Compounds containing fibroblast activation protein ligands and uses thereof

Abstract

The present invention relates to a compound comprising a cyclic peptide of formula (I) and an N-terminal modification group A attached to Xaa1, wherein each and any one of Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, and Xaa7 is an amino acid residue, and Yc is a structure of formula (X). TIFF2022541752000481.tif38135

Description

[Technical Field]

[0001] The present invention relates to compounds; inhibitors of fibroblast activation proteins (FAPs); compositions comprising the compounds and inhibitors, respectively; compounds, inhibitors, and compositions, respectively, for use in methods for the diagnosis of disease; compounds, inhibitors, and compositions, respectively, for use in methods for the treatment of disease; compounds, inhibitors, and compositions, respectively, for use in methods for the diagnosis and treatment of disease, also referred to as "thera(g)nosis" or "thera(g)nostics"; compounds, inhibitors, and compositions, respectively, for use in methods for delivering effectors to FAP-expressing tissue; methods for the diagnosis of disease using the compounds, inhibitors, and compositions, respectively; methods for the treatment of disease using the compounds, inhibitors, and compositions, respectively; methods for the diagnosis and treatment of disease, also referred to as "thera(g)nosis" or "thera(g)nostics" using the compounds, inhibitors, and compositions, respectively; and methods for the delivery of effectors to FAP-expressing tissue using the compounds, inhibitors, and compositions, respectively. [Background technology]

[0002] Despite the increasing availability of therapeutic options, cancer remains the second leading cause of death worldwide. Treatment strategies primarily focus on targeting malignant cancer cells themselves, ignoring the ever-present surrounding tumor microenvironment (TME), which limits the access of therapeutic cancer cell agents (Valkenburg et al., Nat Rev Clin Oncol, 2018, 15:366). The TME is part of the tumor mass and consists of not only a heterogeneous population of cancer cells but also various resident and infiltrating host cells, secreted factors, and extracellular matrix proteins (Quail et al., Nat Med, 2013, 19:1423). The predominant cell type found in the TME is cancer-associated fibroblasts (CAFs) (Kalluri, Nat Rev Cancer, 2016, 16:582). Many different cell types have been described as sources and origins for CAFs, such as fibroblasts, mesenchymal stem cells, smooth muscle cells, cells of epithelial origin, or endothelial cells (Madar et al., Trends Mol Med, 2013, 19:447). CAFs exhibit mesenchymal-like characteristics and are often the predominant cell type within solid tumor masses. CAFs have attracted increasing interest as players in tumor progression and homeostasis (Gascard et al., Genes Dev, 2016, 30:1002; LeBleu et al., Dis Model Mech, 2018, 11).

[0003] In recent years, fibroblast activation protein (FAP) has lost its reputation as a marker of CAFs (Shiga et al., Cancers (Basel), 2015, 7:2443; Pure et al., Oncogene, 2018, 37:4343; Jacob et al., Curr Mol Med, 2012, 12:1220). Due to the ubiquitous presence of CAFs in tumors and stroma, FAP has been identified as a suitable marker for radiopharmaceutical diagnosis and a suitable target for radiopharmaceutical therapy (Siveke, J Nucl Med, 2018, 59:1412).

[0004] Fibroblast activation protein alpha (FAP) is a type II transmembrane serine protease and a member of the S9 prolyl oligopeptidase family (Park et al., J Biol Chem, 1999, 274:36505). The closest family member, DPP4, shares 53% homology with FAP. Like other DPP enzymes (DPP4, DPP7, DPP8, and DPP9), FAP possesses post-proline exopeptidase activity. Furthermore, FAP possesses endopeptidase activity, similar to prolyl oligopeptidase / endopeptidase (POP / PREP). The FAP gene is highly conserved across various species. The extracellular domain of human FAP shares 90% amino acid sequence identity with mouse and rat FAP. Mouse FAP shares 97% sequence identity with rat FAP.

[0005] Structurally, FAP is a 760-amino acid transmembrane protein composed of a short N-terminal cytoplasmic tail (6 amino acids), a single transmembrane domain (20 amino acids), and a 734-amino acid extracellular domain (Aertgeerts et al., J Biol Chem, 2005, 280:19441). This extracellular domain consists of an eight-bladed β-propeller domain and an α / β-hydrolase domain. The catalytic triad, consisting of Ser624, Asp702, and His734, is located at the interface between the β-propeller and hydrolase domains. The active site is accessible through the central hole of the β-propeller domain or through a narrow cavity between the β-propeller and hydrolase domains. FAP is not active as a monomer, but forms active homodimers and heterodimers with DPP4 (Ghersi et al., Cancer Res, 2006, 66:4652). Soluble homodimeric FAPs have also been described (Keane et al., FEBS Open Bio, 2013, 4:43; Lee et al., Blood, 2006, 107:1397).

[0006] FAP has dual enzymatic activity (Hamson et al., Proteomics Clin Appl, 2014, 8:454). Its dipeptidyl peptidase activity cleaves two amino acids N-terminal to the proline residue. FAP substrates rapidly cleaved by its dipeptidyl peptidase activity include neuropeptide Y, peptide YY, substance P, and B-type natriuretic peptide. Collagens I and III, FGF21, and α2-antiplasmin have been shown to be cleaved by FAP's endopeptidase activity. Although FAP cannot cleave native collagens, predigestion with other proteases, such as matrix metalloproteinases, facilitates further collagen cleavage by FAP. Collagen processing can affect the migration ability of cancer cells. In addition to increasing cancer cell invasiveness through extracellular matrix remodeling, several other FAP-mediated tumor-promoting roles have been proposed, including increased proliferation and angiogenesis. Furthermore, stromal expression of FAP is associated with escape from immune surveillance in various cancers, suggesting a role in antitumor immunity (Pure et al., Oncogene, 2018, 37:4343).

