Radiolabeled fibroblast activation protein ligand

Abstract

The present invention relates to ligands of fibroblast activation protein (FAP) for active delivery of radioactive payloads at sites of disease. In particular, the present invention relates to 18 Fluorine, 68 gallium, 64 copper, 111 indium, 177 The present invention relates to the development of FAP ligands for targeted delivery of radionuclides, such as lutetium, as well as methods for diagnostic and / or therapeutic or surgical procedures associated with a disease or disorder, such as cancer, inflammation, or another disease characterized by overexpression of a FAP.

Description

[Technical field]

[0001] The present invention relates to ligands of fibroblast activation protein (FAP) for active delivery of radioactive payloads at sites of disease. In particular, the present invention relates to 18 Fluorine, 68 gallium, 64 copper, 111 indium, 177 The present invention relates to the development of FAP ligands for targeted delivery of radionuclides, such as lutetium, as well as methods for diagnostic and / or therapeutic or surgical procedures associated with a disease or disorder, such as cancer, inflammation, or another disease characterized by overexpression of a FAP. [Background technology]

[0002] Fibroblast activation protein (FAP) is a membrane-bound gelatinase that promotes tumor growth and progression and is overexpressed in cancer-associated fibroblasts. Due to its low expression in normal organs, FAP represents an ideal target for the development of targeted small molecule drug conjugates (SMDCs) and small molecule radioconjugates (SMRCs).

[0003] WO2019154886 and WO2019154859 describe heterocyclic compounds as fibroblast activation protein-alpha inhibitors used to treat different cancer types. WO2019118932 describes substituted N-containing cyclic compounds as fibroblast activation protein-alpha inhibitors used to treat different pathologies. WO2019083990 describes fibroblast activation protein-alpha (FAP-alpha) compounds for imaging and radiotherapy targeting as FAP-alpha inhibitors used to image diseases associated with FAP-alpha and to treat proliferative diseases. WO2013107820 describes substituted pyrrolidine derivatives for use in the treatment of proliferative disorders such as cancer, and diseases manifested by tissue remodeling, or chronic inflammation such as osteoarthritis, noting that the 4-isoquinolinoyl and 8-quinolinoyl derivatives described therein are characterized by very low FAP affinity, noting that the 4-isoquinolinoyl and 8-quinolinoyl derivatives described therein are characterized by very low FAP affinity. WO2005087235 describes pyrrolidine derivatives as dipeptidyl peptidase IV inhibitors for treating type II diabetes. WO2018111989 describes conjugates comprising fibroblast activation protein (FAP) inhibitors, bivalent linkers, and e.g. near infrared (NIR) dyes, useful for removing cancer-associated fibroblasts, imaging cell populations in vitro, and treating cancer.

[0004] Tsutsumi et al. (J Med Chem 1994) describe the preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of a-keto heterocyclic compounds. Hu et al. (Bioorg Med Chem Lett 2005) describe the structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against FAP and two other dipeptidyl peptidases. Edosada et al. (J Biol Chem 2006) describe the dipeptide substrate specificity of FAP and the development of Ac-Gly-BoroPro FAP selective inhibitors. Gilmore et al. (Biochem Biophys Res Commun 2006) describe the design, synthesis and kinetic testing of a series of dipeptide proline diphenylphosphonates against DPP-IV and FAP. Tran et al. (Bioorg Med Chem Lett 2007) describe the structure-activity relationship of various N-acyl-Gly-, N-acyl-Sar- and N-blocked-boroPro derivatives against FAPs. Tsai et al. (J Med Chem 2010) describe structure-activity relationship studies that have resulted in a number of FAP inhibitors with excellent selectivity against DPP-IV, DPP-II, DPP8 and DPP9. Ryabtsova et al. (Bioorg Med Chem Lett 2012) describe the synthesis and evaluation of FAP inhibitory properties of a series of N-acylated glycyl-(2-cyano)pyrrolidines. Poplawski et al. (J Med Chem 2013) describe N-(pyridine-4-carbonyl)-D-Ala-boroPro as a potent and selective FAP inhibitor. Jansen et al. (ACS Med Chem Lett 2013) describe FAP inhibitors based on the N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. Jansen et al. (Med Chem Commun 2014) describe the structure-activity relationships of FAP inhibitors based on the linagliptin scaffold. Jansen et al. (Med Chem Commun 2014) describe xanthine-based FAP inhibitors with low micromolar potency.Jansen et al. (J Med Chem 2014) describe the structure-activity relationships of FAP inhibitors based on the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold. Jackson et al. (Neoplasia 2015) describe the development of pseudopeptide inhibitors of FAP. Meletta et al. (Molecules 2015) describe the use of boronic acid-based FAP inhibitors as non-invasive imaging tracers of atherosclerotic plaques. Dvorakova et al. (J Med Chem 2017) describe the preparation of polymer conjugates containing FAP-specific inhibitors for targeting applications. Loktev et al. (J Nucl Med 2018) describe the development of iodinated and DOTA-coupled radiotracers based on FAP-specific enzyme inhibitors. Lindner et al. (J Nucl Med 2018) describe the modification and optimization of FAP inhibitors for use as diagnostic therapeutic tracers. Giesel et al. (J Nucl Med 2019) describe the clinical imaging performance of a quinoline-based PET tracer that acts as a FAP inhibitor.

[0005] Nevertheless, developing potent FAP binders with advantageous targeting properties, as well as SMDCs and SMRCs based thereon, remains a challenging task. Particularly desirable are SMRCs that exhibit favorable tumor-to-organ biodistribution, high activity labeling, and / or good compound stability, especially with respect to chemical and radiolytic stability and stability in in vitro and in vivo biological systems. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention is directed to the problem of providing an improved SMRC that binds compounds, particularly fibroblast activation proteins (FAPs), for targeted delivery. The compounds ("binders") should be suitable for therapeutic and / or diagnostic use and be able to reach sites at risk of or afflicted by diseases or disorders characterized by overexpression of FAPs. Preferably, the compounds should form stable complexes with FAPs and exhibit extended residence at disease sites and lower accumulation in healthy organs. [Means for solving the problem]

[0007] The present inventors have now discovered novel compounds (in particular: SMRC) that bind fibroblast activation protein (FAP), which are particularly suitable for targeting applications and for addressing the problems described above.

[0008] The present invention provides a compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein the compound structure includes: The following structure:

[0009] [ka]

[0010] A moiety A represented by or containing one or more diagnostic or therapeutic moieties C; and a moiety B which covalently connects A to C and which comprises a carbocyclic or heterocyclic group;

[0011] The present invention further provides a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable excipient. The invention further provides said compound or pharmaceutical composition for use in a method of treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body; as well as a method of treatment of the human or animal body by surgery or therapy or a diagnostic method practiced on the human or animal body comprising administering to a subject in need thereof a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition.

[0012] The invention further provides said compound or pharmaceutical composition for use in a method of treatment or prevention of a subject suffering from or at risk of a disease or disorder; as well as a method of treatment or prevention of a disease or disorder comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or at risk of said disease or disorder.

[0013] The invention further provides said compound or pharmaceutical composition for use in a method of guided surgery performed on a subject suffering from or at risk of a disease or disorder; as well as a method of guided surgery comprising administering a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from or at risk of a disease or disorder.

[0014] The invention further provides said compound or pharmaceutical composition for use in a method of diagnosis of a disease or disorder performed on the human or animal body and involving a nuclear medicine imaging technique such as positron emission tomography (PET); as well as a method of diagnosis of a disease or disorder performed on the human or animal body and involving a nuclear medicine imaging technique such as positron emission tomography (PET), comprising administering to a subject in need thereof a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition.

[0015] The invention further provides said compound or pharmaceutical composition for use in a method of targeted delivery of a therapeutic or diagnostic agent to a subject suffering from, or at risk of, a disease or disorder; as well as a method for targeted delivery of a therapeutically or diagnostically effective amount of said compound or pharmaceutical composition to a subject suffering from, or at risk of, a disease or disorder.

[0016] Preferably, the aforementioned disease or disorder is characterized by overexpression of FAP and is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders, and preferably, the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multidrug-resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct adenocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, tumor-induced osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, skin cancer, kidney cancer, breast cancer and prostate cancer. More preferably, the disease or disorder is selected from melanoma, breast cancer and renal cell carcinoma. [Brief description of the drawings]

[0017] [Figure 1] Figure 14. ESV6-NODAGA-Al-F: Chromatographic purity of the labeling procedure measured by LC-UV-MS (Agilent 6100 Series Single Quadrupole MS System coupled with Agilent 1200 Series LC System. Chromatographic method, water / ACN+0.1% HCOOH 90:10 to 0:100 in 3 min) identified a single species after labeling. [Diagram 2]Figure 1 shows the nano-HPLC chromatogram of ESV6-NODAGA-Al-F: By applying nano-HPLC, a chromatography with higher resolution, three different chemical species were identified: (i) ESV6-NODAGA-Al (883.31254 m / z at 15.34 min), which corresponds to a compound in which the fluorine anion is missing, (ii) ESV6-NODAGA-Al-OH (901.32311 m / z at 13.56 min), which corresponds to a compound in which the fluorine anion is replaced by a hydroxyl anion, and (iii) ESV6-NODAGA-Al-F (903.31877 m / z at 16.42 min). This figure shows that ESV6-NODAGA labeling can result in a mixture of species. [Diagram 3] Figure 2: ESV6-NOTA (compound 1): Chromatographic purity of the labeling procedure measured by LC-UV-MS (Agilent 6100 Series Single Quadrupole MS System coupled with Agilent 1200 Series LC System. Chromatographic method, water / ACN+0.1% HCOOH 90:10 to 0:100 in 3 min) identified a single species after labeling. [Figure 4] Figure 1 shows the nano-HPLC chromatogram of ESV6-NOTA-Al-F (compound AlF@1): By applying nano-HPLC, a chromatography with higher resolution, a single peak was identified (15.24 min and 857.31329 m / z), indicating a high degree of purity for the labeled version of ESV6-NOTA. [Diagram 5] Figure 1 shows a schematic workflow of ex vivo biodistribution experiments: Mice were treated with either ESV6-NODAGA-Al-F (represented as the sum of the three species) or ESV6-NOTA-Al-F (compound AlF@1) and euthanized 2 h later. Tissues were collected, deproteinized, cleaned on two SPEs side-by-side, and analyzed on a nanoLC-HR-MS platform. Isotopically labeled derivatives of the analytes at fixed concentrations were added to the samples prior to sample preparation as internal standards for MS analysis. [Figure 6]Figure 1: Ex vivo biodistribution results: ESV6-NODAGA-Al-F (expressed as the sum of the three species) and ESV6-NOTA-Al-F expressed as pmol / g in tumors 2 hours after injection and in selected organs. ***=p-value<0.001, Q=0.003 using an unpaired t-test (95%). The preferential uptake of ESV6-NOTA-Al-F in T tumors is striking and significantly superior to the tumor uptake exhibited by ESV6-NODAGA-Al-F. [Figure 7] Figure 1 shows quantitative in vivo biodistribution results of ESV6-NOTA-[18F]Al-F in nude mice bearing subcutaneous HT-1080.hFAP tumors: Results are expressed as percentage of injected dose per gram of tissue (A) and as tumor-to-organ ratio (B). The preferential uptake of ESV6-NOTA-[18F]Al-F is striking, while uptake in normal organs is negligible. [Figure 8-1] Figure 1 shows a coelution experiment with a) [68Ga]GaESV6-NOTA, b) [68Ga]GaESV6-NODAGA, and c) ESV6-NOTA-[18F]Al-F and human FAP. In the presence of human FAP, the complex is the only compound present. The binding experiment demonstrates the high affinity of all radiolabeled ESV6 moieties towards human FAP. [Figure 8-2] Figure 1 shows a coelution experiment with a) [68Ga]GaESV6-NOTA, b) [68Ga]GaESV6-NODAGA, and c) ESV6-NOTA-[18F]Al-F and human FAP. In the presence of human FAP, the complex is the only compound present. The binding experiment demonstrates the high affinity of all radiolabeled ESV6 moieties towards human FAP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present inventors have identified compounds, in particular small molecule radioconjugates (SMRCs), that bind to fibroblast activation proteins (FAPs) and are suitable for targeting applications. The SMRCs according to the invention provide good inhibition of FAPs, good affinity for FAPs, and / or are suitable for targeted delivery of payloads, such as therapeutic or diagnostic agents, to sites afflicted by or at risk for a disease or disorder characterized by overexpression of a FAP.

