results of small animal Micro-PET-CT imaging experiments using [Ga]-cRGD-FAPI-03.

[0088] FIG. 7 is a diagram of Example 11[ 68 Figure 3. Results of the Micro-PET-CT imaging experiment of [Ga]-cRGD-FAPI-04 in small animals (U87MG tumor-bearing mice).

[0089] FIG8 is an example of embodiment 11[ 68 Results of the Micro-PET-CT imaging experiment of [Ga]-cRGD-FAPI-04 in small animals (A549-FAP tumor-bearing mice).

[0090] FIG9 is a graph showing the changes in tumor and organ radioactivity over time.

[0091] Figure 10 177 Tissue distribution of Lu radiolabeled molecules in U87MG tumor-bearing mice.

[0092] Figure 11 177 Graph showing the therapeutic effects of Lu-labeled compounds on tumor-bearing mice.

[0093] FIG12 is a diagram showing the results of an in vivo stability test.

[0094] FIG13 is a graph showing the results of the cell efflux experiment.

[0095] FIG14 is a graph showing the results of an in vitro cell internalization experiment. DETAILED DESCRIPTION

[0096] The present invention will be further described below with reference to specific examples. These examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0097] A preparation process of the compound of the present invention is as follows:

[0098] where R 10 is a protecting group known to those skilled in the art, such as Boc; wherein CY, CL, BT, L a , L b All have the meanings described in the present invention; -C(=O)-X 1 -With L c consistent meaning;

[0099] 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);

[0100] 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);

[0101] 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.

[0102] Example 1 DOTA-cRGD-FAPI-01

[0103] Synthesis of compound 2

[0104] Pre-treatment of resin: 2-chlorotrityl resin (10 g, 0.4-3.0 mmol / g) was washed with CH2Cl2three times, each time for 30 min of shaking, and the resin was retained.

[0105] 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 under suction and removal of the solvent. Washing of the solid with DMF (50 mL x 3) to obtain compound 2.

[0106] Synthesis of compound 3

[0107] A 20% piperidine solution in N,N-dimethylformamide (50 mL) was added to compound 2 (the product from the previous step was used directly), and shaken for 1.5 h at room temperature. Filtration under suction and removal of the solvent. Washing of the solid with DMF (50 mL x 3) to obtain compound 3.

[0108] Synthesis of compound 5

[0109] 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, and the pH of the reaction system was about 7-8. 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] + ).

[0110] Synthesis of compound 6

[0111] 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 for 1.5 h at room temperature. 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] + ).

[0112] Synthesis of compound 8

[0113] 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, and the pH of the reaction system was about 7-8. 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] + ).

[0114] Synthesis of compound 9

[0115] 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] + ).

[0116] Synthesis of compound 11

[0117] DMF (50 mL) was added to compound 9 (the product from the previous step was used directly), followed by the addition of compound 10 (3.87 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 mixture was shaken on a shaker for 3 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 11, and the filtrate was sent for LC-MS. LC-Ms (ESI + )m / z: 1115.53 ([M+H] + ).

[0118] Synthesis of compound 12

[0119] 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] + ).

[0120] Synthesis of compound 14

[0121] DMF (50 mL) was added to compound 12 (the product from the previous step was used directly as the starting material), 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 subjected to LC-MS. LC-Ms (ESI + )m / z: 1286.71 ([M+H] + ).

[0122] Synthesis of compound 15

[0123] A 20% piperidine solution in N,N-dimethylformamide (50 mL) was added to compound 14 (the product from the previous step was used directly as the starting material), 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 subjected to LC-MS. LC-Ms (ESI + )m / z: 1064.65 ([M+H] + ).

[0124] Synthesis of compound 16

[0125] 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-arginylglycine (16)

[0126] The above resin solid compound 15 (the product from the previous step was used directly as the starting material) 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 crude compound 16, 11.2 g, which was used directly in the next step without purification.

[0127] Synthesis of compound 17

[0128] 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-pentazacyclopentadecan-2-yl)ethyl acetate (17)

[0129] 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 of the water phase and the organic phase was carried out after standing. 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] + )..

[0130] Synthesis of compound 18

[0131] 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-pentazacyclopentadecan-2-yl)ethyl acetate (18)

[0132] Compound 17 (2.87 g, 2.74 mmol) was dissolved in MeOH (100 mL), 10% Pd / C (292 mg, 0.27 mmol) was added, the reaction atmosphere was replaced with H2, and stirred at room temperature overnight. After the reaction was completed, the Pd / C was removed by celite filtration, and the filtrate was concentrated to obtain crude compound 18, milky white solid, 1.51 g; LC-Ms (ESI + )m / z: 912.83 ([M+H] + )..

[0133] Synthesis of compound 20

[0134] 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-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-1,4,7,10,13-pentazacyclopentadecan-2-yl)acetate (20)

[0135] Compound 19 (399.44 mg, 0.82 mmol) was dissolved in DMF (6 mL) and stirred in an ice water bath for cooling, HATU (404 mg, 1.06 mmol) and DIPEA (211.3 mg, 1.63 mmol) were added, and the stirring was continued for 30 min, then compound 18 (745.5 mg, 0.82 mmol) was added, and the reaction temperature was naturally transitioned to room temperature as the ice water melted. After TLC detection, the reaction was completed, H2O (70 mL) was added to the reaction system, and CH2Cl2(15 mL x 3) was extracted, and the organic phase was combined and washed with saturated aqueous sodium chloride solution. A large amount of sticky white flocculent precipitated, and the water phase and organic phase were separated, and the organic phase (CH2Cl2and white flocculent precipitate) was concentrated under reduced pressure. After the [v(CH2Cl2) / v(MeOH)] = 1 / 0 was slurried, the polar impurities were removed, and compound 20 was obtained as a yellow solid, 983.8 mg; without further purification, it was directly used in the next step reaction. LC-Ms (ESI + )m / z: 1293.97 ([M+H] + ).

[0136] Synthesis of compound 21

[0137] tert-Butyl 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-pentazacyclopentadecan-2-yl)acetate (21)

[0138] Compound 20 (590 mg, 0.45 mmol) was dissolved in CH2Cl2(20 mL), piperidine (4 mL) was added, and stirring was performed at room temperature. After TLC detection showed that the reaction was completed (about 4-5 h), the reaction was concentrated under reduced pressure to remove most of the solvent, and then oil pump was used to remove most of the piperidine. Purification by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 5 / 1 gave the target compound 21, white solid, 290 mg; LC-Ms (ESI + )m / z: 1071.79 ([M+H] + )..