[0007] FAP is transiently expressed during normal development but is only rarely expressed in healthy adult tissues. In transgenic mice, FAP has been shown to be expressed by adipose tissue, skeletal muscle, skin, bone, and pancreas (Pure et al., Oncogene, 2018, 37: 4343; Roberts et al., J Exp Med, 2013, 210: 1137). However, FAP knockout mice have a healthy phenotype, suggesting a redundant role under normal conditions (Niedermeyer et al., Mol Cell Biol, 2000, 20: 1089). At sites of active tissue remodeling, including wound healing, fibrosis, arthritis, atherosclerosis, and cancer, FAP becomes highly upregulated in stromal cells (Pure et al., Oncogene, 2018, 37: 4343).

[0008] FAP expression in the tumor stroma of 90% of epithelial cancers was first reported in 1990 using the monoclonal antibody F19 (Garin-Chesa et al., Proc Natl Acad Sci USA, 1990, 87:7235; Rettig et al., Cancer Res, 1993, 53:3327). FAP-expressing stromal cells were further characterized as cancer-associated fibroblasts (CAFs) and cancer-associated pericytes (Cremasco et al., Cancer Immunol Res, 2018, 6:1472). FAP expression on malignant epithelial cells has also been reported, although its significance remains uncertain (Pure et al., Oncogene, 2018, 37:4343). Table 1 below, taken from Busek et al. (Busek et al., Front Biosci (Landmark Ed), 2018, 23:1933), summarizes the expression of FAP in various malignancies showing tumor type and cellular expression.

[0009] [Table 1-1]

[0010] [Table 1-2]

[0011] FAP expression in CAFs has been demonstrated in nearly all carcinomas and sarcomas (Pure et al., Oncogene, 2018, 37:4343; Busek et al., Front Biosci (Landmark Ed), 2018, 23:1933). Furthermore, CAFs are present in hematological malignancies (Raffaghello et al., Oncotarget, 2015, 6:2589). Therefore, the use of FAP as a therapeutic target is not limited to any particular tumor entity.

[0012] The abundance of FAP-expressing CAFs has been reported to correlate with poor prognosis. Across various human tumor indications, FAP expression has been reported to correlate with higher tumor grade and worse overall survival (Pure et al., Oncogene, 2018, 37:4343).

[0013] As mentioned above, FAP and FAP-expressing cells present in tumor microenvironment have been shown to significantly affect tumor progression (Hanahan et al., Cancer Cell, 2012, 21:309).In addition, due to its relatively selective expression in tumors, FAP is considered as a suitable target for therapeutic and diagnostic agents, as described below (Siveke, J Nucl Med, 2018, 59:1412; Christiansen et al., Neoplasia, 2013, 15:348; Zi et al., Mol Med Rep, 2015, 11:3203).

[0014] Shortly after their discovery, FAPs were exploited as therapeutic targets in cancer, and to date, various strategies have been explored, including, for example, inhibition of FAP enzymatic activity, elimination of FAP-positive cells, or targeted delivery of cytotoxic compounds.

[0015] In 2007, talabostat (Val-boro-Pro, PT-100), an inhibitor of FAP and DPP4, was developed by Point Therapeutics (e.g., U.S. Patent No. 6,890,904, described in WO9916864). Pennisi et al. (Pennisi et al., Br J Haematol, 2009, 145:775) observed a reduction in tumor growth in multiple myeloma animal models as well as in cancer syngeneic mouse models. In addition, several other prolylboronic acid derivatives have been developed and reported as putative selective inhibitors of FAP. These derivatives exhibit instability in aqueous environments at physiological pH (Coutts et al., J Med Chem, 1996, 39:2087) and nonspecific reactivity with other enzymes.

[0016] WO2008 / 116054 disclosed hexapeptide derivatives in which the compounds contain a C-terminal bisamino or boronic acid functionality. US2017 / 0066800 disclosed pseudopeptide inhibitors, such as M83, that are effective against FAP. These inhibitors were evaluated in lung and colon cancer xenografts in immunodeficient mice. Tumor growth inhibition was observed (Jackson et al., Neoplasia, 2015, 17:43). These pseudopeptides inhibit the activity of both prolyl oligopeptidase (POP / PREP) and FAP, thereby precluding their use as specific therapeutic FAP inhibitors.

[0017] US2008 / 280856 disclosed nanomolar concentrations of boronic acid-based inhibitors that exhibit dual specific inhibition of FAP and PREP, thereby precluding their use as specific therapeutic FAP inhibitors.

[0018] Cyclic peptide-based FAP inhibitors have been disclosed, for example, in WO2016 / 146174 and WO2006 / 042282. WO2016 / 146174 discloses a peptide for the diagnosis and treatment of FAP-expressing tumors that exhibits specificity for FAP, and the closely related homolog DPP4 is not recognized by the peptide. WO2006 / 042282 discloses a polypeptide for the treatment of melanoma. In nude mice, inhibition of melanoma growth and melanoma metastasis was demonstrated.