[0019] The compounds according to the invention form stable complexes with FAPs and exhibit increased affinity, increased inhibitory activity, slower rate of dissociation from the complex, and / or prolonged residence at the disease site. The compounds according to the invention may further have increased tumor-to-liver, tumor-to-kidney, and / or tumor-to-intestine uptake ratios; more potent antitumor efficacy (e.g., measured by mean tumor volume increase), and / or lower toxicity (e.g., as determined by evaluation of % change in body weight). The compounds according to the invention preferably achieve FAP-specific cell binding; FAP-selective accumulation on cell membranes; FAP-selective accumulation inside the cytosol. Furthermore, the compounds according to the invention may preferably be rapidly and homogeneously localized to tumor sites in vivo with high tumor-to-organ selectivity, especially for melanoma and / or renal cell carcinoma. Radioactive payloads (e.g., 18 Fluorine)-containing compounds according to the invention preferably achieve a dose-dependent response, for example, where target saturation is reached between 500 pmol / g and 1000 pmol / g and / or is maintained for up to 12 hours, more preferably 1 to 9 hours, even more preferably 1 to 3 hours after intravenous administration.

[0020] PET imaging is one of the preferred applications of the compounds described herein.The affinity, lipophilicity and stability of the compound to FAP may be one of the relevant factors that determine the suitability of SMRC for such applications.For example, PET and gamma count-based biodistribution can be used to determine tracer kinetics and uptake.Without wishing to be bound by theory, the compounds described herein are believed to exhibit favorable biodistribution and kinetics with high and reliable uptake in cancer tissue, which is believed to be due to the combination of moiety A with very high FAP binding affinity, special linking group B, and radioactive therapeutic or diagnostic moiety C.

[0021] The present invention provides a compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein the compound structure has the following structure:

[0022] [ka]

[0023] The compound includes a moiety A represented by or containing: A is a binding moiety (i.e., a moiety that binds to the FAP) that is covalently linked via moiety B to one or more diagnostic or therapeutic moieties C (i.e., a payload such as a radioactive group including a radionuclide).

[0024] B has the following structure:

[0025] [ka]

[0026] It can be expressed by In the formula, each b 1 and b 3 is independently an integer from 0 to 4, preferably 0 or 1; each b 2is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; Each B 2 is, independently,

[0027] [ka]

[0028] wherein: Y and Z are carbocyclic or heterocyclic groups, preferably C 3~13 Carbocyclic group or C 2~12 A linking group that forms part of a heterocyclic group where all valences are satisfied. *-Y preferably represents *-C, *-CR, *-N, *-NR, *-NRC(O)C, *-NRC(O)CR, *-NRC(O)CR2C, *-NRC(O)CR2CR, *-NRC(S)NRC, *-NRC(S)NRCR, *-NRC, *-NRCR, *-NRCR2C, or *-NRCR2CR; Z-· preferably represents C-·, CR-·, N-·, NR-·, CC(O)NRCRC(O)NR-·, CCR2C(O)NR-·, CRCR2C(O)NR-·, CNRC(S)NR-·, NRC(S)CRNR-·, CNR-·, CRNR-·, CCR2NR-·, or CRCR2NR-·; Each * represents an attachment point that is closer to part A than to part C; each · represents an attachment point that is closer to part C than to part A.

[0029] Each B 3 are independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene containing one or more heteroatoms selected from N and O; preferably a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene. B 2and C preferably contains no more than 10 covalently connected atoms or is a bond, more preferably no more than 7, and most preferably no more than 6 covalently connected atoms.

[0030] B 1 , B 2 and B. 3 each is independently optionally substituted with one or more of R. Each R is H, OH, SH, NH2, halogen, cyano, oxo, carboxy, C(O)NH2C 1~6 Alkyl, C 1~6 Alkoxy, C(O)C 1~6 Alkyl, C 1~6 Alkylthio, C 1~5 Heteroalkyl, C 1~5 Heteroalkoxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkoxy, C 6~10 Aryl, C 6~10 Aryloxy, C 5~10 Heteroaryl and C 5~10 heteroaryloxy, among which SH, NH2, C(O)NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C(O)C 1~6 Alkyl, C 1~6 Alkylthio, C 1~5 Heteroalkyl, C 1~5 Heteroalkoxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkoxy, C 6~10 Aryl, C 6~10 Aryloxy, C 5~10 Heteroaryl and C 5~10 Heteroaryloxy is OH, SH, NH2, halogen, cyano, oxo, carboxy, C 1~6 Alkyl, C 1~5 Heteroalkyl, C 3~6 Cycloalkyl, C 6~10 Aryl and C 5~10One or more of the heteroaryls may be optionally substituted, and two or more of R may be joined together to form a portion of a carbocyclic or heterocyclic ring system.

[0031] The compounds according to the invention have formula I:

[0032] [ka]

[0033] It can be expressed as: Thus, B is a moiety that contains a covalent bond or a chain of atoms that covalently attaches A to C. C is a therapeutic or diagnostic agent, which may be, for example, an atom, molecule, particle, or radionuclide. Part A Without wishing to be bound by any theory, it is contemplated that some of the beneficial technical effects achieved by the compounds of the present invention are related to the particular structure of the linking moiety A, where the quinoline ring is substituted at the 8-position with a nitrogen-containing group, such as an amino or amide group:

[0034] [ka]

[0035] It has previously been shown that higher target protein affinity of a compound results in longer tumor retention in vivo (Wichert et al., Nature Chemistry 7, 241-249 (2015)). It is also believed that the compounds of the present invention have increased affinity, slower dissociation rates for FAPs when compared to prior art compounds, and therefore have extended retention at disease sites at therapeutically or diagnostically relevant levels, preferably for more than 1 hour, more preferably for more than 6 hours after injection. Preferably, highest enrichment is achieved after 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours; and / or enrichment at disease sites is maintained at therapeutically or diagnostically relevant levels for or at least for a period of 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours after injection, more preferably for more than 6 hours. The radioactive payload (e.g., 18 Fluorine)-containing compounds according to the present invention can achieve a dose-dependent response, for example, target saturation is reached between 500 pmol / g and 1000 pmol / g and / or maintained for up to 12 hours, more preferably 1 to 9 hours, and even more preferably 1 to 3 hours after intravenous administration.

[0036] Preferably, the binding moiety A has the following structure A 1 , A 2 Or A 3 wherein m is 0, 1, 2, 3, 4, or 5, preferably 1; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2:

[0037] [ka]

[0038] More preferably, moiety A has the structure A 2 and most preferably, where m is 1. Part B Moiety B is a moiety that comprises a covalent bond or a chain of atoms that covalently attaches A to payload C, ie, via one or more covalent bonds.

[0039] Moiety B links one or more payload and / or binder moieties to form the targeting conjugates of the invention. In some embodiments, the structure of the compound includes one moiety A and more than one moiety C per molecule, for example, 2, 3, 4, 5, 6, 7, 8, 9 or 10 moieties C per molecule. In such embodiments, one moiety C can be attached to moiety B at the position indicated by · in any of the general formulas disclosed herein, and the remaining moieties C are attached as substituents at further positions on moiety B.

[0040] Moiety B has the following structure:

[0041] [ka]

[0042] It can be expressed by In the formula, each b 1 and b 3 is independently an integer from 0 to 4, preferably 0 or 1; each b 2 is independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; Each B 2 is, independently,

[0043] [ka]

[0044] where Y and Z are linking groups forming part of a carbocyclic or heterocyclic group; Each * represents an attachment point closer to part A than to part C; Each · represents an attachment point that is closer to part C than to part A; Each B 1 is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, wherein said heteroalkylene contains one or more heteroatoms selected from N and O; Each B 3 is independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, wherein said heteroalkylene contains one or more heteroatoms selected from N and O; B 1 , B 2 and B. 3 each of which is independently optionally substituted with one or more R; Each R is H, OH, SH, NH2, halogen, cyano, oxo, carboxy, C(O)NH2C 1~6 Alkyl, C 1~6 Alkoxy, C(O)C 1~6 Alkyl, C 1~6 Alkylthio, C 1~5 Heteroalkyl, C 1~5 Heteroalkoxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkoxy, C 6~10 Aryl, C 6~10 Aryloxy, C 5~10 Heteroaryl and C 5~10 heteroaryloxy, among which SH, NH2, C(O)NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C(O)C 1~6 Alkyl, C 1~6 Alkylthio, C 1~5 Heteroalkyl, C 1~5 Heteroalkoxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkoxy, C 6~10 Aryl, C 6~10 Aryloxy, C5~10 Heteroaryl and C 5~10 Heteroaryloxy is OH, SH, NH2, halogen, cyano, oxo, carboxy, C 1~6 Alkyl, C 1~5 Heteroalkyl, C 3~6 Cycloalkyl, C 6~10 Aryl and C 5~10 optionally substituted with one or more of heteroaryl, and two or more of R can be joined together to form a portion of a carbocyclic or heterocyclic ring system; All valences are satisfied.