[0139] Synthesis of compound 24: tris-tert-butyl 2,2',2"-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (24)

[0140] 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 stirring was performed at room temperature overnight. After TLC detection showed that the reaction was completed, dilution was performed by adding H2O (50 mL), extraction was performed by CH2Cl2(40 mL x 3), the combined organic phases were dried over Na2SO4, filtration was performed under suction, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by [v(EtOAc) / v(PE)] = 5 / 1 to give compound 24, white solid, 809 mg;

[0141] Synthesis of compound 26

[0142] (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)

[0143] Compound 24 (1.17 g, 1.75 mmol) and compound 25 (415.2 mg, 1.75 mmol) were dissolved in THF (20 mL), and stirring was performed at room temperature overnight. After TLC detection showed that the reaction was completed, THF was removed by concentration under reduced pressure. Dilution was performed by adding H2O (10 mL), extraction was performed by EtOAc (10 mL x 3), the combined organic phases were dried over Na2SO4, filtration was performed under suction, and purification was performed by silica gel column chromatography [v(CH2Cl2) / v(MeOH)] = 50 / 1 to give compound 26, white foam, 685 mg; LC-Ms (ESI + )m / z: 792.60 ([M+H] +).

[0144] 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-triazicosa-1,4,7- triyl)triacetate (27)

[0145] Compound 26 (214.4 mg, 0.27 mmol) was dissolved in DMF (5 mL) and stirred in an ice water bath, HATU (133.8 mg, 0.35 mmol) and DIPEA (70 mg, 0.54 mmol) were added, after stirring 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 showed that the reaction was complete, H2O (50 mL) was added to the reaction system, extracted with CH2Cl2(15 mL x 3), the organic phases were 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 gave 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] + ).

[0146] 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)acetamino)-9,12-dioxa-5,15-diazicosa-20-oic acid (28)

[0147] 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 celite-assisted filtration, 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] + ).

[0148] Synthesis of compound 31 : tert-butyl 2-(3a, 5, 5-trimethylhexahydro-4, 6- methanobenzo[d][l, 3, 2]dioxol-2-yl)pyrrolidine- 1 -carboxylate (31)

[0149] Compound 29 (10 g, 46.50 mmol) was dissolved in THF, and compound 30 (7.92 g, 46.50 mmol) was added. 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.

[0150] Synthesis of compound 32: (2R)-2-(3a, 5, 5-trimethylhexahydro-4, 6- methanobenzo[d][l, 3, 2]dioxol-2-yl)pyrrolidine hydrochloride (32)

[0151] HCl / EtOAc (2 N, 60 mL) was added dropwise to compound 31 (13.85 g, 39.66 mmol), and the reaction was allowed to proceed at room temperature, generating a large amount of white solid. 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%); chiral resolution was performed by dissolving the solid compound (8.17 g, 32.79 mmol) in 63 ml of CH2Cl2to form a white suspension, stirring in a 40 °C oil bath for 8 h, filtering, and taking the white solid, 3.67 g. The solid was dissolved in 12 ml of isopropanol, and the reaction was allowed to proceed at room temperature overnight. After filtration, the white solid was obtained, which was the desired compound 32, 3.29 g; white solid; 1H-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).

[0152] 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)

[0153] Compound 32 (3.29 g, 11.52 mmol) was dissolved in CH2Cl2, 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 successively, and the reaction was carried out at room temperature. Purification by silica gel column chromatography [v(PE) / v(EtOAc)] = 10 / 1-5 / 1 gave compound 34, 2.69 g (containing a small amount of DIPEA).

[0154] 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)

[0155] Compound 34 (500 mg, 1.19 mmol) was dissolved in 2 mL CH2Cl2, 2 mL TFA was added, and stirring was carried out at room temperature. After TLC detection showed that the reaction was complete, the reaction system was concentrated under reduced pressure to give crude compound 35. Without purification and characterization, it was directly used in the next step; LC-Ms (ESI + )m / z: 321.15 ([M+H] + ).

[0156] 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)

[0157] Compound 35 (517 mg, 1.19 mmol) was dissolved in DMF, DIPEA (461 mg, 3.57 mmol) was added, after adjusting pH to about 7-8, compound 36 (299 mg, 1.19 mmol) and HATU (678 mg, 1.78 mmol) were added. After TLC detection of the reaction completion, 10 mL EtOAc was added to dilute the reaction system, 40 mL H2O was added to wash the organic phase. Extraction was performed with EtOAc (50 mL), the organic phase was combined, saturated aqueous sodium chloride solution was used to wash the organic phase, dried, suction filtered, 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 foamy solid; LC-Ms (ESI + )m / z: 554.34 ([M+H] + )..

[0158] 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)

[0159] 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 TLC detection of the reaction completion, the reaction system was concentrated under reduced pressure, and used directly in the next step without purification; LC-Ms (ESI + )m / z: 454.10 ([M+H] + )..

[0160] 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-bridged methylenebenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)prop-2-yl)carbamoyl) benzyl)amino)propyl)-9,12-dioxa-3,6,16-triazadocosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trisyl)triacetate (39)

[0161] 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 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, extracted with CH2Cl2(15 mL x 3), 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] + ).

[0162] 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-pentaazacyclopentadec-2-yl)-4-(((4-(R)-1-((R)-2-boropyrrolidin-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

[0163] Compound 39 was dissolved in H2O, after stirring for 1 h, phenylboronic 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 oven, 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] + ).

[0164] [ 68 Ga]-cRGD-FAPI-01 and [ 177 Lu]-cRGD-FAPI-01 are complexes prepared by radiolabeling with DOTA-cRGD-FAPI-01 as ligand, after labeling, the compounds were quality controlled and purified by analytical radio-HPLC, the radiochemical purity of all the complexes was greater than 95%, the obtained complexes will be used for in vitro and in vivo experiments.

[0165] Example 2 68 Ga]-cRGD-FAPI-01 preparation

[0166] 68 Ga: The ligand compound DOTA-cRGD-FAPI-01 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.25 M); then the germanium gallium generator was eluted with dilute hydrochloric acid (4 mL, 0.05 mol / L) into the above mixture, after oscillation, the newly obtained mixture was reacted at 90-100 °C for 10-15 min. Then, it was diluted with sterile water for injection, and separated and purified by C18 column purification (ethanol / water (1 / 1, v / v), 2 mL) to obtain [ 68 Ga]-cRGD-FAPI-01.