[0019] WO99 / 75151 and WO01 / 68708 disclosed a humanized FAP monoclonal antibody, F19 (sibrotuzumab). Furthermore, the anti-FAP antibody F19 and its humanized versions were disclosed in WO99 / 57151 and WO01 / 68708. Development approaches included, for example, the generation of high-affinity, species-cross-reactive, FAP-specific scFvs, which were converted into bivalent derivatives (Brocks et al., Mol Med, 2001, 7:461). In phase I and II clinical trials, sibrotuzumab demonstrated specific tumor enrichment but failed to demonstrate measurable therapeutic activity in patients with metastatic colorectal cancer, with only 2 of 17 patients achieving stable disease (Hofheinz et al., Onkologie, 2003, 26:44). The F19 antibody was shown not to block any cellular or protease functions of FAP, which may explain the lack of therapeutic efficacy (Hofheinz et al., Onkologie, 2003, 26:44; Scott et al., Clin Cancer Res, 2003, 9:1639).

[0020] US2018 / 022822 disclosed novel molecules that specifically bind to human FAP and its epitopes as human-derived antibodies and chimeric antigen receptors (CARs) useful in the treatment of diseases and conditions induced by FAP. Treatment of mice bearing orthotopic MC38 colorectal tumors with anti-FAP antibodies reduced tumor diameter and the number of metastases. WO2012 / 020006 disclosed glycoengineered antibodies carrying modified oligosaccharides in the Fc region. Subsequently, bispecific antibodies specific for FAP and DR5 were developed as the subject of WO2014 / 161845. These antibodies induced tumor cell apoptosis in in vitro and in vivo preclinical tumor models with FAP-positive stroma (Brunker et al., Mol Cancer Ther, 2016, 15:946). Antibody-drug conjugates and immunotoxins targeting FAP are described in WO2015 / 118030. In vitro toxicity as well as in vivo inhibition of tumor growth was demonstrated after application of anti-hu / moFAP hu36:cytolysin ADC candidates. It is unclear whether these antibodies were able to inhibit FAP activity.

[0021] A small molecule FAP inhibitor based on (4-quinolinol)glycyl-2-cyanopyrrolidine, which exhibits low nanomolar inhibitory potency and high selectivity against related DPPs and PREPs, was described by Jansen et al. (Jansen et al., J Med Chem, 2014, 57:3053; Jansen et al., ACS Med Chem Lett, 2013, 4:491) and disclosed in WO2013 / 107820. However, that compound is not structurally related to the compounds of the present invention and contains a warhead that provides covalent binding to FAP.

[0022] Recently, several FAP-targeted radiopharmaceutical approaches have been developed, which are illustratively described herein. WO2010 / 036814 disclosed small molecule inhibitors of FAP for use as therapeutic agents by inhibition of FAP enzymatic activity or as radiopharmaceuticals by binding to FAP.

[0023] WO2019 / 083990 disclosed imaging and radiotherapeutic agents based on small molecule FAP inhibitors described by Jansen et al. (Jansen et al., J Med Chem, 2014, 57:3053; Jansen et al., ACS Med Chem Lett, 2013, 4:491). Furthermore, several authors have described the selective uptake in tumors of cancer patients of imaging and radiotherapeutic agents based on FAP inhibitors, as described by Jansen et al. (Jansen et al., J Med Chem, 2014, 57:3053; Jansen et al., ACS Med Chem Lett, 2013, 4:491) (Lindner et al., J Nucl Med, 2018, 59:1415; Loktev et al., J Nucl Med, 2018, 59:1423; Giesel et al., J Nucl Med, 2019, 60:386; Loktev et al., J Nucl Med, 2019, Mar 8 (Electronic ahead of print); Giesel et al., Eur J Nucl Med Mol Imaging, 2019, 46:1754; Kratochwil et al., J Nucl Med, 2019, 60:801).

[0024] 131 Clinical evaluation of an I-labeled, humanized form of the F19 antibody (sibrotuzumab) demonstrated selective uptake by tumors, but not normal tissues, in patients with colorectal cancer or non-small cell lung cancer (Scott, et al., Clin Cancer Res, 2003, 9:1639). This may be due to the long circulation time of the antibody, making it unsuitable for diagnostic, therapeutic, or diagnostic-therapeutic procedures involving radionuclides.

[0025] WO2011 / 040972 disclosed a high-affinity antibody that recognizes both human and mouse FAP antigens as a potent radioimmunoconjugate. ESC11 IgG1 induces down-modulation and internalization of surface FAP (Fischer et al., Clin Cancer Res, 2012, 18:6208). WO2017 / 211809 disclosed a tissue-targeted thorium-227 conjugate in which the targeting moiety has specificity for FAP. However, the long circulation time of antibodies makes them unsuitable for diagnostic, therapeutic, or diagnostic-therapeutic procedures involving radionuclides.

[0026] FAP has also been described to be involved in diseases other than oncological indications, examples of which are given below. Fibroblast-like synoviocytes in rheumatoid arthritis joints of patients show significantly increased expression of FAP (Bauer et al., Arthritis Res Ther, 2006, 8:R171; Milner et al., Arthritis Res Ther, 2006, 8:R23). In rheumatoid arthritis, stromal cells play a key role in organizing the structure of the synovial tissue of the joint by producing extracellular matrix components, recruiting infiltrating immune cells, and secreting inflammatory mediators. Considerable evidence supports the role of these cells in driving the persistence of inflammation and joint damage (Bartok et al., Immunol Rev, 2010, 233:233; Turner et al., Curr Opin Rheumatol, 2015, 27:175). In rheumatoid arthritis, FAP plays a pathological role in cartilage turnover, at least by promoting proteoglycan loss and subsequent cartilage degradation (Bauer et al., Arthritis Res Ther, 2006, 8:R171; Waldele et al., Arthritis Res Ther, 2015, 17:12).Therefore, it can serve as a marker for patient stratification, or as a therapeutic target for the evaluation and follow-up of treatment success (Bauer et al., Arthritis Res Ther, 2006, 8:R171).In mice, treatment response is 99mThis has been demonstrated using SPECT / CT imaging with Tc-labeled anti-FAP antibodies (van der Geest et al., Rheumatology (Oxford), 2018, 57:737; Laverman et al., J Nucl Med, 2015, 56:778; van der Geest et al., J Nucl Med, 2017, 58:151).