[0045] In any of the embodiments described therein, * represents a point of attachment to moiety A, or a point of attachment where the shortest path to moiety A contains fewer atoms than for ·, as the case may be; · represents a point of attachment to moiety C, or a point of attachment where the shortest path to moiety C contains fewer atoms than for ·, as the case may be * represents a point of attachment to a moiety C that contains fewer atoms than for the moiety C. The following symbols and all have the meaning of the point of attachment of a particular group or atom (e.g., R) to a further moiety:

[0046] [ka]

[0047] Each B 1 are independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, wherein said heteroalkylene contains one or more heteroatoms selected from N and O; preferably a bond, alkylene, or heteroalkylene, wherein said heteroalkylene contains one or more heteroatoms selected from N and O. A and B 2 The shortest path between preferably contains 6 or fewer covalently connected atoms or is a bond, more preferably 3 or fewer, and most preferably 2 or fewer covalently connected atoms.

[0048] In a preferred embodiment, b 1 is 0 or 1;b 2 is 1;b 3 is 1; z is 1. Preferably, B 1 is a bond, alkylene or heteroalkylene, said heteroalkylene containing one or more heteroatoms selected from N and O.

[0049] Preferably, A and B 2 Preferably, the shortest path between contains 6 or fewer covalently connected atoms or is a bond, more preferably 3 or fewer, and most preferably 2 or fewer covalently connected atoms.

[0050] Preferably, B 3 is a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene; 2 and C preferably contains no more than 10 covalently connected atoms or is a bond, more preferably no more than 7, and most preferably no more than 6 covalently connected atoms.

[0051] Preferably,

[0052] [ka]

[0053] is C 3~13 Carbocyclic group or C 2~12 It is a heterocyclic group. Preferably, *-Y represents *-C, *-CR, *-N, *-NR, *-NRC(O)C, *-NRC(O)CR, *-NRC(O)CR2C, *-NRC(O)CR2CR, *-NRC(S)NRC, *-NRC(S)NRCR, *-NRC, *-NRCR, *-NRCR2C, or *-NRCR2CR; Z-· represents C-·, CR-·, N-·, NR-·, CC(O)NRCRC(O)NR-·, CCR2C(O)NR-·, CRCR2C(O)NR-·, CNRC(S)NR-·, NRC(S)CRNR-·, CNR-·, CRNR-·, CCR2NR-·, or CRCR2NR-·.

[0054] In a preferred embodiment, each B 1 is a bond; C 1~10 , preferably C 1~4 , more preferably C 1~2 Alkylene; C containing 1 or 2 N atoms 1~10 , preferably C 1~4、 More preferably, C 1~2 Heteroalkylene group; NR(C 1~10 , C 1~4 , or C 1~2 (alkylene)NR;(C 1~10 , C 1~4 , or C 1~2 alkylene)NR;NR(C 1~10 , C 1~4 , or C 1~2 alkylene;C(O);C(O)CR2;C(O)(C 6~10 aryl)CR2;C(O)(C 1~10 alkylene)C(O);C(O)(C 1~10 alkyl)C(O)NR;C(O)(C 5~10 Heteroaryl)CR2;C(O)(C 6~10 aryl)CR2;C(O)(C 5~10 Heteroaryl)CR2;C(S)NR;C(S)NR(C 6~10 aryl)CR2; and C(S)NR(C 5~10 heteroaryl)CR2.

[0055] More preferably, B 1 is a bond, C(O)CH2CH2C(O), NHCH2CH2NH, CH2CH2NH, NHCH2CH2,

[0056] [ka]

[0057] and; Most preferably, it is a bond or NHCH2CH2NH. In a preferred embodiment, each B 3 is a bond; C 1~10 , preferably C 1~4、 More preferably, C 1~2 Alkylene; C containing 1 or 2 N atoms 1~10 , preferably C 1~4、 More preferably, C 1~2 Heteroalkylene group; NR(C 1~10 , C 1~4 , or C 1~2 (alkylene)NR;(C 1~10 , C 1~4 , or C 1~2 alkylene)NR;NR(C 1~10 , C 1~4 , or C 1~2 alkylene;C(O);C(O)CR2;C(O)(C 6~10 aryl)CR2;C(O)(C 5~10 Heteroaryl)CR2;C(O)(C 6~10 aryl)CR2;C(O)(C 5~10 Heteroaryl)CR2;C(O)(C 6~10 aryl)CR2;C(O)(C 5~10 Heteroaryl)CR2;C(S)NR;C(S)NR(C 6~10 aryl)CR2; and C(S)NR(C 5~10 heteroaryl)CR2.

[0058] More preferably, B 3 is a bond, C(O)CH2CH2C(O), NHCH2CH2NH, CH2CH2NH, NHCH2CH2,

[0059] [ka]

[0060] and; Most preferably a bond,

[0061] [ka]

[0062] It is. In a preferred embodiment, moiety A has the structure A 2 m is 1; b 1 is 0 or 1;b 2 is 1;b 3 is 1; z is 1; each of s, u, t and v, if present, is 1, and w is 0 or 1.

[0063] In one embodiment, B 2 are independently selected from:

[0064] [ka]

[0065] During the ceremony, each s, u, t and v is independently 0, 1, or 2; each w is independently 0, 1, 2, or 3; Each X is independently N, NH, NR, S, S(O), SO2, O, C, CR, CH, CR2, or CH2; preferably N.

[0066] In a preferred embodiment, each of s, u, t and v, if present, is 1; and w is 0 or 1. In a preferred embodiment, B 2 is selected from:

[0067] [ka]

[0068] In a more preferred embodiment, B 2 is selected from:

[0069] [ka]

[0070] In the most preferred embodiment, B 2 is selected from:

[0071] [ka]

[0072] In one particular embodiment, B 2 teeth,

[0073] [ka]

[0074] and more preferably

[0075] [ka]

[0076] and most preferably

[0077] [ka]

[0078] It is. In another particular embodiment, B 2 teeth,

[0079] [ka]

[0080] and more preferably

[0081] [ka]

[0082] and most preferably

[0083] [ka]

[0084] It is. In another particular embodiment, B 2 teeth,

[0085] [ka]

[0086] and more preferably

[0087] [ka]

[0088] and most preferably

[0089] [ka]

[0090] It is. In another particular embodiment, B 2 teeth,

[0091] [ka]

[0092] and more preferably

[0093] [ka]

[0094] and most preferably

[0095] [ka]

[0096] It is. In another particular embodiment, B 2 teeth,

[0097] [ka]

[0098] and more preferably

[0099] [ka]

[0100] and most preferably

[0101] [ka]

[0102] It is. In another particular embodiment, B 2 teeth,

[0103] [ka]

[0104] and more preferably

[0105] [ka]

[0106] and most preferably

[0107] [ka]

[0108] It is. Moiety B preferably comprises, more preferably consists of, units from the following list:

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] [ka]

[0119] Part C The moiety C represents in the present invention a payload, which may generally be any atom (including H), molecule or particle, capable of functioning as a therapeutic or diagnostic agent. Preferably, the moiety C is not a hydrogen atom and may be selected from: a chelator group suitable for radiolabeling; a radioactive group comprising a radioisotope; a chelate of a radioisotope with a chelator; a fluorophore group; a cytotoxic and / or cytostatic agent; an immunomodulatory agent; or a protein.

[0120] The payload moiety C may comprise or consist of a chelator for radiolabelling. The payload part C is 223 Ra, 89 Sr, 94m Tc, 99m Tc, 186 Re, 188 Re, 203 Pb, 66 Ga 67 Ga, 68 Ga, 43 Sc, 44 Sc 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu, 86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 117mSn and 169 The radioactive group may comprise or consist of a radioisotope, including an isotope such as E. Preferably, in a preferred embodiment, the radioisotope is 68 Ga 62 Cu, 64 Cu, 111 In, 18 It's F.

[0121] In a preferred embodiment, 18 F is bonded to a cation; more preferably, the cation is aluminum (Al) in any of its oxidation states. The payload may be a chelate of an isotope, preferably a radioisotope, as listed below.

[0122] Particularly preferred embodiments of the moiety C as well as of the compounds according to the invention are set out in the appended claims. Suitable chelating groups for radiolabeling include 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), 2,2',2''-(1,4,7-triazonane-1,4-diyl)diacetic acid (NODA), 2,2'-((2-((4-(2-amino-2-oxoethyl)benzyl)(carboxymethyl)amino)cyclohexyl)azanediyl)diacetic acid) (RESCA), sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecaacetic acid, and the like. [2,2',2''-(10-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-GA), [1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

[0123] The chelating group has the following formula C 1 , C2 , C 3 , C 4 , and C 5 :

[0124] [ka]

[0125] and During the ceremony: Each q is independently 0, 1, 2, 3, 4, or 5; preferably 0; R 1e , R 1f , R 1g , R 1h and R 1i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 2e , R 2f , R 2g , R 2h and R 2i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 3e , R 3f , R 3g , R 3h , R 4h and R 3i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 4e is independently H, COOH, aryl-COOH, or heteroaryl-COOH, provided that when q is 0, R 4e is H; Each X is independently NH, NR, S, O, CR2, or H,H; preferably O; each Q is N or O, preferably N; where Q is O, then CHR 2e , CH2R 2f , CH2R 2g , CH2R 2hand CH2R 2i does not exist; L is -CHC(O)- or -NHC(S)-.

[0126] In a preferred embodiment, q is 0 and R 1e , R 1f , R 1g , R 1h , R 1i , R 2e , R 2f , R 2g , R 2h , and R 2i are each independently COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 3e , R 3f , R 3g , R 3h , R 4h and R 3i are each independently H, COOH, aryl-COOH or heteroaryl-COOH; preferably COOH; R 4e is H; Q is N.

[0127] The chelating group may be any of the following:

[0128] [ka]

[0129] It may have a structure selected from: The radioactive group is generally 223 Ra, 89 Sr, 94m Tc, 99m Tc, 186 Re, 188 Re, 203 Pb, 67 Ga, 68 Ga, 47 Sc, 111 In, 97 Ru, 62 Cu, 64 Cu,86 Y, 88 Y, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu, 123 I, 124 I, 125 I, 131 I, 18 F, 211 At, 225 Ac, 89 Sr, 117m Sn and 169 The radioisotope may include Er.

[0130] Radioactive groups useful in the present invention, for example, chelate complexes with one or more of the chelators described herein, 18 F, when present, is preferably bound to chelated Al, Zr, Si, Ga, or In, more preferably 18 F is bound to the chelated Al by the chelator. In the context of the present disclosure, further contemplated are complexes of the chelators described herein, in which F is present and is preferably bound to chelated Al, Zr, Si, Ga, or In, in which F is any isotope of fluorine, e.g., 18 F and / or 19 It may contain F.