[0167] Example 3 177 Lu]-cRGD-FAPI-01 preparation

[0168] 177 Lu: The ligand compound DOTA-cRGD-FAPI-01 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.4 M), then 185 MBq of [ 177LuCl3solution and gentisic acid (2.0 mg) was added, and the reaction mixture was reacted at 95 °C for 30-60 min, cooled to room temperature, 177 Lu]-cRGD-FAPI-01 was used directly after dilution with physiological saline.

[0169] Example 4 Synthesis of DOTA-cRGD-FAPI-02

[0170] Compound 46

[0171] 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 for 4 h. The solid was suction filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), suctioned dry and the solvent was removed to give compound 41 (13.9 g).

[0172] To compound 41 (the product from the previous step was used directly) was added 20% piperidine in DMF (piperidine / DMF = 1 / 4, 50 mL) and shaken for 1 h at room temperature. The solid was suction filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), suctioned dry and the solvent was removed to give compound 42.

[0173] To compound 42 (the product from the previous step was used directly) was added DMF (50 mL), followed by 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 shaken for 2 h. The solid was suction filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), suctioned dry and the solvent was removed to give compound 44.

[0174] To compound 44 (the product from the previous step was used directly) was added 20% piperidine in DMF (50 mL) and shaken for 1 h at room temperature. The solid was suction filtered and the solvent was removed. The solid was washed with DMF (50 mL x 3) and then with EtOAc (50 mL x 3), suctioned dry and the solvent was removed to give compound 45.

[0175] 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 mixture was filtered, 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 mixture was filtered and the solvent was removed to give compound 46. A small amount of 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] + .

[0176] 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]dioxaborol-2-yl)pyrrolidin-1-yl)prop-2-yl)carbamoyl)phenyl)- 6,9-dioxa-2,12,15-triazahexadecyl-17-yl)-1,4,7-triazacyclododecane-1,4,7- triyl)triacetate (48)

[0177] 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 the mixture was filtered, and 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- tetraazacyclododecan-1-yl)acetamido)-6,9,18-trioxa-2,12-diazanonadecyl)benzoic acid (47). Pale yellow oil; 0.35 g.

[0178] Compound 47 (0.35 g, 0.32 mmol) was dissolved in DMF (1.5 mL), 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, stirred at room temperature for 2 h. TLC (MeOH:DCM = 1:10) was used to monitor the reaction completion, work-up: the reaction was diluted with water (7 mL) and washed, a yellow sticky semi-solid was precipitated, the crude product after drying was purified by column chromatography [V(MeOH) / V(DCM) = 1 / 50→1 / 30] to give the target product 48. Light yellow oil; 0.19 g; LC-MS (ESI + )m / z: 1387.25 ([M+H] + ).

[0179] Compound 49: (14S)-3, 13-dioxo-l-(4-((2R)-l-oxo-l-((2R)-2-(3a, 5, 5- trimethylhexahydro-4, 6-methanoben [d] [1, 3, 2] dioxaboran-2-yl) pyrrolidin-l- yl)prop-2-yl)aminocarbonyl)phenyl)-14-(2-(4, 7, 10-tris(2-(tert-butoxy)-2- oxoethyl)-l, 4, 7, 10-tetraazacyclododecan-l-yl)acetamido)-6, 9-dioxa-2, 12- diazahexadecyl-17-oxoacetic acid)-14-(2-(4, 7, 10-tetraazacyclododecan-l- yl)acetamidophenol)-6, 9-dioxa-2, 12-diazahexadecan-17-carboxylic acid (49)

[0180] 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, stirred at room temperature for 2 h. TLC (MeOH:DCM = 1:10) was used to monitor the reaction completion, work-up: filtered, the filtrate was concentrated to give the target product 49. Light yellow oil 0.15 g; the compound was used directly in the next reaction without further purification. LC-MS (ESI + )m / z: 1297.08 ([M+H] + ).

[0181] Compound 51: (R)-2-((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5- ((benzyloxy)carbonyl)amino)pentanoic acid

[0182] 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), then 100 mL of FmocOSu (12.67 g, 37.6 mmol) in 1,4-dioxane solution was added dropwise, and stirred at room temperature for 22 h. Sample MS detection, [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, the pH was adjusted to 3-4 with 1M HCl, at this time a large amount of white solid was precipitated, most of the water was filtered off, the wet filter cake was dissolved in 400 mL of DCM, extracted and separated, the organic phase was retained, 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 give 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 + ]).

[0183] Compound 53: (R)-2-((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(((benzyloxy)carbonyl)amino)pentanoic acid

[0184] Compound 51 (15.12 g, 31 mmol) was dissolved in 120 mL of chlorobenzene, then paraformaldehyde (9.29 g, 0.3 mol, 10 eq), TsOH·H2O (0.59 g, 3.1 mmol, 0.1 eq) were added in turn, and stirred at 60°C for 1 h. TLC (V(MeOH):V(DCM) = 1:10, Rf = 0.4) monitoring, the raw material was completely reacted, sample MS detection, [M+Na +] value and the starting compound 7 was completely reacted. The heating was stopped, and the work-up was performed by adding 250 mL of saturated NaHC03solution to the reaction solution under ice-bath stirring for 5 min, followed by extraction with 200 mL of EtOAc, retaining the organic phase, re-extracting the aqueous phase with 200 mL of EtOAc once more, combining the organic phases, drying over anhydrous Na2S04, filtering, and concentrating at 45 °C to obtain the crude product of 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-oxazolidine-3-carboxylate (52) in the form of a white foamy solid, 5.60 g. LC-Ms (ESI + )m / z: 537.2 ([M+Na + ]).

[0185] Intermediate 52 (2.5 g, 4.9 mmol) was dissolved in 20 mL of DCE, followed by the addition of TFA (8.50 g, 75 mmol, 15 eq), triethylsilane (2.90 g, 25 mmol, 5 eq) in sequence, and the reaction was stirred at 60 °C under reflux for 4 h. TLC (MeOH:DCM = 1 :10, Rf = 0.4) monitoring showed that the starting material was completely reacted, and the [M+Na + ] value of compound 53 was obtained, and the starting material, intermediate 52, was completely reacted. The heating was stopped, and the work-up was performed by adding 100 mL of saturated NaHC03solution to the reaction solution under ice-bath stirring for 5 min, followed by extraction with 100 mL of EtOAc, retaining the organic phase, re-extracting the aqueous phase with 50 mL of EtOAc once more, combining the organic phases, drying over anhydrous Na2S04, filtering, and concentrating at 45 °C to obtain the crude product of 53, which was purified by column chromatography [MeOH:DCM = 1 :0→1 :50] to obtain 53 in the form of a light yellow oil, 2.40 g. LC-Ms (ESI + )m / z: 539.2 ([M+Na + ]).