[0027] Furthermore, FAP has been recognized not only as a marker of activated fibroblasts in the injury response (Tillmanns et al., Int J Cardiol, 2013, 168:3926) but also as an important player in the wound healing process (Ramirez-Montagut et al., Oncogene, 2004, 23:5435). Jing et al. demonstrated a time-dependent course of changes in FAP expression after burn wound injury in rats (Jing et al., Nan Fang Yi Ke Da Xue Xu Bao, 2013, 33:615). Inhibition of FAP activity in reactive wound fibroblasts in keloid scars, a common benign fibroproliferative reticular skin lesion, may provide a therapeutic option for preventing disease progression (Dienus et al., Arch Dermatol Res, 2010, 302:725).

[0028] In fibrosis, for example, in idiopathic pulmonary fibrosis, Crohn's disease, and liver fibrosis, upregulated expression of FAP has been observed. In an ex vivo model of Crohn's disease, a chronic inflammatory bowel disease characterized by excessive and unbalanced extracellular matrix (ECM) deposition, upregulated FAP expression was observed. FAP inhibition reconstituted extracellular matrix homeostasis (Truffi et al., Inflamm Bowel Dis, 2018, 24:332). A similar observation was made by Egger et al. (Egger et al., Eur J Pharmacol, 2017, 809:64) using a mouse model of pulmonary fibrosis. Inhibition of FAP results in a reduction of fibrotic pathology. FAP is also expressed in areas of tissue remodeling in chronically injured livers (Wang et al., Front Biosci, 2008, 13:3168), and FAP expression by hepatic stellate cells correlates with the histological severity of liver disease (Gorrell et al., Adv Exp Med Biol, 2003, 524:235). Therefore, FAP is also a promising target for the treatment of liver fibrosis (Lay et al., Front Biosci (Landmark Ed), 2019, 24:1).

[0029] FAP is expressed in atherosclerotic lesions and is upregulated in activated vascular smooth muscle cells (Monslow et al., Circulation, 2013, 128:A17597). Monslow et al. demonstrated that targeted inhibition of FAP in atherosclerotic lesions can reduce overall lesion volume, inhibit inflammatory cell homing, and increase lesion stability through its ability to alter lesion structure by favoring matrix-rich lesions over inflammation. More importantly, many atherosclerotic pathologies share a common pathological feature: the rupture of atherosclerotic plaques, which leads to atherosclerotic lesions (Davies et al., Br Heart J, 1985, 53:363; Falk, Am J Cardiol, 1989, 63:114e). Rupture of the fibrous cap in advanced atherosclerotic plaques is an important precipitating factor for acute coronary syndromes, which can result in myocardial infarction and sudden cardiac death. One of the key events in promoting plaque instability is the degradation of the fibrous cap, which exposes the underlying thrombogenic plaque core to blood flow, leading to thrombosis and subsequent vascular occlusion (Farb et al., Circulation, 1996, 93:1354; Virmani et al., J Am Coll Cardiol, 2006, 47:C13). Brokopp et al. showed that FAP contributes to type I collagen disruption in the fibrous cap (Brokopp et al., Eur Heart J, 2011, 32:2713). Radiolabeled tracers have been developed and their applicability for atherosclerosis imaging has been demonstrated (Meletta et al., Molecules, 2015, 20:2081). DETAILED DESCRIPTION OF THE INVENTION

[0030] The problem underlying the present invention is to provide compounds suitable as diagnostic and / or therapeutic agents, particularly when conjugated to a diagnostically and / or therapeutically active effector. A further problem underlying the present invention is to provide compounds suitable as diagnostic and / or therapeutic agents, particularly when conjugated to a diagnostically and / or therapeutically active effector, such that the compounds are potent inhibitors of FAP activity, preferably with a pIC50 of greater than or equal to 6.0. A further problem underlying the present invention is to provide compounds suitable as diagnostic and / or therapeutic agents in the diagnosis and / or treatment of diseases in which diseased cells and / or diseased tissues express FAP, particularly when conjugated to a diagnostically and / or therapeutically active effector. A further problem underlying the present invention is to provide compounds suitable for delivering diagnostically and / or therapeutically effective agents to diseased cells and / or diseased tissues, respectively, more particularly to diseased cells and / or diseased tissues expressing FAP, preferably diseased tissues that include or contain cancer-associated fibroblasts. The present invention also provides methods for diagnosing, treating, and / or preventing diseases, as well as methods for the combined diagnosis and treatment of diseases, preferably diseases involving cells and / or tissues expressing FAP, more particularly diseased cells and / or tissues expressing FAP, and preferably diseased tissues including or containing cancer-associated fibroblasts. A further object of the present invention is to provide methods for identifying subjects likely to respond or not respond to disease treatment, and methods for selecting subjects likely to respond or not respond to disease treatment from a group of subjects. A further object of the present invention is to provide pharmaceutical compositions comprising compounds having the characteristics outlined above. A further object of the present invention is to provide kits suitable for use in any of the above methods.