[0131] Particularly useful diagnostic or therapeutic agents C for use in the present invention are chelates of the radioisotopes listed below with any of the chelating agents listed under (a) above.

[0132] Alternatively, the diagnostic or therapeutic agent C may have the following structure containing a covalently bound radioactive nuclide:

[0133] [ka]

[0134] is a group selected from any one of wherein X is as further defined above and can be, for example, N, S, S(O), SO2, O, CR, CH; preferably CH or N.

[0135] For example, a preferred structure containing a covalently bound radioactive nuclide is

[0136] [ka]

[0137] It is. In the context of the present disclosure, any isotope of F or I, in each case 18 F, 123 I, 124 I, 125 I or 131 Compounds which may be present in place of I are also contemplated.

[0138] Most preferably, moiety C is a chelator selected from:

[0139] [ka]

[0140] More preferably, wherein 18 F is bound to Al which is chelated by a chelator. These chelators are derived from:

[0141] [ka]

[0142] Without wishing to be bound by theory, these chelators and their Al-F complexes appear to be particularly advantageous in terms of active labeling, stability, especially with respect to chemical and radiolytic stability and stability.

[0143] Preferred compounds are those listed in the accompanying claims, in particular claim 14, as well as ions or radionuclides as listed above, e.g. AlF (e.g. Al bound 18 F and / or 19 F), or Ga (e.g., in any oxidation state 67 Ga and / or 68 Particularly preferred compounds are 1 and its AlF complex AlF@1, which is 18 F and / or 19 F, more preferably bonded to Al 18 It may contain F.

[0144] [ka]

[0145] Alternatively, moiety C may be a fluorophore group. Preferably, the fluorophore group is selected from xanthene dyes, acridine dyes, oxazine dyes, cyanine dyes, styryl dyes, coumarin dyes, porphine dyes, fluorescent metal-ligand complexes, fluorescent proteins, nanocrystals, perylene dyes, boron-dipyrromethene dyes and phthalocyanine dyes. Preferred structures may be selected from:

[0146] [ka]

[0147] Alternatively, moiety C may be a cytotoxic and / or cytostatic agent, such as a chemotherapeutic agent. Preferably, such therapeutic agents are selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, antibiotics, mitotic disruptors, DNA intercalating agents, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins, epidermal growth factor inhibitors, antivascular agents, and combinations of two or more thereof.

[0148] Such agents can inhibit or prevent the function of cells and / or cause the destruction of cells. Examples of cytotoxic agents include radioisotopes, chemotherapeutic agents, and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogs and derivatives thereof. The cytotoxic agent can be selected from the group consisting of auristatins, DNA minor groove binders, DNA minor groove alkylating agents, enediynes, lexitropsins, duocarmycins, taxanes, puromycins, dolastatins, maytansinoids and vinca alkaloids, or combinations of two or more thereof. Preferred cytotoxic and / or cytostatic payload moieties are listed in claim 8(e).

[0149] In one embodiment, the payload is a topoisomerase inhibitor, an alkylating agent (e.g., nitrogen mustards; ethylenimines; alkylsulfonates; triazenes; piperazines; and nitrosoureas), antimetabolites (e.g., mercaptopurine, thioguanine, 5-fluorouracil), an antibiotic (e.g., anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin, dactinomycin), a mitotic disruptor (e.g., a plant alkaloid - e.g., vincristine and / or a microtubule antagonist - e.g., paclitaxel), a DNA methylating agent, a DNA intercalating agent (e.g., For example, the chemotherapeutic agent is selected from the group consisting of carboplatin and / or cisplatin, daunomycin and / or doxorubicin and / or bleomycin and / or thalidomide), DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators, hormone response modifiers, hypoxia-selective cytotoxins (e.g., tirapazamine), epidermal growth factor inhibitors, antivascular agents (e.g., xanthenone 5,6-dimethylxanthenone-4-acetic acid), radiation-activated prodrugs (e.g., nitroarylmethyl quaternary (NMQ) salts) or bioreductive drugs, or a combination of two or more thereof. In some embodiments, the payload (i.e., moiety C) is not derived from an anthracycline, and preferably is not derived from PNU 159682.

[0150] The chemotherapeutic agent is selected from the group consisting of erlotinib (TARCEVA®), bortezomib (VELCADE®), fulvestrant (FASLODEX®), Sutent (SU11248), letrozole (FEMARA®), imatinib mesylate (GLEEVEC®), PTK787 / ZK222584, oxaliplatin (Eloxatin®), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®), lapatinib (GSK572016), lonafarnib (SCH 66336), sorafenib (BAY43-9006) and gefitinib (IRESSA®), AG1478, AG1571 (SU 5271; Sugen), or a combination of two or more thereof.

[0151] Chemotherapeutic agents include alkylating agents, such as thiotepa, CYTOXAN®, and / or cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and / or piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and / or uredopa; ethyleneimines and / or methylamelanamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and / or trimethylomelanamine; acetogenins, such as bullatacin. and / or blatacinone; camptothecin; bryostatin; kallistatin; cryptophycin; dolastatin; duocarmycin; erytherobin; pancratistatin; sarcodictin; spongistatin; nitrogen mustards - e.g., chlorambucil, chlornaphazine, clophosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquine, phenesterine, prednimustine, trofosfamide and / or uracil mustard; nitroso Ureas - e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine and / or ranimustine; dynemycin; bisphosphonates - e.g., clodronate; esperamicin; neocarzinostatin chromophore; aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN ( Registered trademark), doxorubicin - for example morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and / or deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin - for example mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;Anti-metabolites - e.g., methotrexate and 5-fluorouracil (5-FU); folic acid analogues - e.g., denopterin, methotrexate, pteropterin, trimetrexate; purine analogues - e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues - e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxiridine; androgens - for example, calcineurone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal drugs - for example, aminoglutethimide, mitotane, trilostane; folic acid supplements - for example, folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravucil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; eflornithine; elliptinium acetate; epothymidine Lon;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Macrocyclic depsipeptides, e.g., maytansine and ansamitocin;Mitoguazone;Mitoxantrone;Mopidammol;Nitraerin;Pentostatin;Phenamet;Pirarubicin;Losoxantrone;Podophyllic acid;2-Ethylhydrazide;Procarbazine;Razoxane;Rhizoxin;Sizofiran;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2''-Tri Chlorotriethylamine; Trichothecenes - e.g., Veracrine A, Roridin A and / or Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside; Cyclophosphamide; Thiotepa; Taxoids - e.g., TAXOL®, Paclitaxel, Abraxane, and / or TAXOTERE®, Doxetaxel; Chlorambucil; GEMZAR®. Gemcitabine; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs - e.g., Cisplatin and Carboplatin; Vinblastine; Platinum; Etoposide; Ifosfamide; Mitoxantrone; Vincristine; NAVELBINE®, Vinorelbine; Novantrone; Teniposide;edatrexate; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and pharma- ceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above.

[0152] The payload may be a tubulin disrupting agent, including but not limited to: taxanes - e.g., paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilone A and B, desoxyepothilones, cryptophycin, curacin A, combretastatin A-4-phosphate, BMS 247550, BMS 184476, BMS 188791; LEP, RPR 109881A, EPO 906, TXD 258, ZD 6126, vinflunine, LU 103793, dolastatin 10, E7010, T138067 and T900607, colchicine, phenstatin, chalcone, indanocine, T138067, oncocidin, vincristine, vinblastine, vinorelbine, vinflunine, halichondrin B, isohohohalichondrin B, ER-86526, pironetin, spongistatin 1, spiket P, cryptophycin 1, LU103793 (cematodin or cemadotin), rhizoxin, sarcodictine, erytherobin, laulimalide, VP-16 and D-24851 and pharma- ceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

[0153] The payload may be a DNA intercalator, including, but not limited to, acridine, actinomycin, anthracycline, benzothiopyranoindazole, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cisplatin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan, and topotecan, as well as pharmaceutically acceptable salts, acids, derivatives, or combinations of two or more of any of the above.

[0154] The payload may be an anti-estrogen and selective estrogen receptor modulator, including anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as, but not limited to, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyphene, keoxifene, LY117018, onapristone and / or phareston toremifene, and pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above. The payload may be an aromatase inhibitor that inhibits the enzyme aromatase that regulates estrogen production in the adrenal gland, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, AROMASIN®. Exemestane, formestane, fadrozole, RIVISOR®, vorozole, FEMARA®, letrozole, and ARIMIDEX®, and / or anastrozole, and pharmaceutically acceptable salts, acids, derivatives, or combinations of any two or more of the above.

[0155] The payload may be an antiandrogen, such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and / or troxacitabine, as well as pharma- ceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above.

[0156] In a preferred embodiment, moiety C is an auristatin (i.e., having a structure derived from a member of the auristatin compound family) or an auristatin derivative. More preferably, moiety C has a structure according to the following formula:

[0157] [ka]

[0158] During the ceremony: R 1d are independently H or C1-C6 alkyl; preferably H or CH3; R 2d are independently C1-C6 alkyl; preferably CH3 or iPr; R 3d are independently H or C1-C6 alkyl; preferably H or CH3; R 4d are independently H, C1-C6 alkyl, COO(C1-C6 alkyl), CON(H or C1-C6 alkyl), C3-C 10 Aryl or C3-C 10 Heteroaryl; preferably H, CH3, COOH, COOCH3 or thiazolyl; R 5d are independently H, OH, C1-C6 alkyl; preferably H or OH; R 6d are independent, C3~C 10 Aryl or C3-C 10 Heteroaryl; preferably optionally substituted phenyl or pyridyl.

[0159] In a further preferred embodiment, the moiety C is selected from the following structures:

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] Alternatively, moiety C may be an immunomodulatory agent, preferably selected from molecules known to be able to modulate the immune system, such as ligands of CD3, CD25, TLRs, STING, 4-1BBL, 4-1BB, PD-1, mTor, PDL-1, NKG-2D IMiD, where the ligands may be agonists and / or antagonists.

[0165] Alternatively, moiety C may be a protein or an antibody. Preferably, the payload is a cytokine (e.g., an interleukin such as IL2, IL10, IL12, IL15; a member of the TNF superfamily; or an interferon such as interferon gamma).

[0166] Any payload can be used in unmodified or modified form. A combination of some unmodified and some modified payloads can be used.For example, payload can be chemically modified.One form of chemical modification is the derivatization of carbonyl group--e.g., aldehyde. treatment The compounds described herein can be used to treat disease. Treatment can be therapeutic and / or prophylactic, aiming to prevent, reduce or stop undesirable physiological changes or disorders. Treatment can prolong survival when compared to expected survival without treatment.