[0186] Compound 61

[0187] DMF (200 mL) was added to compound 6 (the product obtained in the previous step was directly used as the starting material), followed by the addition of compound 10 (12.98 g, 20 mmol), HATU (9.13 g, 24 mmol), and DIPEA (5.17 g, 40 mmol) in sequence, and the reaction was shaken for 2 h. Filtration was performed, 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 solid was dried and then the solvent was removed to obtain compound 60.

[0188] To compound 60 (the product from the previous step was used directly), 200 mL of 20% diethylamine in DMF was added and shaken at room temperature for 2 h. The solid 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 was dried and the solvent was removed to give compound 61 (14.8 g). 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 sent for LC-MS. LC-Ms (ESI + )m / z: 703.4 ([M+H] + ).

[0189] Compound 63

[0190] To compound 61 (the product from the previous step was used directly), DMF (200 mL) was added, 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), 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 62.

[0191] 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 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 sent for LC-MS. LC-Ms (ESI + )m / z: 979.6 ([M+H] + .

[0192] Compound 66

[0193] To compound 63 (the product from the previous step was used directly), DMF (200 mL) was added, followed by compound 64 (2.21 g, 4.8 mmol), HATU (2.74 g, 7.2 mmol) and DIPEA (1.24 g, 9.6 mmol), 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).

[0194] To compound 65 (the product from the previous step was used directly) was added 150 mL of 20% diethylamine in DMF 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 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 sent for LC-MS. LC-Ms (ESI + )m / z: 1076.91 ([M+H] + .

[0195] Compound 80

[0196] To compound 68 (the product from the previous step was used directly) was added 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 at room temperature for 2 h. The solid 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 was dried and the solvent was removed to give compound 70.

[0197] To compound 70 (the product from the previous step was used directly) was added 200 mL of 20% diethylamine in DMF and shaken at room temperature for 2 h. The solid 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 was dried and the solvent was removed to give compound 71.

[0198] To compound 68 (the product from the previous step was used directly) was added 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 at room temperature for 2 h. The solid 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 was dried and the solvent was removed to give compound 70.

[0199] To compound 70 (the product from the previous step was used directly) was added 200 mL of 20% diethylamine in DMF and shaken at room temperature for 2 h. The solid 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 was dried and the solvent was removed to give compound 71.

[0200] 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 with EtOAc (200 mL x 3), and dried and the solvent was removed to give compound 73.

[0201] 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 with EtOAc (200 mL x 3), and dried and the solvent was removed to give compound 74.

[0202] 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 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 with EtOAc (200 mL x 3), and dried and the solvent was removed to give compound 76.

[0203] To compound 76 (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 with EtOAc (200 mL x 3), and dried and the solvent was removed to give compound 77.

[0204] The resin-bound compound 77 (the product from the previous step was used directly) was eluted 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 and purified by column chromatography [MeOH:DCM = 1:20-1:8] to give 78 as a yellow solid, 3.10 g.

[0205] Compound 78 (3.00 g, 2.6 mmol) was dissolved in DMF (30 mL), HATU (1.47 g, 3.9 mmol, 1.5 eq) and DIPEA (0.67 g, 5.2 mmol, 2 eq) were added, and stirred at room temperature for 1.5 h. LC (MeOH:DCM = 1:10, Rf = 0.6) monitoring, MS monitoring, and MS value of target compound 80 were detected, H2O (100 mL) was added to wash the reaction solution, and a large amount of yellow sticky solid was precipitated. After suction filtration, the filter cake was dried and purified by column chromatography [V(MeOH) / V(DCM) = 1 / 30→1 / 15] to obtain the target product 80. Yellow solid; 1.10 g; LC-Ms (ESI + )m / z: 1632.88 ([M+H] + ).

[0206] Compound 81

[0207] 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, and hydrogen was replaced. The temperature was raised to 50°C and stirred for 16 h. MS monitoring and MS value of target molecule 81 were detected. Post-treatment: filtration, and concentration of the filtrate to obtain 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] + ).

[0208] Compound 82

[0209] 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 stirred at room temperature overnight. After the reaction was completed, H2O (360 mL) was added, and the layers were separated. 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 obtain compound 82, white solid 2.0 g, LC-Ms (ESI + )m / z: 1880.69 ([M+H] + ).

[0210] Compound 83

[0211] Compound 82 (2.0 g, 1.1 mmol) was added to a 20% piperidine solution in dichloromethane and stirred at room temperature for 1.5 h. After the reaction was completed, water was added to dilute it and 1 M HC1 was added to adjust pH = 7, and then filtered to obtain white solid compound 83, 800 mg. LC-Ms (ESI + )m / z: 1657.69 ([M+H] + ).

[0212] Compound 84

[0213] 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, and the reaction was carried out at room temperature for 3 hours, extracted with EtOAc (10 mL), the organic phase was combined and washed with saturated aqueous sodium chloride solution, dried, filtered, and concentrated under reduced pressure. Vacuum drying gave a yellowish gel, compound 84, 350 mg. LC-Ms (ESI + )m / z: 1469.87 ([M / 2+H] + ).

[0214] Compound 86: DOTA-cRGD-FAPI-02: 2,2',2'-(10-(S)-4-(2-(3-(4-(((R)-1-(((R)-2- boronazolidin-1-yl)-1-oxopropan-2-yl)aminocarbamoyl)benzyl)amino)-3-oxopropoxy) ethoxy)ethyl)aminocarbonyl)-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-nonaoxaoctacosahydro-1H-pyrrolo[1,2-a][1,4,7,10,13,16,19,22,25] nonaazacycloheptane-3-yl)-2,7,17-trio-11,14-dio-3,8,18-triazapolyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0215] Compound 84 (350 mg, 0.0359 mmol, 1 eq) was dissolved in DCM (3 mL), and TFA (3 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction solution was dried in vacuum 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-nonaoxa-28-hydro-1H-pyrrolo[1,2a][1,4,7,10,13,16,19,22]octaazacycloheptadecin-3-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)propan-2-yl)carbamoyl)benzyl)amino)propoxy)ethoxy)ethyl)aminocarbonyl)-11,14-dioxa-3,8,18-triazanocyclododecane-1,4,7-triyl)triacetic acid (85), 350 mg.