[0031] There is a need for compounds that are suitable as diagnostic and / or therapeutic agents, particularly when conjugated to a diagnostically and / or therapeutically active effector. There is also a need for compounds that are suitable as diagnostic and / or therapeutic agents, particularly when conjugated to a diagnostically and / or therapeutically active effector, such that the compound is a potent inhibitor of FAP activity, preferably where the compound has a pIC50 of equal to or greater than 6.0. There is also a need for compounds that are suitable as diagnostic and / or therapeutic agents in the diagnosis and / or treatment of diseases in which diseased cells and / or diseased tissues express FAP, particularly when conjugated to a diagnostically and / or therapeutically active effector. There is also a need for compounds that are suitable for delivering diagnostically and / or therapeutically effective agents to diseased cells and / or diseased tissues, respectively, more particularly to diseased cells and / or diseased tissues that express FAP, preferably where the diseased tissues include or contain cancer-associated fibroblasts. There is also a need for methods for the diagnosis of disease, for the treatment and / or prevention of disease, and for the combined diagnosis and treatment of disease, preferably wherein such diseases involve cells and / or tissues expressing FAP, more particularly diseased cells and / or diseased tissues expressing FAP, and preferably wherein the diseased tissues include or contain cancer-associated fibroblasts. Furthermore, there is a need for methods for identifying subjects likely to respond or not respond to disease treatment, and for selecting subjects likely to respond or not respond to disease treatment from a group of subjects. Furthermore, there is a need for pharmaceutical compositions comprising compounds having the characteristics outlined above. Furthermore, there is a need for kits suitable for use in any of the above methods. The present invention satisfies these needs.

[0032] These and other problems are solved by the subject matter of the appended claims. These and other problems underlying the present invention are also solved by the following embodiments. Embodiment 1. Formula (I)

[0033] [ka]

[0034] Cyclic peptides and an N-terminal modification group A attached to Xaa1, the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction; Xaa1 is a compound represented by formula (II)

[0035] [ka]

[0036] is a residue of an amino acid R 1a is -NH-, R 1b is H or CH3, n=0 or 1, the N-terminal modification group A is covalently bound to the nitrogen atom of Xaa1; The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2, The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether, Xaa2 is represented by formula (III), (IV), or (XX)

[0037] [ka]

[0038] is a residue of an amino acid R 2a , R 2b , R 2care each independently selected from the group consisting of (C1-C2)alkyl and H, and the (C1-C2)alkyl is optionally substituted with a substituent selected from the group consisting of OH, NH2, halogen, and (C5-C7)cycloalkyl; p=0, 1, or 2; v=1 or 2, w=1, 2, or 3, the amino acid of formula (IV) is optionally substituted at positions 3 and 4 of the indicated ring with one or two substituents selected from the group consisting of methyl, OH, NH, and F; Xaa3 is a compound of formula (V) or (XX)

[0039] [ka]

[0040] is a residue of an amino acid X 3 CH2, CF2, CH-R 3b , S, O, and NH; p=1 or 2, v=1 or 2, w=1, 2, or 3, R 3a is H, methyl, OH, NH2, or F, R 3b is methyl, OH, NH2, or F, Xaa4 is a compound represented by formula (VI)

[0041] [ka]

[0042] is a residue of an amino acid R 4a H, OH, COOH, CONH2, X 4 , and -NH-CO-X 4 and X is selected from the group consisting of 4is selected from the group consisting of (C1-C6) alkyl, (C5-C6) aryl, and (C5-C6) heteroaryl; and X 4 is optionally substituted by one or two substituents selected from the group consisting of methyl, CONH2, halogen, NH2, and OH; q=1, 2, or 3; one or two hydrogen atoms of said one, two, or three CH— groups are optionally and independently replaced by methyl, ethyl, (C-C)aryl, or (C-C)heteroaryl; R 4b is methyl or H, Xaa5 is structure (VII)

[0043] [ka]

[0044] is a residue of an amino acid R 5 is selected from the group of OH and NH; r=1, 2, or 3, Xaa6 is an amino acid selected from the group consisting of aromatic L-α-amino acids and heteroaromatic L-α-amino acids, Xaa7 is a compound represented by formula (IX)

[0045] [ka]

[0046] is an aminothiol or amino acid residue of R 7a -CO-, -COOH, -CONH2, -CH2-OH, -(CO)-NH-R 7b , -(CO)-(NR 7c )-R 7b , or H and R 7b and R 7c are each independently (C1-C4) alkyl; t is 1 or 2, Yc is the formula (X)

[0047] [ka]

[0048] The S atom of Xaa1 is linked to the S atom of Xaa7 through the formation of two thioether linkages, thereby forming a structure of formula (XXI)

[0049] [ka]

[0050] forming a ring structure of the substitution pattern of the aromatic group of formula (X) is ortho, meta, or para; n=0 or 1, t=1 or 2, Y 1 is CH or N, Y 2 is N or CR c1 and R c1 is H or CH2-R c2 and R c2 is of formula (XI), (XII), or (XXII)

[0051] [ka]

[0052] The structure is R c3 and R c4 are each independently selected from the group consisting of H and (C1-C4) alkyl; u=1, 2, 3, 4, 5, or 6, x and y are each independently 1, 2, or 3; X=O or S, In formulas (XI) and (XXII), one of the nitrogen atoms is R c1In formula (XII), -X- is bonded to -CH2- in R c1 is bonded to -CH2- the N-terminal modification group A is a blocking group AbI or an amino acid Aaa; compound. Embodiment 2. Formula (I)

[0053] [ka]

[0054] Cyclic peptides and an N-terminal modification group A attached to Xaa1, the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction; Xaa1 is a compound represented by formula (II)

[0055] [ka]

[0056] is a residue of an amino acid R 1a is -NH-, R 1b is H or CH3, n=0 or 1, the N-terminal modification group A is covalently bound to the nitrogen atom of Xaa1; The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2, The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether, Xaa2 is represented by formula (III), (IV), or (XX)

[0057] [ka]