[0167] The disease treated by the compounds may be any disease that may benefit from treatment, including chronic and acute disorders or diseases, including conditions that predispose to the disorder.

[0168] The terms "cancer" and "cancerous" are used in their broadest sense to refer to the physiological condition in mammals that is typically characterized by unregulated cell growth. A tumor contains one or more cancerous cells.

[0169] When treating cancer, the therapeutic effect observed may be a reduction in the number of cancer cells; a reduction in tumor size; inhibition or delay of cancer cell invasion into peripheral organs; inhibition of tumor growth; and / or alleviation of one or more symptoms associated with cancer.

[0170] In animal models, efficacy can be determined by physical measurement of the tumor during treatment and / or by determining partial and complete remission of the cancer. For cancer therapy, efficacy can be measured, for example, by determining the time to disease progression (TTP) and / or by determining the response rate (RR).

[0171] Particularly preferred embodiments of the methods of treatment related to the invention are set out in the accompanying claims. Disclosed herein furthermore is a method of treatment, for example, by surgery or therapy, or a diagnostic method carried out on the human or animal body, which involves administering a therapeutically or diagnostically effective amount of the compound or pharmaceutical composition described herein to a subject in need thereof.More specifically, disclosed herein is a method of treatment, for example, by therapy or prevention, of a subject suffering from or at risk of disease or disorder; or a method of guided surgical treatment carried out on a subject suffering from or at risk of disease or disorder; a method of diagnosis of disease or disorder, for example, carried out on the human or animal body and / or involving nuclear medicine imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); a method of targeted delivery of therapeutic or diagnostic agents to a subject suffering from or at risk of disease or disorder. In the above-mentioned method, the disease or disorder can be independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorder, and preferably, the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multidrug-resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct adenocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, tumor-induced osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, skin cancer, kidney cancer and prostate cancer.When used in the methods disclosed herein, the compound has a prolonged residence at the disease site at a therapeutically or diagnostically relevant level, preferably more than 1 hour after injection, more preferably more than 6 hours. Pharmaceutical Compositions Also disclosed is a pharmaceutical composition comprising a compound according to any of the preceding embodiments and a pharma- ceutically acceptable excipient. Such pharmaceutical composition is further disclosed for use in (a) a method for the treatment of the human or animal body by surgery or therapy, or a diagnostic method performed on the human or animal body; or (b) a method for the treatment or prophylaxis of a subject suffering from or at risk of a disease or disorder; or (c) a method for guided surgery performed on a subject suffering from or at risk of a disease or disorder; or (d) a method for the diagnosis of a disease or disorder performed on the human or animal body and involving a nuclear medicine imaging technique, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); or (e) a method for targeted delivery of a therapeutic or diagnostic agent to a subject suffering from or at risk of a disease or disorder, wherein in each of (b)-(e) above, wherein the disease or disorder is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling and keloid disorders, preferably wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multidrug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct adenocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, tumor-induced osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer and prostate cancer; preferably wherein the compound has an extended residence at the disease site at therapeutically or diagnostically relevant levels, preferably for more than 1 hour, more preferably for more than 6 hours after injection.

[0172] The compounds described herein may be in the form of pharmaceutical compositions that may be for human or animal use in human and veterinary medicine, typically comprising any one or more of pharmaceutically acceptable diluents, carriers or excipients.Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro, ed. 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with respect to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions can comprise, as - or in addition to - carriers, excipients or diluents, any suitable binders, lubricants, suspending agents, coating agents, solubilizers.

[0173] Preservatives, stabilizers, dyes and even flavorings can be provided in the pharmaceutical composition.Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.Antioxidants and suspending agents can also be used.

[0174] There are different composition / formulation requirements depending on different delivery systems.For example, pharmaceutical compositions can be formulated to be administered using mini-pumps, or can be formulated to be administered by mucosal routes, for example as nasal sprays or aerosols for inhalation or orally ingestible solutions, or can be formulated to be administered parenterally, where the compositions are formulated in injectable form for delivery by intravenous, intramuscular or subcutaneous routes.Alternatively, formulations can be designed to be administered by multiple routes.

[0175] If the agent is administered mucosally, via the gastrointestinal mucosa, it should be able to remain stable during transit through the gastrointestinal tract; for example, it should be resistant to proteolysis, stable at acid pH, and resistant to the detergent effects of bile.

[0176] Where appropriate, the pharmaceutical composition can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by using a skin patch, in the form of a tablet containing excipients such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of an elixir, solution or suspension containing flavoring or coloring agents, or the pharmaceutical composition can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.For parenteral administration, the composition can be best used in the form of a sterile aqueous solution, which can contain other substances, for example, sufficient salts or monosaccharides, to make the solution isotonic with blood.For buccal or sublingual administration, the composition can be administered in the form of a tablet or lozenge, which can be formulated in a conventional manner.

[0177] The compound of the present invention can be administered in the form of pharmaceutically acceptable salt or active salt.Pharmaceutically acceptable salt is well known to those skilled in the art, and includes, for example, those described by Berge et al. in J.Pharm.Sci., 66, 1-19 (1977). Salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0178] Routes for administration (delivery) can include, but are not limited to, one or more of oral (e.g., as a tablet, capsule, or as an orally ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., via an injectable form), gastrointestinal, intrathecal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, intravaginal, epidural, and sublingual.

[0179] Typically, a physician will determine the actual dosage that will be most appropriate for an individual subject. The specific dose level and frequency of administration for any particular patient can vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual being treated.

[0180] The formulations can be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water, for administration. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the type previously described. Illustrative unit dosage formulations contain a daily dose or a unit sub-dose of the active ingredient, or an appropriate fraction thereof. chemical synthesis The compounds described herein can be prepared by chemical synthesis techniques.

[0181] It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during the synthesis of the compounds. This can be accomplished by conventional techniques, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons Inc. (1991), and in "Protecting Groups" by PJ Kocienski, Georg Thieme Verlag (1994).

[0182] It is possible that in some reactions any stereocenters present may be epimerized under certain conditions, for example if a base is used in the reaction with a substrate having an optical center containing a base-sensitive group. As is well known in the art, it should be possible to avoid such potential problems by choice of reaction sequence, conditions, reagents, protection / deprotection regimes, etc. definition Derivatives. Derivatives include chemical modifications of compounds. Examples of such modifications include replacement of hydrogen with halo, alkyl, acyl or amino groups, etc. Modifications can increase or decrease one or more hydrogen bonding interactions, charge interactions, hydrophobic interactions, van der Waals interactions and / or dipole interactions.

[0183] Analogs. This term includes any enantiomers, racemates and stereoisomers, as well as all pharma- ceutically acceptable salts and hydrates of such compounds. Unless otherwise stated, the following definitions apply to chemical terms used in connection with the compounds of the present invention and compositions containing such compounds.

[0184] Alkyl refers to a branched or unbranched saturated hydrocarbyl group. Suitably, the alkyl group contains 1 to 100, preferably 3 to 30, more preferably 5 to 25 carbon atoms. Preferably, alkyl refers to methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0185] Alkenyl refers to a branched or unbranched hydrocarbyl group containing one or more carbon-carbon double bonds. Suitably, an alkenyl group contains from 2 to 30 carbon atoms, preferably from 5 to about 25 carbon atoms.

[0186] Alkynyl refers to a branched or unbranched hydrocarbyl group containing one or more carbon-carbon triple bonds. Suitably, the alkynyl group contains from about 3 to about 30 carbon atoms, for example, from about 5 to about 25 carbon atoms.

[0187] Halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Cycloalkyl refers to an alicyclic moiety having, suitably, 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. More frequently, the cycloalkyl group is monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, and the like.

[0188] Aryl refers to an aromatic carbocyclic ring system suitably containing 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl may be a polycyclic ring system having two or more rings, at least one of which is aromatic. The term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl, and the like.

[0189] The prefix "hetero" means that one or more of the carbon atoms of the group may be replaced by nitrogen, oxygen, phosphorus, silicon or sulfur, unless otherwise specified. Heteroalkyl groups include, for example, alkyloxy and alkylthio groups. A heterocycloalkyl or heteroaryl group herein can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulfur. In particular, the 3- to 10-membered ring or ring system, and more particularly the 5- or 6-membered ring, can be saturated or unsaturated. For example, oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, 1,3-dioxo-1,3-dihydro-isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, coumaryl, isopropyl ... and selected from dazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, [beta]-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl, 3,4-dihydro-2H-isoquinolin-1-one, 3,4-dihydro-2H-isoquinolinyl, and the like.

[0190] "Substituted" means that, unless otherwise specified, one or more, particularly up to 5, more particularly 1, 2 or 3 of the hydrogen atoms in said moiety are replaced independently of one another by a corresponding number of substituents. The term "optionally substituted" as used herein includes being substituted or unsubstituted. Of course, it is understood that the substituents are only in positions where they are chemically possible, and the skilled person can determine (either experimentally or theoretically) without undue effort whether a particular substitution is possible. For example, an amino group or a hydroxy group having a free hydrogen may be unstable if it is bound to a carbon atom with an unsaturated (e.g., olefinic) bond. Preferably, the term "substituted" means that one or more, particularly up to 5, more particularly 1, 2 or 3 of the hydrogen atoms in said moiety are replaced independently of one another by a corresponding number of substituents selected from OH, SH, NH2, halogen, cyano, carboxy, alkyl, cycloalkyl, aryl and heteroaryl. Additionally, the substituents described herein may themselves be substituted with any substituent, subject to the aforementioned limitations on suitable substitution recognized by those of skill in the art. Preferably, any of the aforementioned substituents may be further substituted with any of the aforementioned substituents, each of which may be further substituted with any of the aforementioned substituents.

[0191] The substituents may suitably include halogen atoms and halomethyl groups, such as CF3 and CCl3; oxygen-containing groups, such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen-containing groups, such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur-containing groups, such as thiol, alkylthiol, sulfonyl and sulfoxide; heterocyclic groups, which may themselves be substituted; alkyl groups, which may themselves be substituted; and aryl groups, such as phenyl and substituted phenyl, which may themselves be substituted. Alkyl includes substituted and unsubstituted benzyl.