[0216] Compound 85 (350 mg) was dissolved in H2O, and stirred for 1 h. Then, phenylboronic acid (67.4 mg, 0.56 mmol) and a solution of MeCN / TBME (V / V) = 1 / 6 (3 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 dried in a vacuum drying oven. Finally, 100 mg of a crude product was obtained, which was separated by a reverse-phase preparative column to obtain 3.5 mg of a white solid. LC-Ms (ESI + )m / z: 1089.66 ([(M-2H2O) / 2+H] + ).

[0217] Example 5[ 68 Preparation of Ga-cRGD-FAPI-02

[0218] 68 Ga: The ligand compound DOTA-cRGD-FAPI-02 (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 reacted at 90-100 °C for 10-15 min. Then, it was diluted with sterilized water for injection, and separated and purified by C18 column purification (ethanol / water (1 / 1, v / v), 2 mL) to obtain Ga-cRGD-FAPI-02. 68 Ga-cRGD-FAPI-02.

[0219] Example 6 177 Preparation of [Lu]-cRGD-FAPI-02

[0220] 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.

[0221] Example 7 DOTA-cRGD-FAPI-03

[0222] Compound 87

[0223] 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]+).

[0224] Compound 88

[0225] 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]+).

[0226] Compound 89

[0227] 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]+).

[0228] Compound 91

[0229] To compound 89 (the product of the previous step was used directly), a 20% piperidine DMF solution 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 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]+).

[0230] Compound 93

[0231] 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.

[0232] 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 sodium chloride aqueous 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] + ).

[0233] Compound 94

[0234] Compound 93 (2.87g, 2.74mmol) was dissolved in MeOH (100mL), 10% Pd / C (280mg) was added, stirred at room temperature under hydrogen atmosphere overnight. After the reaction was completed, filtered, concentrated in vacuum to get the crude compound 94 as a milky white solid, 2.8g; LC-Ms (ESI+) m / z: 984.83 ([M+H]+). + ) m / z: 984.83 ([M+H]+) + ).

[0235] Compound 95

[0236] Compound 94 (2.8g, 2.8mmol,) was dissolved in DMF (10mL), compound 19 (1.1g, 2.8mmol,) was added, HATU (1.4g, 3.7mmol) and DIPEA (1.8g, 14mmol) were added, stirred at room temperature overnight. After the reaction was completed, H2O (360mL) was added, the layering phenomenon appeared, after separation of the water phase and the organic phase, the organic phase was washed with saturated aqueous sodium chloride solution (180mL). The organic phase was concentrated, column chromatography (DCM / MeOH (V / V) = 50 / 1-10 / 1) to get compound 95, white solid 2.0g; LC-Ms (ESI+) m / z: 1365.69 ([M+H]+).

[0237] Compound 96

[0238] Compound 95 (2.0g, 1.46mmol) was added to a 20% piperidine solution in DMF, stirred at room temperature for 1.5h. After the reaction was completed, water was added to dilute and 1M HCl was added to adjust pH = 7, filtered, to get white solid compound 96; LC-Ms (ESI+) m / z: 1143.69 ([M+H]+) +

[0239] ​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

[0240] 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 gum 350 mg by drying under vacuum; LC-Ms (ESI + )m / z: 1212.87 ([M+2H] + / 2).

[0241] 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)- 3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadec-2-yl)-2,7,17-trioxy-11,14-dioxo- 3,8,18-triazacyclododecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trisyl)triacetic acid

[0242] 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] + ).

[0243] Example 8 68 Preparation of

[0244] 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 C18 column purification (ethanol / water (1 / 1, v / v), 2 mL) to obtain 68 Ga]-cRGD-FAPI-03.

[0245] Example 9 177 Preparation of

[0246] 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 a commercially available 185 MBq of 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.

[0247] Example 10 Preparation of cRGD-FAPI-04

[0248] Compound 98

[0249] Compound 38 (0.47 mmol, theoretical amount) was dissolved in DMF (0.5 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 19 (Fmoc-PEG2-COOH) (146 mmol, 0.53 mmol) was dissolved in DMF (4 mL) and cooled in an ice water bath, 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 temperature of the reaction system 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 extraction was performed with EtOAc (15 mL x 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification was performed by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 20 / 1 to obtain the target compound 98, 112 mg; LC-Ms (ESI + )m / z: 713.76 [M+H] + .

[0250] Compound 100

[0251] Compound 98 (112 mg, 0.16 mmol) was dissolved in 1 mL of CH2Cl2, 1 mL of TFA was added, and stirring was performed 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]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)benzamide trifluoroacetate salt (99), which was directly used in the next step without purification;

[0252] Compound 28 (112 mg, 0.064 mmol) was dissolved in DMF (5 mL) and stirred and cooled in an ice water bath, HATU (31.5 mg, 0.83 mmol) and DIPEA (16.5 mg, 0.13 mmol) were added, and after continuing stirring for 30 min, compound 99 (43 mg, 0.070 mmol) was added, and the temperature of the reaction was naturally transitioned to room temperature as the ice water melted. After TLC detection of the completion of the reaction, H2O (50 mL) was added to the reaction system, and extraction was performed with CH2Cl2 (15 mL x 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to obtain the crude target compound 100, which was directly used in the next step without purification. LC-Ms (ESI + )m / z: 1175.66 [(M+2H) + / 2], 784.30 [(M+3H)+ / 3]。

[0253] 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-triazadocosan-1,4,7-triyl)triacetic acid

[0254] The compound 100 obtained in the above step was dissolved in CH2Cl2(1 mL), and CF3COOH (1 mL) was added, and stirred at room temperature for 1 h. The reaction solution was detected by LC-Ms, and compound 100 was consumed completely. After being concentrated under reduced pressure, the crude intermediate was obtained. The intermediate 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 stirred for another 3 h. The solution was allowed to stand, and the organic phase and the aqueous phase were separated. The aqueous phase was placed in a vacuum drying box to dry, and finally, 190 mg of the crude product was obtained. 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].

[0255] Example 11[ 68 Preparation of Ga]-cRGD-FAPI-04

[0256] 68 Ga: The ligand compound DOTA-cRGD-FAPI-04 (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, and the resulting mixture was shaken at 90-100 °C for 10-15 min. Then, it was diluted with sterile water for injection, and separated and purified by C18 column purification (ethanol / water (1 / 1, v / v), 2 mL).68 Ga]-cRGD-FAPI-04.