[0058] is a residue of an amino acid R 2a , R 2b , R2c are each independently selected from the group consisting of (C1-C2)alkyl and H, and the (C1-C2)alkyl is optionally substituted with a substituent selected from the group consisting of OH, NH2, halogen, and (C5-C7)cycloalkyl; p=0, 1, or 2; v=1 or 2, w=1, 2, or 3, the amino acid of formula (IV) is optionally substituted at positions 3 and 4 of the indicated ring with one or two substituents selected from the group consisting of methyl, OH, NH, and F; Xaa3 is a compound of formula (V) or (XX)

[0059] [ka]

[0060] is a residue of an amino acid X 3 CH2, CF2, CH-R 3b , S, O, and NH , p=1 or 2, v=1 or 2, w=1, 2, or 3, R 3a is H, methyl, OH, NH2, or F, R 3b is methyl, OH, NH2, or F, Xaa4 is a compound represented by formula (VI)

[0061] [ka]

[0062] is a residue of an amino acid R 4a H, OH, COOH, CONH2, X 4 , and -NH-CO-X 4 and X is selected from the group consisting of 4is selected from the group consisting of (C1-C6) alkyl, (C5-C6) aryl, and (C5-C6) heteroaryl; and X 4 is optionally substituted by one or two substituents selected from the group consisting of methyl, CONH2, halogen, NH2, and OH; q=1, 2, or 3; one or two hydrogen atoms of said one, two, or three CH— groups are optionally and independently replaced by methyl, ethyl, (C-C)aryl, or (C-C)heteroaryl; R 4b is methyl or H, Xaa5 is structure (VII)

[0063] [ka]

[0064] is a residue of an amino acid R 5 is selected from the group of OH and NH; r=1, 2, or 3, Xaa6 is an amino acid selected from the group consisting of aromatic L-α-amino acids and heteroaromatic L-α-amino acids, Xaa7 is a compound represented by formula (IX)

[0065] [ka]

[0066] is an aminothiol or amino acid residue of R 7a -CO-XXX, -COOH, -CONH2, -CH2-OH, -(CO)-NH-R 7b , -(CO)-(NR 7c )-R 7b or H, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom; R 7b and R 7care each independently (C1-C4) alkyl; the amino acid or peptide is optionally substituted with a Z group; t is 1 or 2, Yc is the formula (X)

[0067] [ka]

[0068] The S atom of Xaa1 is linked to the S atom of Xaa7 through the formation of two thioether linkages, thereby forming a structure of formula (XXI)

[0069] [ka]

[0070] forming a ring structure of the substitution pattern of the aromatic group of formula (X) is ortho, meta, or para; n=0 or 1, t=1 or 2, Y 1 is CH or N, Y 2 is N or CR c1 and R c1 is H or CH2-R c2 and R c2 is of formula (XI), (XII), or (XXII)

[0071] [ka]

[0072] The structure is R c3 and R c4 are each independently selected from the group consisting of H and (C1-C4) alkyl; R c5 is a H or Z group, u=1, 2, 3, 4, 5, or 6, x and y are each independently 1, 2, or 3; X=O or S, In formulas (XI) and (XXII), one of the nitrogen atoms is R c1 In formula (XII), -X- is bonded to -CH2- in R c1 is bonded to -CH2- the N-terminal modification group A is a blocking group Ab1 or an amino acid Aaa, the amino acid Aaa being optionally substituted with a Z group, each Z group comprising a chelator and optionally a linker; compound. Embodiment 3. R c5 is a Z group comprising a chelator and optionally a linker; R 7a -CO-XXX, -COOH, -CONH2, -CH2-OH, -(CO)-NH-R 7b , -(CO)-(NR 7c )-R 7b , or H and R 7b and R 7c are each independently (C1-C4) alkyl, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, and the amino acid or peptide is not substituted with a Z group that includes a chelator and, optionally, a linker; when the N-terminal modification group A is the amino acid Aaa, the amino acid Aaa is not substituted with a Z group comprising a chelator and optionally a linker; The compound of embodiment 2, wherein preferably said compound comprises only a single Z group comprising a chelator and optionally a linker. Embodiment 4. R 7ais different from -CO-XXX, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom; and when the N-terminal modification group A is an amino acid Aaa, then the amino acid Aaa is not substituted with a Z group that comprises a chelator and optionally a linker. Embodiment 5. R 7a is -CO-XXX, where XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, and the amino acid or peptide is substituted with a Z group that comprises a chelator and optionally a linker; R c1 or R c5 is H, when the N-terminal modification group A is the amino acid Aaa, the amino acid Aaa is not substituted with a Z group comprising a chelator and optionally a linker; The compound of embodiment 2, wherein preferably said compound comprises only a single Z group comprising a chelator and optionally a linker. Embodiment 6. The N-terminal modification group A is an amino acid Aaa substituted with a Z group comprising a chelator and optionally a linker; R c1 or R c5 is H, R 7a -CO-XXX-COOH, -CONH2, -CH2-OH, -(CO)-NH-R 7b , -(CO)-(NR 7c )-R 7b , or H and R 7b and R 7c are each independently (C1-C4) alkyl, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, and the amino acid or peptide is not substituted with a Z group that includes a chelator and, optionally, a linker; The compound of embodiment 2, wherein preferably said compound comprises only a single Z group comprising a chelator and optionally a linker. Embodiment 7. R 7ais different from -CO-XXX, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom. Embodiment 8. The amino acids Aaa each have the structure (XIV):

[0073] [ka]