[0192] More preferably, "substituted" is selected from the group consisting of OH, SH, NH, halogen, cyano, oxo, carboxy, C(O)NHC 1~6 Alkyl, C 1~6 Alkoxy, C(O)C 1~6 Alkyl, C 1~6 Alkylthio, C 1~5 Heteroalkyl, C 1~5 Heteroalkoxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkoxy, C 6~10 Aryl, C 6~10 Aryloxy, C 5~10 Heteroaryl and C 5~10 Heteroaryloxy means substitution with one or more groups selected from the group consisting of SH, NH2, C(O)NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C(O)C 1~6 Alkyl, C 1~6 Alkylthio, C 1~5 Heteroalkyl, C 1~5 Heteroalkoxy, C 3~6 Cycloalkyl, C 3~6 Cycloalkoxy, C 6~10 Aryl, C 6~10 Aryloxy, C 5~10 Heteroaryl and C 5~10Heteroaryloxy is OH, SH, NH2, halogen, cyano, oxo, carboxy, C 1~6 Alkyl, C 1~5 Heteroalkyl, C 3~6 Cycloalkyl, C 6~10 Aryl and C 5~10 and optionally substituted with one or more of the heteroaryl; two or more of the previously mentioned groups can be joined together to form a carbocyclic or heterocyclic ring system moiety.

[0193] When two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties can be the same or different, and the identity of each moiety is therefore independent of the identity of the other moiety or moieties. EXAMPLES

[0194] Materials & Methods Introduction and Procedures Yields refer to chromatographically purified compounds.

[0195] Mass spectrometry (LC-MS-UV) spectra were obtained on an Agilent 6100 Series Single Quadrupole MS System coupled to an Agilent 1200 Series LC System using an InfinityLab Poroshell 120 EC-C18 column, 4.6 mm × 56 mm, with a 0.8 mL min -1 A linear gradient of solvents A and B (A=Millipore water with 0.1% formic acid [FA], B=MeCN with 0.1% formic acid [FA]) was recorded at a flow rate of 100 rpm.

[0196] Nano HPLC-HR-MS: Chromatographic separation was performed on an Easy nanoLC 1000 (Thermo Scientific) using a gradient program from 95% A (0.1% FA), 5% B (ACN 0.1% FA) to 5% A, 95% B in 45 min on an Acclaim PepMap RSLC column (50 μm×15 cm, particle size 2 μm, pore size, 100 Å, Thermo Scientific). Sample cleanup and concentration were performed on a pre-column Acclaim PepMAP 100 (75 μm×2 cm, particle size 3 μm, pore size 100 Å; Thermo Scientific) attached to the system. The LC system was coupled to a Q-Exactive mass spectrometer (Thermo Fisher) via a Nano Flex ion source (Thermo Scientific). Ionization was performed at a spray voltage of 2 kV, a capillary temperature of 250° C., and a 60 S-lens RF level. Mass spectrometry was operated in single ion monitoring mode (SIM) according to the mass range reported in Table 1. The detector was operated in positive ion mode with the following parameters: resolution 70000 (FWHM at 400 m / z), AGC target 5 × 10 4 , and a maximum injection time of 200 ms. Data analysis was performed with Thermo Xcalibur Qual Broswer v2.2 (Thermo Scientific) and Prism8 (GrapPhad).

[0197] Preparative reversed-phase high pressure liquid chromatography (RP-HPLC) was performed on an Agilent 1200 Series System using a Phenomenex Gemini® 5 μm NX-C18 semi-preparative column, 110 Å, 150 mm × 10 mm, with 5 mL min. -1 The flow rate was 0.10 s with a linear gradient of solvents A and B (A=Millipore water with 0.1% trifluoroacetic acid [TFA], B=MeCN with 0.1% trifluoroacetic acid [TFA]).

[0198] Example 1: Preparation and labeling of "ESV6-NODAGA" synthesis Synthesis of intermediate I-1

[0199] [ka]

[0200] In a 25mL round bottom flask, 8-aminoquinoline-4-carboxylic acid (100mg, 0.531mmol, 1eq), (S)-1-(2-aminoacetyl)-4.4-difluoropyrrolidine-2-carbonitrile hydrochloride (132mg, 0.585mmol, 1.1eq) and HATU (202mg, 0.531mmol, 1eq) were suspended in 900μL DMF and 4mL DCM. DIPEA (371μL, 2.127mmol, 4eq) was added dropwise and the reaction was stirred until completion (checked via LC / MS using the method 90:10 water / acetonitrile 0.1% FA to 100% acetonitrile 0.1% FA in 3min, positive). The crude was diluted with DCM, washed with water, dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The dried crude was purified via CombiFlash Nextgen 300+ (parameters: flow rate 50 ml / min, 40 gr silica column, 100% DCM to 85:15 DCM / MeOH in 5 min) to give an amber oil (172 mg, 90% yield). MS(ESI+)m / z 360.1[M+H] + Synthesis of intermediate I-2

[0201] [ka]

[0202] In a 25 mL round bottom flask, intermediate A (48 mg, 0.134 mmol, 1 eq.), succinic anhydride (669 mg, 6.683 mmol, 50 eq.) and DMAP (8 mg, 0.067 mmol, 0.5 eq.) were dissolved in 3 mL of THF. The reaction was heated at 60° C. for 6 h and checked via LC / MS (method 3 min 90:10 water / acetonitrile 0.1% FA to 100% acetonitrile 0.1% FA, positive). The reaction was dried under vacuum, diluted with water, extracted with DCM, dried over Na2SO4, filtered and concentrated under vacuum. The dried crude was purified via CombiFlash Nextgen 300+ (parameters: flow rate 30 ml / min, 24 gr silica column, DMC / MeOH 90:10 to 70:30 in 4 min) to give an amber oil (58 mg, 95% yield). MS(ESI+)m / z 460.1[M+H] + (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (I-2) to ESV6-NODAGA

[0203] [ka]

[0204] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (15 mg, 0.032 mmol, 1.0 equiv.) was dissolved in dry DMSO (400 μL). Dicyclohexylcarbodiimide (9 mg, 0.042 mmol, 1.3 equiv.) and N-hydroxysuccinimide (4.5 mg, 0.039 mmol, 1.3 equiv.) were added and the reaction was stirred overnight at room temperature protected from light. A 100 μL solution of 2,2'-(7-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (16.2 mg, 0.039 mmol, 1.2 equiv.) in PBS was added and the reaction was stirred for 2 h. The crude product was purified by reverse phase HPLC (95:5 to 20:80 water / ACN + 0.1% TFA in 20 min) and lyophilized to give a white solid (21 mg, 75%). MS(ESI+)m / z 859.9[M+H] + Labeling: ESV6-NODAGA to ESV6-NODAGA-Al-F

[0205] [ka]

[0206] ESV6-NODAGA (1 mg, 1.16 μmol, 1 equiv) was dissolved in a mixture of DMSO (0.05 mL) and acetate buffer pH=4 (0.2 mL). AlF3 (1 mg, 11.6 μmol, 10 equiv) was added and the mixture was heated at 95° C. for 15 min. The mixture was then purified via RP-HPLC (95:5 to 0:100 water / ACN+0.1% TFA in 20 min) and the desired fractions were collected and lyophilized to give a white solid (0.8 mg, 80%). MS(ESI+)m / z 903.4[M+H] + Example 2: Preparation and labeling of "ESV6-NOTA" synthesis (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (I-2) to tert-butyl (S)-4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)piperazine-1-carboxylate (I-3)

[0207] [ka]

[0208] Intermediate I-2 (50 mg, 0.11 mmol, 1 equiv), N-Boc-piperazine (24 mg, 0.13 mmol, 1.2 equiv) and HATU (49 mg, 0.13 mmol, 1.2 equiv) were dissolved in DMF (1 mL). DIPEA (0.08 mL, 0.44 mmol, 4 equiv) was added dropwise and the mixture was stirred for 30 min at room temperature. The mixture was purified via RP flash chromatography (2:98 to 100:0 ACN / water + 0.1% HCOOH in 40 min). The desired fractions were collected and lyophilized to give a white solid (40 mg, 58%). MS(ESI+)m / z 627.9[M+H] + tert-Butyl (S)-4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)piperazine-1-carboxylate (I-3) to (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4-oxo-4-(piperazin-1-yl)butanamide)quinoline-4-carboxamide (I-4)

[0209] [ka]

[0210] Intermediate I-3 (40 mg, 0.06 mmol, 1 eq.) was dissolved in DCM (1 mL) and TFA (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 3 h, then the solvent was evaporated and the crude was purified via RP flash chromatography (ACN / water + 0.1% HCOOH from 2:98 to 100:0 in 40 min). The desired fractions were collected and lyophilized to give a colorless oil (17 mg, 51%). MS(ESI+)m / z 527.9[M+H] + (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-8-(4-oxo-4-(piperazin-1-yl)butanamide)quinoline-4-carboxamide (I-4) to (S)-2,2'-(7-(2-(4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)piperazin-1-yl)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (ESV6-NOTA; 1).

[0211] [ka]

[0212] Intermediate I-4 (8 mg, 0.02 mmol, 1 equiv) and NOTA-NHS (19 mg, 0.04 mmol, 2 equiv) were dissolved in DMF (0.2 mL). DIPEA (0.01 mL, 0.08 mmol, 4 equiv) was added to the mixture and stirred at room temperature for 1 h. The mixture was purified via RP-HPLC (water / ACN+0.1% TFA from 90:10 to 0:100 in 12 min). The desired fractions were collected and lyophilized to give a white solid (4 mg, 25%). MS(ESI+)m / z 812.7[M+H] + Labeling: ESV6-NOTA(1) to ESV6-NOTA-Al-F(AlF@1) (S)-2,2'-(7-(2-(4-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)piperazin-1-yl)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (1) to ESV6-NOTA-Al-F(AlF@1)

[0213] [ka]

[0214] Compound 1 (1 mg, 1.16 μmol, 1 equiv.) was dissolved in a mixture of DMSO (0.05 mL) and acetate buffer pH=4 (0.2 mL). AlF3 (1 mg, 11.6 μmol, 10 equiv.) was added and the mixture was heated at 95° C. for 15 min. The mixture was then purified via RP-HPLC (95:5 to 0:100 water / ACN+0.1% TFA in 20 min), and the desired fractions were collected and lyophilized to give a white solid (0.8 mg, 80%).

[0215] as an isotopically labeled building block for the synthesis of 1, following the same procedure described for ESV6-NODAGA-Al-F 13 Using C4 succinic anhydride, 13 C4-ESV6-NODAGA-Al-F was generated.

[0216] as an isotopically labeled building block for the synthesis of 1, following the same procedure described for ESV6-NOTA-Al-F 13 C4 succinic anhydride was used to generate 13C4-ESV6-NOTA-Al-F.