[0257] Example 12[ 177 Preparation of Lu]-cRGD-FAPI-05

[0258] 177 Lu: The ligand compound DOTA-cRGD-FAPI-03 (50 μg) was dissolved in sodium acetate solution (1 mL, 0.4 M), then 185 MBq of purchased 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, 177 The 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, 177 Lu]-cRGD-FAPI-05 was directly used after dilution with physiological saline.

[0259] Example 13 Preparation of cRGD-FAPI-05

[0260] Compound 102

[0261] 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 TLC detection of the completion of the reaction, 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, suction filtered, and purified by silica gel column chromatography [v(CH2Cl2) / v(MeOH)] = 30 / 1 to obtain compound 102, white foam, 9.28 g; LC-Ms (ESI+) m / z: 792.60 [M+H]+.

[0262] Compound 103

[0263] Compound 38 (1.02 mmol, theoretical amount) was dissolved in DMF (0.5 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 102 (807.8 mg, 1.02 mmol) was dissolved in DMF (5 mL) and cooled in an ice water bath, and HATU (465.4 mg, 1.22 mmol) and DIPEA (395.5 mg, 3.06 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 detecting that the reaction was completed by TLC, H2O (50 mL) was added to the reaction system, and extraction was performed with EtOAc (15 mL x 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification was performed by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 20 / 1 to obtain the target compound 103, 626 mg; LC-Ms (ESI+) m / z: 1227.33 [M+H]+.

[0264] Compound 104

[0265] Compound 103 (869 mg, 0.7080 mmol) was dissolved in MeOH (9 mL), 10% Pd / C (150.7 mg, 1.416 mmol) was added, and H2 was replaced, and it was stirred at room temperature overnight. After the reaction was completed, Pd / C was removed by celite-assisted filtration, and the filtrate was concentrated to obtain the crude compound 104, which was a colorless transparent gel; LC-Ms (ESI+) m / z: 569.3 [(M+2H)+ / 2], 1137.69 [M+H]+.

[0266] Compound 105

[0267] Compound 104 (224.4 mg, 0.20 mmol) was dissolved in DMF (5 mL) and stirred and cooled in an ice water bath, HATU (90 mg, 0.24 mmol) and DIPEA (51 mg, 0.39 mmol) were added, and after continuing to stir for 30 min, compound 18 (180 mg, 0.20 mmol) was added, and the reaction temperature was naturally transitioned to room temperature as the ice water melted. After detecting that the reaction was completed by TLC, H2O (50 mL) was added to the reaction system, and extraction was performed with CH2Cl2 (15 mL x 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried, concentrated under reduced pressure, and the target compound 105 was obtained as a light yellow oil by silica gel column chromatography [v(CH2Cl2) / v(MeOH) = 50 / 1-20 / 1], 160 mg; LC-Ms (ESI+) m / z: 1016.70 [(M+2H)+ / 2], 678.22 [(M+3H)+ / 3].

[0268] Compound 106

[0269] Compound 105 was dissolved in CH2Cl2(1 mL), CF3COOH (1 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-Ms, and compound 105 was consumed completely. The mixture was concentrated under reduced pressure to give 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 mixture was stirred for another 3 h. The solution was allowed to stand, and the organic phase and the aqueous phase were separated. The aqueous phase was dried in a vacuum drying oven to give a crude product 130 mg. Compound 106 (i.e., cRGD-FAPI-05) was obtained as a white solid by reverse-phase preparative column separation. LC-Ms (ESI + )m / z: 1421.05 [M+H] + .

[0270] Preparation of cRGD-FAPI-06

[0271] Compound 107

[0272] 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 mixture was stirred for another 30 min. Compound 18 (756 mg, 0.83 mmol) was added, and the reaction temperature was naturally increased to room temperature as the ice water melted. After the reaction was completed as detected by TLC, H2O (50 mL) was added to the reaction system, and extraction was performed with EtOAc (20 mL x 3). The organic phase was combined, washed with saturated aqueous NaCl solution, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography [v(CH2Cl2) / v(MeOH) = 30 / 1] to give compound 107 as a light yellow oil, 775 mg; LC-Ms (ESI + )m / z: 562.64 [(M+3H) + / 3].

[0273] Compound 108

[0274] Compound 107 (192 mg, 0.11 mmol) was dissolved in MeOH (5 mL), and 10% Pd / C (24.2 mg, 0.23 mmol) was added. The mixture was replaced with H2 and stirred at room temperature overnight. After the reaction was completed, the Pd / C was removed by filtration with the aid of diatomaceous earth, and the filtrate was concentrated to give compound 108 as a colorless transparent gel; LC-Ms (ESI +m / z: 1595.36 [M+H] + .

[0275] Compound 109

[0276] Compound 38 (0.59 mmol, theoretical amount) was dissolved in DMF (6 mL), DIPEA was slowly added dropwise, and the solution was adjusted to a pH of about 7-8 for standby. In addition, compound 108 (941.6 mg, 0.59 mmol) was dissolved in DMF (5 mL) and cooled in an ice water bath, HATU (269.2 mg, 0.71 mmol) and DIPEA (152.5 mg, 1.18 mmol) were added, and after stirring for 30 min, the standby solution was added. The temperature of the reaction system was naturally transitioned to room temperature, and stirring was performed overnight. After TLC detection of the completion of the reaction, H2O (50 mL) was added to the reaction system, and extraction was performed with EtOAc (15 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. Purification was performed by thin layer chromatography [v(CH2Cl2) / v(MeOH)] = 20 / 1 to obtain the target compound 109, 359.5 mg; LC-Ms (ESI + m / z: 1017.1 [(M+2H) + / 2].

[0277] cRGD-FAPI-06: Compound 110

[0278] Compound 109 was dissolved in CH2Cl2(1.5 mL), CF3COOH (1.5 mL) was added, and stirring was performed at room temperature for 1 h. The reaction solution was detected by LC-Ms, and compound 109 was completely consumed. After concentration under reduced pressure, a crude intermediate was obtained. The intermediate was dissolved in H2O, stirred for 1 h, and then phenylboronic acid (15.6 mg, 0.13 mmol) and 4.0 mL of a solution of MeCN / TBME (V / V) = 1 / 6 were added. After continuing to stir for 3 h, 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 box to obtain a crude product of 110 mg. Compound 110 was separated by a reversed-phase preparative column to obtain a white solid of 2.2 mg. LC-Ms (ESI + m / z: 1421.06 [M+H] + .

[0279] Effect experiment 1: in vitro competitive binding test (IC 50 )

[0280] 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 -10-11 M) were co-cultured for 1 hour at 37°C. After the incubation, the cells were washed twice with PBS buffer, lysed with 1 M NaOH and counted using a gamma counter. IC 50 Values were calculated by non-linear fitting and SPSS algorithm.