[0074] is a D-amino acid residue or an L-amino acid residue of R a2 is selected from the group consisting of (C1-C6) alkyl, modified (C1-C6) alkyl, (C1-C3) alkyl, modified (C1-C3), (C3-C8) carbocycle, aryl, heteroaryl, and (C3-C8) heterocycle; In the modified (C1-C6) alkyl, one -CH2- group is replaced by -S- or -O-, and in the modified (C1-C3) alkyl, one H is replaced by OH, F, or COOH, or two H are replaced by F, and R a3 The compound of any one of embodiments 2, 6, and 7, wherein is a Z group. Embodiment 9. The blocking group Abl is R a1 -C(O)-, R a1 -S(O2)-, R a1 -NH-C(O)-, and R a1 -OC(O)-, and R a1 may each independently be OH, F, COOH, (C3-C8) cycloalkyl, 6. The compound of any one of embodiments 1, 2, 3, 4, and 5, wherein the (C1-C8)alkyl is (C1-C8)alkyl substituted with up to two substituents selected from the group consisting of aryl, aryl, heteroaryl, and (C3-C8)heterocycle, wherein one of the -CH2- groups in the (C1-C8)alkyl is optionally replaced by -S- or -O-. Embodiment 10. The blocking group Abl is R a1 -C(O)- or Ra1 -S(O2)- and R a1 is (C1-C6) alkyl, and optionally one of the -CH2- groups is replaced by -S- or -O-. Embodiment 11. The compound of embodiment 10, wherein the blocking group Abl is hexanoyl or pentylsulfonyl, preferably the blocking group Abl is hexanoyl. Embodiment 12. The amino acids Aaa each have the structure (XIV):

[0075] [ka]

[0076] is a D-amino acid residue or an L-amino acid residue of R a2 is selected from the group consisting of (C1-C6)alkyl, modified (C1-C6)alkyl, (C1-C3)alkyl, modified (C1-C3)alkyl, (C3-C8)carbocycle, aryl, heteroaryl, and (C3-C8)heterocycle, in which one -CH2- group is replaced by -S- or -O-, in which one H is replaced by OH, F, or COOH or two H are replaced by F, and R a3 The compound according to any one of embodiments 1, 2, 3, 4, 5, wherein is preferably H or acetyl. Embodiment 13. R a2 is (C1-C6) alkyl, and one of said (C1-C6) -CH2- groups is replaced by -S-. Embodiment 14. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, preferably 12 to 13, wherein Aaa is selected from the group consisting of amino acid residues of Nle, nle, Met, and met, and derivatives thereof. Embodiment 15. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, wherein Xaa1 is a D-amino acid residue selected from the group consisting of cys, hcy, and pen, or Xaa1 is an L-amino acid residue selected from the group consisting of Cys, Hcy, and Pen. Embodiment 16 The compound of embodiment 15, wherein Xaa1 is Cys. Embodiment 17 The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, wherein Xaa2 is an amino acid residue selected from the group consisting of Pro, Gly, Nmg, and derivatives thereof. Embodiment 18 The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17, wherein Xaa3 is an amino acid residue selected from the group consisting of Pro, Hyp, Tfp, Cfp, Dmp, Aze, and Pip, and derivatives thereof. Embodiment 19 The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18, wherein Xaa4 is an amino acid residue selected from the group consisting of Thr, Hse, Asn, Gln, and Ser, and derivatives thereof. Embodiment 20. The method of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19, wherein Xaa5 is an amino acid residue selected from the group consisting of Gln and Glu, and derivatives thereof. Compound. Embodiment 21. Xaa6 is selected from the group consisting of formulas (VIIIa), (VIIIb), (VIIIc), and (VIIId)

[0077] [ka]

[0078] is any one of the amino acid residues R 6a and R 6b are each independently selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl; R 6c represents 0 to 3 substituents, each of which is independently Cl, F, Br, NO2, NH2, CN, CF3, OH, OR 6d and C1-C4 alkyl; R 6d is selected from the group consisting of methyl, ethyl, propyl, and isopropyl; The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, wherein s is 0 or 1. Embodiment 22. Xaa6 is selected from the group consisting of formulas (VIIIa), (VIIIb), (VIIIc), and (VIIId)

[0079] [ka]

[0080] is any one of the amino acid residues R 6a and R 6b are H, respectively, R 6c represents 0 to 2 substituents, each of which is independently Cl, F, Br, NO2, NH2, CN, CF3, OH, OR 6d and methyl; R 6d is selected from the group consisting of methyl, ethyl, propyl, and isopropyl; The compound of embodiment 21, wherein s is 0. Embodiment 23 The compound of any one of embodiments 21 to 22, wherein Xaa6 is an amino acid residue selected from the group consisting of Phe, Ocf, Ppa, Thi, 1Ni, Otf, and Mpa, and derivatives thereof. Embodiment 24 The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23, wherein Xaa7 is an aminothiol residue selected from the group consisting of Cys, Cysol, AET, Hcy, cys, and hcy. Embodiment 25 The compound of embodiment 24, wherein Xaa7 is an aminothiol residue selected from the group consisting of Cys, Cysol, and AET. Embodiment 26. Formula (LI), (LII), (LIII), or (LIV)

[0081] [ka]

[0082] 26. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25, wherein the compound is Embodiment 27. Formula (LI), (LII), (LIII), or (LIV)

[0083] [ka]

[0084] 24, and 25, preferably any one of claims 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25, comprising the structure: Embodiment 28. R c2 Formula (XXIIa), (XIb), and (XIIa)

[0085] [ka]

[0086] It is one of the structures R c4 is H or methyl, u=1, 2, 3, 4, or 5, In formulas (XIb) and (XXIIa), any one of the nitrogen atoms is R c1 In formula (XIIa), -S- is bonded to -CH2-, and in formula (XIIa), -S- is bonded to -CH2-. c1 28. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27, wherein the —CH— is bonded to —CH—. Embodiment 29. Yc is a compound represented by formula (XIII)