[0217] Example 3: Ex vivo characterization of "ESV6-NODAGA-Al-F" and "ESV6-NOTA-Al-F" All animal experiments were performed in accordance with the Swiss Animal Welfare Act and regulations under license number ZH06 / 2021 granted by the Veterinaramt des Kantons Zurich. Subcutaneous tumor implantation Tumor cells were grown to 80% confluence and detached with trypsin-EDTA 0.05%. SK-RC-52.hFAP, cells (FAP positive cells) were resuspended in Hanks' Balanced Salt Solution medium. 5 × 10 6 From 10×10 6 Aliquots of cells (100-150 μL suspension) were injected subcutaneously in the right or left flank of female athymic Balb / c AnNRj-Foxn1 mice (6-8 weeks old, Janvier). Ex vivo biodistribution experiments.

[0218] Mice bearing subcutaneous SK-RC-52.hFAP tumors were injected intravenously with ESV6-NODAGA-Al-F and ESV6-NOTA-Al-F (10 nmol dissolved in sterile PBS, pH 7.4). Animals were sacrificed 2 hours after intravenous injection, and organs and tumors were subsequently excised, snap frozen in situ, and stored at -80°C. Sample preparation Protein precipitation was induced by resuspending 50 mg of mouse tissue in 600 μL of a solution containing 95% ACN and 0.1% FA. In parallel, 50 μL of a solution containing 600 nM of the internal standard ( 13 C4-ESV6-NODAGA-Al-F or 13 C4-ESV6-NOTA-Al-F) was also added to the solution. The samples were then homogenized in a tissue dissolver (TissueLyser II, QIAGEN) for 15 min at 30 Hz. After homogenization, the samples were centrifuged at 14000g for 10 min and the supernatant was dried in a vacuum centrifuge at room temperature.

[0219] The sample was then resuspended in 1 mL of a solution containing 3% ACN and 0.1% TFA and subsequently cleaned using an Oasis HLB SPE column (Waters). The eluted sample was again dried under vacuum at room temperature, resuspended in 1 mL of 3% ACN and 0.1% TFA and cleaned using a Sep-Pak SPE column (Waters). The eluted sample was then dried under vacuum at room temperature.

[0220] The dried samples were finally resuspended in 30 μL of a solution containing 3% ACN and 0.1% FA. 3 μl of each sample (10% of the total) was then injected into the nanoLC-HR-MS system (as illustrated in FIG. 5). NanoLC-HR-MS analysis Chromatographic separation was performed on an Easy nanoLC 1000 on an Acclaim PepMap RSLC column (50 μm×15 cm, particle size 2 μm, pore size 100 Å) using a gradient program from 95% A (0.1% FA), 5% B (ACN 0.1% FA) to 5% A, 95% B in 45 min. Sample cleanup and concentration were performed on a pre-column Acclaim PepMAP 100 (75 μm×2 cm, particle size 3 μm, pore size 100 Å) attached to the system. The LC system was coupled to a Q-Exactive mass spectrometer via a Nano Flex ion source. Ionization was performed at a spray voltage of 2 kV, a capillary temperature of 250° C., and a 60 S-lens RF level. Mass spectrometry was operated in single ion monitoring mode (SIM) according to the mass ranges reported in Table 1. The detector was operated in positive ion mode with the following parameters: resolution 70000 (FWHM at 400 m / z), AGC target 5 × 10 4 , and a maximum injection time of 200 ms. Data analysis was performed with Thermo Xcalibur Qual Broswer v2.2 and Prism8.

[0221] [Table 1]

[0222] The results shown in FIG. 6 demonstrate a striking tumor-to-organ ratio for ESV6-NOTA-Al-F. Example 4: "ESV6-NOTA-[ 18 Quantitative in vivo biodistribution of [F]Al-F animal research All animal experiments were performed in accordance with the Swiss Animal Welfare Act and regulations under license number ZH06 / 2021 granted by the Veterinaramt des Kantons Zurich. Subcutaneous tumor implantation HT-1080.hFAP cells (FAP-positive tumor cells) were grown to 80% confluence in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic and detached with trypsin-EDTA 0.05%. Cells were resuspended in Hanks' Balanced Salt Solution medium. 5×10 6 An aliquot of cells (100 μL of suspension) was injected subcutaneously in the right flank of female athymic Balb / cAnNRj-Foxn1 mice (6-8 weeks old). Biodistribution studies in tumor-bearing mice Female athymic Balb / cAnNRj-Foxn1 mice (6 to 8 weeks old) implanted with HT-1080.hFAP tumors in the right flank as described above were cultured at 250 mm 3 The mice were randomized (n=5 per group) to receive ESV6-NOTA-[ 18 A radiolabeled preparation of [F]Al-F was injected intravenously (10 nmol / mouse; 77 KBq). Mice were euthanized 1 h after injection by CO2 asphyxiation. Organs were extracted, weighed, and radioactivity was measured in a gamma counter. Values ​​are expressed as percent ID / g ± SD. Results are reported in Figure 7. Radiolabeling of ESV6-NOTA The FASTlab 2 synthesis module and cassette were used to synthesize aluminum (Al 3+ ) via fluoride complexes, 18Radiolabeling of ESV6-NOTA (200-300 μg) with F was performed. During installation of the vials and reagents on the cassette, a 5 mL reactor vessel was pre-filled with 25 μL of 2 mM aluminum chloride (AlCl3, anhydrous, powder, 99.999% trace metals standard) in sodium acetate buffer (0.1 M, pH = 4.1). [ 18 [F]-fluoride was transferred to the module and placed on a Sep-Pak light Accel plus QMA cartridge (Cl - The cartridge was washed with 6 mL of water (HPCE grade). 18 [F]-fluoride was eluted from the QMA cartridge into the reactor vessel with 500 μL of elution solution (250 μL of NaCl 0.9%; 99.999% trace metals standard NaCl; in water for injection, and 250 μL of absolute ethanol). The solution was stirred for 5 min at room temperature under a gentle stream of nitrogen to obtain [ 18 F]AlF was formed. The precursor solution (600 μL of 350 μg / mL ESV6-NOTA in sodium acetate 0.1 M pH 4.5) was added to the reactor, which was sealed and heated at 95 °C for 10 min. The reactor was then cooled to 40 °C and the reaction mixture was diluted with 3.5 mL of NaCl 0.9% and passed through a pre-activated C18 cartridge, the C18 was washed with 5 mL of NaCl 0.9% and eluted with 1.5 mL of absolute EtOH. The final formulation was obtained by diluting the product with NaCl 0.9%. ESV6-NOTA-[ 18 The radiochemical purity for each batch of [F]Al-F was determined by radio-HPLC and is reported in Table 2.

[0223] [Table 2]

[0224] Example 5: 68 Ga]GaESV6-NODAGA and [ 68 Radiosynthesis of [Ga]GaESV6-NOTA In the FASTlab 2 synthesis module using the cassette, 68[Ga]GaESV6-NODAGA / NOTA (15–25 μg) was synthesized using an Eckert & Ziegler generator (1850 MBq, GalliaPharm) and eluted with HCl (4.5 ml, 0.1 M TRASIS ALLinONE Reagent Kit). 68 Ga(t 1 / 2 =68 minutes, β + = 89%, and EC = 11%). 68 [Ga]GaCl3 was transferred to the reactor vessel, the precursor dissolved in sodium acetate (750 μL, 0.7M TRASIS ALLinONE Reagent Kit) was aspirated into the reactor, and the solution was stirred for 5 min at room temperature under a gentle stream of nitrogen. The reaction mixture was then passed through a pre-activated C18 cartridge, washed with NaCl 0.9% (5 ml, TRASIS ALLinONE Reagent Kit), and eluted with elution solution (700 μL absolute ethanol and 800 μL water for injection). The final formulation was obtained by diluting the product with NaCl 0.9%. 68 The radiochemical purity for each batch of [Ga]GaESV6-NODAGA / NOTA was determined by radio-HPLC and is reported in Tables 3 and 4, respectively.

[0225] [Table 3]

[0226] [Table 4]

[0227] The composite acceptance criteria and mean results are reported in Table 5.

[0228] [Table 5]

[0229] Example 6: Binding to human FAP 68 Ga]GaESV6-NODAGA,[68 Ga]GaESV6-NOTA and ESV6-NOTA-[ 18 Characterization of [F]Al-F Radiolabeled ESV6 derivatives binding to hFAP were tested by loading a solution of either preincubated 68Ga / [18F]AlF / -ESV6 derivative (500 KBq) and human FAP (2 μM, 100 μl) onto a PD-10 column pre-equilibrated with running buffer (50 mM Tris, 100 mM NaCl, and 1 mM ethylenediaminetetraacetic acid [EDTA], pH=7.4) and flushed with running buffer. A fraction of the flow-through (500 μL) was collected in a 3 ml test tube, and the radioactivity, which correlated with the concentration of the radioactive compound, was immediately measured on a gamma counter (λ=511 KeV for 68Ga and 18F).

[0230] For all radiolabeled compounds, coelution experiments of the radiopharmaceuticals in the absence and presence of human FAP protein indicate excellent affinity for their biological targets, as can be seen from FIG.

Claims

1. The compound structure is: The following structure: 【Chemical 1】 a moiety A represented by or comprising: one or more diagnostic or therapeutic moieties C; and A moiety B that covalently connects A to C, represented by the following structure: 【Chemistry 2】 [In the formula, each b １ and b ３ are independently an integer from 0 to 4, preferably 0 or 1; each b ２ are independently an integer from 1 to 4, preferably 1 or 2; z is an integer from 1 to 3, preferably 1 or 2; Each B ２ is, independently, 【Chemistry 3】 (In the formula: Y and Z are carbocyclic or heterocyclic groups, preferably C ３～１３ Carbocyclic group or C ２～１２ is a linking group that forms part of the heterocyclic group; *-Y is *-C, *-CR, *-N, *-NR, *-NRC(O)C, *-NRC(O)CR, *-NRC(O)CR ２ C, *-NRC(O)CR ２ CR, *-NRC(S)NRC, *-NRC(S)NRCR, *-NRC, *-NRCR, *-NRCR ２ C, or *-NRCR ２ represents CR; Z-・ is C-・, CR-・, N-・, NR-・, CC(O)NRCRC(O)NR-・, CCR ２ C(O)NR-・,CRCR ２ C(O)NR-・, CNRC(S)NR-・, NRC(S)CRNR-・, CNR-・, CRNR-・, CCR ２ NR- or CRCR ２ represents NR-; Each * represents an attachment point closer to part A than to part C; Each ・ represents an attachment point closer to part C than to part A. is represented by; Each B １ are independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, wherein said heteroalkylene contains one or more heteroatoms selected from N and O; preferably a bond, alkylene, or heteroalkylene, wherein said heteroalkylene contains one or more heteroatoms selected from N and O; wherein A and B ２ and the shortest path between preferably contains no more than 6, more preferably no more than 3, and most preferably no more than 2 covalently connected atoms or is a bond; Each B ３ are independently a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, C(S)N(R)arylalkylene, or heteroalkylene, said heteroalkylene containing one or more heteroatoms selected from N and O; preferably a bond, alkylene, oxoalkylene, di(oxo)alkylene, C(O)alkylarylalkylene, or C(S)N(R)arylalkylene; wherein B ２ and C preferably contains no more than 10 covalently connected atoms or is a bond, more preferably no more than 7, and most preferably no more than 6; B １ , B ２ and B ３ each of which may be independently substituted by one or more of R; Each R is H, OH, SH, NH ２ , halogen, cyano, oxo, carboxy, C(O)NH ２ C １～６ Alkyl, C １～６ Alkoxy, C(O)C １～６ Alkyl, C １～６ Alkylthio, C １～５ Heteroalkyl, C １～５ Heteroalkoxy, C ３～６ Cycloalkyl, C ３～６ Cycloalkoxy, C ６～１０ Aryl, C ６～１０ Aryloxy, C ５～１０ Heteroaryl and C ５～１０ heteroaryloxy, among which SH, NH ２ , C(O)NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C(O)C １～６ Alkyl, C １～６ Alkylthio, C １～５ Heteroalkyl, C １～５ Heteroalkoxy, C ３～６ Cycloalkyl, C ３～６ Cycloalkoxy, C ６～１０ Aryl, C ６～１０ Aryloxy, C ５～１０ Heteroaryl and C ５～１０ Heteroaryloxy is OH, SH, NH ２ , halogen, cyano, oxo, carboxy, C １～６ Alkyl, C １～５ Heteroalkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl and C ５～１０ optionally substituted with one or more of the heteroaryl, and two or more of R can be joined together to form part of a carbocyclic or heterocyclic ring system; All valences are satisfied. a compound, an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. Formula I below: 【Chemistry 4】 2. The compound of claim 1, represented by:

3. Moiety A has the following structure A １ , A ２ or A ３ , preferably A ２ 3. The compound of claim 1, wherein m is 0, 1, 2, 3, 4, or 5, preferably 1; and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably 2: 【Chemistry 5】 。

4. Each B ２ but: 【Chemistry 6】 (In the formula, each s, u, t, and v is independently 0, 1, or 2; each w is independently 0, 1, 2, or 3; Each X is independently N, NH, NR, S, S(O), SO ２ ,O,C,CR,CH,CR ２ or CH ２ is) are independently selected from Preferably, B ２ but: 【Chemistry 7】 Selected from: More preferably, B ２ but: 【Chemistry 8】 Selected from: Most preferably, B ２ but: 【Chemistry 9】 Selected from:

3. The compound of claim 1 or 2.

5. B ２ but, 【Chemistry 10】 and More preferably 【Chemistry 11】 and Most preferably 【Chemistry 12】 That is, 3. The compound of claim 1 or 2.

6. B ２ but, 【Chemistry 13】 and More preferably 【Chemistry 14】 and Most preferably 【Chemistry 15】 That is, 3. The compound of claim 1 or 2.

7. B ２ but, 【Chemistry 16】 and More preferably 【Chemistry 17】 and Most preferably 【Chemistry 18】 That is, 3. The compound of claim 1 or 2.

8. B ２ but, 【Chemistry 19】 and More preferably 【Chemistry 20】 and Most preferably 【Chemical 21】 That is, 3. The compound of claim 1 or 2.

9. B ２ but, 【Chemical 22】 and More preferably 【Chemical 23】 and Most preferably 【Chemistry 24】 That is, 3. The compound of claim 1 or 2.

10. B ２ but, 【Chemistry 25】 and More preferably 【Chemical Formula 26】 and Most preferably 【Chemical 27】 That is, 3. The compound of claim 1 or 2.

11. Each B １ is a bond; C １～１０ , preferably C １～４ , more preferably C １～２ Alkylene; C containing one or two N atoms １～１０ , preferably C １～４ , more preferably C １～２ Heteroalkylene group; NR(C １～１０ , C １～４ , or C １～２ alkylene)NR; (C １～１０ , C １～４ , or C １～２ alkylene)NR; NR(C １～１０ , C １～４ , or C １～２ alkylene); C(O); C(O)CR ２ ; C(O)(C ６～１０ Aryl)CR ２ ; C(O)(C １～１０ alkylene)C(O);C(O)(C １～１０ alkyl)C(O)NR;C(O)(C ５～１０ Heteroaryl)CR ２ ; C(O)(C ６～１０ Aryl)CR ２ ; C(O)(C ５～１０ Heteroaryl)CR ２ ;C(S)NR;C(S)NR(C ６～１０ Aryl)CR ２ and C(S)NR(C ５～１０ Heteroaryl)CR ２ independently selected from: ２ CH ２ C(O),NHCH ２ CH ２ N.H., C.H. ２ CH ２ NH, NHCH ２ CH ２ , 【Chemical 28】 and / or Each B ３ is a bond; C １～１０ , preferably C １～４、 More preferably C １～２ Alkylene; C containing one or two N atoms １～１０ , preferably C １～４、 More preferably C １～２ Heteroalkylene group; NR(C １～１０ , C １～４ , or C １～２ alkylene)NR; (C １～１０ , C １～４ , or C １～２ alkylene)NR; NR(C １～１０ , C １～４ , or C １～２ alkylene); C(O); C(O)CR ２ ; C(O)(C ６～１０ Aryl)CR ２ ; C(O)(C ５～１０ Heteroaryl)CR ２ ; C(O)(C ６～１０ Aryl)CR ２ ; C(O)(C ５～１０ Heteroaryl)CR ２ ; C(O)(C ６～１０ Aryl)CR ２ ; C(O)(C ５～１０ Heteroaryl)CR ２ ;C(S)NR;C(S)NR(C ６～１０ Aryl)CR ２ and C(S)NR(C ５～１０ Heteroaryl)CR ２ independently selected from: ２ CH ２ C(O),NHCH ２ CH ２ N.H., C.H. ２ CH ２ NH, NHCH ２ CH ２ , 【Chemical 29】 That is, 3. The compound of claim 1 or 2.

12. moiety C is selected from a chelator group suitable for radiolabeling; a radioactive group comprising a radioisotope; a chelate of a radioisotope with a chelator; a fluorophore group; a cytotoxic and / or cytostatic agent; an immunomodulatory agent; or a protein; wherein preferably C is: (a) a chelator group suitable for radiolabeling: (i) 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), 2,2',2''-(1,4,7-triazonane-1,4-diyl)diacetic acid (NODA), 2,2'-((2-((4-(2-amino-2-oxoethyl)benzyl)(carboxymethyl)amino)cyclohexyl)azanediyl)diacetic acid) (RESCA), sulfur colloid, diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N,N',N'' N,N',N'''-tetraacetic acid (DOTA), [2,2',2''-(10-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-GA), [1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA), iminodiacetic acid, bis(carboxymethylimidazole)glycine, 6-hydrazinopyridine-3-carboxylic acid (HYNIC); or (ii) a compound of the following formula C １ , C ２ , C ３ , C ４ , and C ５ : 【Chemistry 30】 (In the formula: Each q is independently 0, 1, 2, 3, 4, or 5; preferably 0; R １ｅ , R １ｆ , R １ｇ , R １ｈ and R １ｉ are each independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ２ｅ , R ２ｆ , R ２ｇ , R ２ｈ and R ２ｉ are each independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ３ｅ , R ３ｆ , R ３ｇ , R ３ｈ , R ４ｈ and R ３ｉ are each independently H, COOH, aryl-COOH, or heteroaryl-COOH; preferably COOH; R ４ｅ are independently H, COOH, aryl-COOH, or heteroaryl-COOH, provided that when q is 0, R ４ｅ is H; Each X is independently NH, NR, S, O, CR ２ or H,H; preferably O; each Q is N or O, preferably N; where Q is O, CH ２ R ２ｅ , C.H. ２ R ２ｆ , C.H. ２ R ２ｇ , C.H. ２ R ２ｈ and C.H. ２ R ２ｉ does not exist; L is -CH ２ -C(O)- or -NHC(S)- or (iii) Below: 【Chemical 31】 having a structure selected from It is a group; (b) A radioactive group containing a radioisotope is ２２３ Ra, ８９ Sr, ９４ｍ Tc, ９９ｍ Tc, １８６ Re, １８８ Re, ２０３ Pb, ６７ Ga, ６８ Ga, ４７ Sc, １１１ In, ９７ Ru, ６２ Cu, ６４ Cu, ８６ Y. ８８ Y. ９０ Y. １２１ Sn, １６１ Tb, １５３ Sm, １６６ Ho, １０５ Rh, １７７ Lu, １２３ I, １２４ I, １２５ I, １３１ I, １８ F. ２１１ At, ２２５ Ac, ８９ Sr, １１７ｍ Sn and １６９ Er, where: １８ F is preferably bound to chelated Al, Zr, Si, Ga, or In, more preferably １８ F is bound to Al chelated by a chelator; (c) The chelate of the radioisotope is a chelate of an isotope listed under (b) above and / or with a chelating agent listed under (a) above; or moiety C has the following structure: 【Chemical 32】 is a group selected from any one of 3. The compound of claim 1 or 2.

13. C is, 【Chemical 33】 is a chelator selected from Preferably, １８ F is bound to Al chelated by a chelator; The compound of claim 4.

14. below: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 a compound having a structure selected from: an individual diastereoisomer thereof, a hydrate thereof, a solvate thereof, a crystalline form thereof, an individual tautomer thereof, or a pharmaceutically acceptable salt thereof.

15. (a) a method for the treatment of the human or animal body by surgery or therapy, or a diagnostic method practiced on the human or animal body; or (b) a method for the treatment or prevention of a subject suffering from or at risk of a disease or disorder; or (c) a method for guided surgery performed on a subject suffering from or at risk of a disease or disorder; or (d) a method for the diagnosis of a disease or disorder performed on the human or animal body and involving a nuclear medicine imaging technique such as positron emission tomography (PET) or single photon emission computed tomography (SPECT); or (e) Methods for targeted delivery of therapeutic or diagnostic agents to subjects suffering from or at risk for a disease or disorder.

3. A compound according to claim 1 or 2 for use in wherein in each of the preceding (b)-(e), said disease or disorder is independently selected from cancer, inflammation, atherosclerosis, fibrosis, tissue remodeling, and keloid disorders, preferably wherein cancer is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, multidrug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct adenocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, tumor-induced osteomalacia, sarcoma, CUP (carcinoma of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, skin cancer, kidney cancer, breast cancer, and prostate cancer; wherein in each of the preceding uses or methods, the compound preferably has prolonged residence at the disease site at therapeutically or diagnostically relevant levels, preferably for more than 1 hour, more preferably for more than 6 hours after injection; The compound.

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