[0281] In vitro competitive binding assay (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.

[0282] Table 1 Note: " / " means not detected.

[0283] The test results showed that the compounds of the present application had significant affinity for both αvβ3 and FAP targets. 177 The affinity of the compounds of the present application for FAP after labeling with 68Ga was superior to the affinity of PNT6555 and FAP-2286 for FAP.

[0284] PNT6555 structure reference: J Nucl Med 2024; 00: 1-9

[0285] FAP2286 structure reference: Eur J Nucl Med Mol Imaging 49, 3651-3667 (2022)

[0286] cRGDfK (DOTA-RGD) structure reference: Diagnostics 2021, 11(7), 1295

[0287] Effect experiment 2: in vitro stability test

[0288] The radiolabeled test compounds were 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, and after centrifugation, the supernatant was determined for radiochemical purity in radio-HPLC, and the nuclide complex slowly degraded.

[0289] Results: As shown in Figures 1-3, Example 2 68 Ga]-cRGD-FAPI-01, Example 8 68Ga]-cRGD-FAPI-03 and Example 11 68 Ga]-cRGD-FAPI-04 has good stability in PBS, human serum and mouse serum.

[0290] Effect experiment 3: Small animal Micro-PET-CT imaging

[0291] 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 the compound was injected through the tail vein of the mouse 68 Ga-labeled ligand (7.4-1.1 MBq) and 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.

[0292] The nude mice (n=3-4) carrying U87MG tumors were anesthetized and placed in a prone position in a Micro-PET imaging scanner, and the compound was injected through the tail vein of the mouse 68 Ga-labeled ligand (7.4-1.1 MBq) and 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.

[0293] Small animal Micro-PET-CT imaging:

[0294] 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. The 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 out of the body through the kidneys. Within 120 min, the radioactive concentration slowly increases, showing a higher uptake in the tumor. Within 30 min, the %ID / g has reached more than 10 and slowly increases.

[0295] As shown in Figure 5, Example 5 PET-CT results in a CAPAN-2 tumor model with high expression of ανβ6 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 out of the body through the kidneys; there is obvious radioactive concentration in the tumor site, and within 60 min, the %ID / g reaches more than 2 and slowly increases.

[0296] As shown in Figure 6, Example 868 Ga]-cRGD-FAPI-03 showed significant radioactivity concentration in the tumor site of U87MG tumor-bearing mice. 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 quickly excreted out of the body through the kidneys. Within 120 min, the radioactivity concentration slowly increased, showing higher uptake in the tumor and lower uptake in other organs. Within 30 min, the %ID / g reached more than 12 and increased slowly.

[0297] As shown in Figure 7, Example 11[ 68 Ga]-cRGD-FAPI-04 showed significant radioactivity concentration in the tumor site of U87MG tumor-bearing mice. 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 quickly excreted out of the body through the kidneys. Within 120 min, the radioactivity concentration slowly increased, showing higher uptake in the tumor and lower uptake in other organs. Within 30 min, the %ID / g reached more than 8 and increased slowly.

[0298] PET-CT results showed that Example 8[ 68 Ga]-cRGD-FAPI-03 and[ 68 Ga]PNT6555, 68 Ga]FAP-2286, 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:

[0299] Table 2. 68 Distribution of [Ga] labeled compounds in the tumor of mice

[0300] As shown in Figure 8, Example 11[ 68 Ga]-cRGD-FAPI-04 showed significant radioactivity concentration in the tumor site of A549-FAP tumor-bearing mice. 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 quickly excreted out of the body through the kidneys. Within 120 min, the radioactivity concentration 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 single targeting αvβ3 68 Ga]cRGDfK(DOTA-RGD).

[0301] Effect experiment 4: in vivo biodistribution

[0302] The compound to be tested was radiolabeled with 50-150 uCi and injected into A549-FAP or U87MG tumor-bearing mice through the tail vein. One hour after injection, the animals were sacrificed, and the organs of interest were collected, stained, weighed, and measured for radioactivity using a gamma counter. The percentage of injected dose per gram of tissue (%ID / g) was calculated using the formula: %ID / g = (radioactivity concentration in the region of interest (μCi / g)) / (total radioactivity administered (μCi)) x 100%

[0303] Tissue distribution in U87MG tumor-bearing mice: when the tumor reached a certain size, the mice were injected with the compound to be tested through the tail vein (about 0.05 mCi per mouse). After administration, the animals were euthanized using carbon dioxide inhalation at 1 h, 4 h, 24 h, 72 h, and 168 h. The tumor, blood, and organs (liver, kidney, muscle, etc.) were collected. All samples were measured for radioactivity using a gamma counter. 177 The compound to be tested was radiolabeled with 50-150 uCi and injected into A549-FAP or U87MG tumor-bearing mice through the tail vein. One hour after injection, the animals were sacrificed, and the organs of interest were collected, stained, weighed, and measured for radioactivity using a gamma counter. The percentage of injected dose per gram of tissue (%ID / g) was calculated using the formula: %ID / g = (radioactivity concentration in the region of interest (μCi / g)) / (total radioactivity administered (μCi)) x 100%

[0304] 177 Biodistribution of Lu-labeled compounds in tumor-bearing mice

[0305] Tissue distribution in U87MG tumor-bearing mice: when the tumor reached a certain size, the mice were injected with the compound to be tested through the tail vein (about 0.05 mCi per mouse). After administration, the animals were euthanized using carbon dioxide inhalation at 1 h, 4 h, 24 h, 72 h, and 168 h. The tumor, blood, and organs (liver, kidney, muscle, etc.) were collected. All samples were measured for radioactivity using a gamma counter. 177 Lu radiolabeled Example 9 177 Lu]-cRGD-FAPI-03 and 177 The compound to be tested was radiolabeled with 50-150 uCi and injected into A549-FAP or U87MG tumor-bearing mice through the tail vein. One hour after injection, the animals were sacrificed, and the organs of interest were collected, stained, weighed, and measured for radioactivity using a gamma counter. The percentage of injected dose per gram of tissue (%ID / g) was calculated using the formula: %ID / g = (radioactivity concentration in the region of interest (μCi / g)) / (total radioactivity administered (μCi)) x 100% 177 The radioactivity values of Example 9 in the tumor site were significantly higher than those of Example 9, especially in the bone, intestine, and blood.

[0306] Radioactivity ratio of each molecule in the tumor and major organs: as shown in Table 3 and Figure 10, the radioactivity ratio of each molecule in the tumor and major organs was calculated according to the formula: radioactivity ratio = (radioactivity in the tumor) / (radioactivity in the major organs) 177The tissue distribution data of Lu radiolabeled molecules in U87MG tumor-bearing mice were calculated to calculate the radioactivity ratio of each molecule in the tumor and main organs. The tumor / blood, tumor / liver, tumor / kidney and tumor / muscle ratios of Example 9 were higher than those of PNT6555, indicating better safety. The tumor / kidney ratio and tumor / blood ratio of Example 9 were significantly better than those of FAP-2286, indicating good safety.

[0307] Table 3

[0308] 177 Therapeutic effect of Lu-labeled compounds on tumor-bearing mice

[0309] 6-8-week-old nude mice were inoculated subcutaneously on the right side of the back with 1×10 7 U87MG cells, and when the tumors grew to 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 were an average tumor volume of 150-200 mm 3 , and a CV of <30%. Radioactive labeled compounds were injected intravenously, with about 0.5-1 mCi per mouse. Health and appearance observations were performed daily after the start of the experiment, and animal body weight and tumor size were measured before the sampling time points.

[0310] 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 had a more excellent inhibitory effect on tumor growth than [ 177 Lu]PNT6555 at the same dose, as shown in Figure 11.

[0311] The compound developed in the present application, which can dual-target fibroblast activation protein and integrin family subtypes, has high affinity for FAP targets and integrin αvβ3 or αvβ6, can simultaneously target both types of targets, exhibits excellent metabolic kinetics, high tumor uptake and long tumor retention time, and is expected to be applied to diagnose or treat diseases characterized by overexpression of fibroblast activation protein and integrin family subtypes (e.g., integrin αvβ3 or αvβ6).

[0312] Effect experiment 5: in vivo stability test

[0313] The radionuclide complex (Example 12, i.e., 177The compound of Example 12 was injected into C75 mice via the tail vein, and 60 min later, the eyeballs were removed to collect blood. Acetonitrile was added to the blood to precipitate plasma proteins. After centrifugation, the supernatant was determined for radiochemical purity by radio-HPLC. The nuclide complex was slowly degraded.

[0314] The experimental results are shown in Figure 12. Example 12 has good stability in mice for 1 h. It is shown that Example 12 has strong structural stability and enzymatic stability.

[0315] Effect experiment 6: cell efflux experiment

[0316] A549-FAP cells with high FAP expression or U87MG cells capable of expressing FAP and ανβ3 were inoculated in 6-well plates or 24-well plates and cultured with fresh medium without fetal bovine serum. 0.5 uCi of radiolabeled test compound (Examples 2, 8, and 11, respectively) was added to each well, and incubation was performed at 37°C for 1 h. After incubation, the 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 a γ-counter.

[0317] The experimental results are shown in Figure 13. Using U87MG cells, Example 2 and Example 8 slowly effluxed within 120 min, and Example 11 effluxed faster. It is shown that the compounds of the present application have a long retention time in vivo.

[0318] Effect experiment 7: in vitro cell internalization experiment

[0319] A549-FAP cells with high FAP expression or U87MG cells capable of expressing FAP and ανβ3 were inoculated in 6-well plates or 24-well plates and cultured with fresh medium without fetal bovine serum. 0.5 uCi of radiolabeled test compound (Examples 2, 8, and 11, respectively) was added to each well, and incubation was performed at 37°C for 1 h. After incubation, the medium was removed and the cells were washed twice with ice PBS buffer. Glycine hydrochloride solution (1M, 1 mL, pH = 2.2) was added to the mixture, and incubation was performed at 37°C for 10 min. After incubation, the 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 of the glycine hydrochloride solution and the lysed cell solution was determined by a γ-counter.

[0320] The results are shown in Figure 14, using U87MG cells, and the total uptake and internalization of Example 2, Example 8 and Example 11 were significantly higher than the single FAP-targeting PNT6555 and the single ανβ3-targeting 68 Ga]DOTA-cRGDfK(blue bars, DOTA-RGD). This demonstrates that the dual targeting compounds provided by the application are able to target both FAP and ανβ3, significantly increasing tumor cell uptake and internalization.

[0321] The above description is only the preferred embodiment of the application, and is not intended to limit the application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the application shall be included in the protection scope of the application.

Claims

1. A compound or a pharmaceutically acceptable salt, tautomer, racemate, hydrate, solvate, or isotopically-labeled form thereof, characterized in that: (i) a chelator 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 identical 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 an 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-aspartic acid 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- 6alkylthio, 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 the group consisting of 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 cyclohexyl, cyclopentyl), (For example phenylene); wherein each A is independently selected from CR 2 or N; each B is independently selected from -C(R 2 )2-, O, -S(=0) m -, -N(R 1 ) n - , or -C(=Z)-; Further, the L a , L b , L c each independently is selected from -(CH2) q -((CH2) q -O) x -NH-C(=O)-(CH2) q -, q -((CH2) q -O) x -NH-C(=O)-(CH2) q -, q -((CH2) x -O) q -, q -((CH2) x -O) 1 -, 1 -((CH2) q -O) x -(CH2) q -, q -((CH2) q -O) x -(CH2) q -, 2 -((CH2) q -O) q -, q -((CH2) q -O) x -, q -((CH2) x -O) q -(CH2) q -, q -((CH2) x -O) wherein the selection of q, x, A or B in the same structural formula can be the same or different, and do not affect each other; preferably, the L a , L b , L c each independently is selected from phenylmethyl, methylenepyridyl (e.g. 2-methylen-4-pyridyl), methylenecyclohexyl-, 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), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HATMA), hexaazatriphenylhexaamine (HAT 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; 10. A pharmaceutical composition comprising a compound of any one of claims 1-9 and a pharmaceutically acceptable excipient. 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 6. The compound according to any one of claims 1 to 5, wherein ​ Further preferably, said second targeting moiety (CY) is: R, R 7 and R 8 are each independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; said R, R 7 and R 8 are each independently further optionally mono- or poly-substituted with identical or different substituents R 9 ; said 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 are each independently selected from the group consisting of 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 are each independently further optionally mono- or poly-substituted with identical or different R 9 ; Further preferably, the second targeting moiety (CY) is selected from one or more of the following structural formulae:

7. The compound of claim 1, wherein The compound structure is wherein CL, BT, CY, L a , L b , L c , R 1 and R 2 have the meanings as given in any one of claims 1 to 6.

8. The compound of claim 2, wherein The compound is selected from one of the following structures:

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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