[0087] [ka]

[0088] 29. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28, wherein the compound has the structure: Embodiment 30. Yc comprises an NH group, preferably a reactive NH group, said NH group allowing for conjugation to a moiety of Yc, preferably said NH group having the structure R c2 Provided by R c2 Formula (XXIb), (XIc), and (XIIb)

[0089] [ka]

[0090] and R c4 is H or methyl, 30. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29, wherein u=1, 2, 3, 4, or 5. Embodiment 31. The structure R c2 is represented by formula (XXIIb) or (XIIc)

[0091] [ka]

[0092] 31. The compound of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, wherein Embodiment 32. A compound according to any one of embodiments 30 to 31, The compound, wherein the compound comprises a Z group, the Z group is covalently linked to Yc, preferably a structure of formula (X), the Z group comprising a chelator and optionally a linker. Embodiment 33. The Z group is R c2 and covalently bonded to the formula (XXIIc), (XId), and (XIId)

[0093] [ka]

[0094] Form one of the following structures, R c4 is H or methyl, The compound of embodiment 32, wherein u=1, 2, 3, 4, or 5. Embodiment 34. The Z group comprises a linker, and the linker connects the chelator to Yc, preferably R c2 34. The compound of any one of embodiments 32-33, wherein the compound is covalently linked to Embodiment 35. Between Yc and the linker, preferably Rc2 and the linker is an amide. Embodiment 36. The compound of any one of embodiments 34 to 35, wherein the chelator is covalently linked to the linker, and the covalent linkage is selected from the group consisting of an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage, a sulfonamide linkage, a triazole linkage, and a disulfide linkage. Embodiment 37. A compound according to any one of embodiments 32, 33, 34, 35 and 36, preferably any one of claims 34, 35 and 36, wherein the linker is selected from the group comprising Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12 and other PEG-amino acids, most preferably Ttds, O2Oc, Apac, 4Amc, PEG6 and PEG12. Embodiment 38. The chelator is covalently linked to Yc, preferably R c2 34. The compound of any one of embodiments 32-33, wherein the compound is covalently linked to Embodiment 39 The compound of embodiment 38, wherein the chelator is linked directly to Yc. Embodiment 40 The compound of any one of Embodiments 38 to 39, wherein the Z group lacks any linker. Embodiment 41. Between Yc and the chelator, preferably R c2 The compound of any one of embodiments 38, 39, and 40, wherein the covalent linkage between and said chelator is an amide. Embodiment 42. The chelator is DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcofagin, FSC, NETA, H4octapa, Pycup, N x S 4-x(N4, N2S2, N3S), Hynic, 99m The compound according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, and 41, preferably any one of embodiments 32, 33, 34, 35, 36, 37, 38, 39, 40, and 41, being selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOTA, and NODAGA. Embodiment 43. Any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 42, preferably claims 1, 2, 3, 4, 5, 6, 7, 8, 12, 13, 14, 15, 16, 17, 18 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, Embodiment 44. The compound of embodiment 43, wherein the Z group comprises a linker, said linker covalently linking said chelator to said amino acid Aaa, preferably to the α-nitrogen of said amino acid Aaa. Embodiment 45 The compound of embodiment 44, wherein the covalent linkage between the linker and the α-nitrogen of amino acid Aaa is an amide. Embodiment 46. The compound of any one of embodiments 44 to 45, wherein the chelator is covalently linked to the linker, and the covalent linkage is selected from the group consisting of an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage, a sulfonamide linkage, a triazole linkage, and a disulfide linkage. Embodiment 47. The compound of any one of embodiments 43, 44, 45, and 46, wherein the linker is selected from the group including Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12, and other PEG-amino acids, most preferably Ttds, O2Oc, Apac, 4Amc, PEG6, and PEG12, and preferably the linker amino acid is selected from the group consisting of Tdts, O2Oc, and PEG6. Embodiment 48 The compound of any one of embodiments 43, 44, 45, 46, and 47, wherein the chelator is covalently linked to amino acid Aaa. Embodiment 49 The compound of embodiment 48, wherein the chelator is linked directly to amino acid Aaa. Embodiment 50 The compound of any one of embodiments 48 to 49, wherein the Z group lacks any linker. Embodiment 51 The compound of any one of embodiments 48, 49, and 50, wherein the covalent linkage between the amino acid Aaa and the chelator is an amide. Embodiment 52. The chelator is DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcofagin, FSC, NETA, H4octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic, 99mThe compound according to any one of embodiments 43, 44, 45, 46, 47, 48, 49, 50, and 51, which is selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOTA, and NODAGA. Embodiment 53. Any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, wherein an amino acid or peptide is attached to Xaa7, the majority of the amino acids of the peptide are charged or polar, and the net charge of the peptide is -2, -1, 0, +1, or +2. , 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 and 52, preferably a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 42. Embodiment 54. The peptide has the formula (XXXa-f): Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16 (XXXa) Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15 (XXXb) Xaa10-Xaa11-Xaa12-Xaa13-Xaa14 (XXXc) Xaa10-Xaa11-Xaa12-Xaa13 (XXXd) Xaa10-Xaa11-Xaa12 (XXXe) Xaa10-Xaa11 (XXXf) and Xaa10 is Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf, Lys, Ttds, or Bhk; Xaa11 is His, his, Lys, Ttds, Arg, Ape, or Ala; Xaa12 is Phe, Nmf, Tic, Aic, Ppa, Mpa, Amf, Nmf, phe, Lys, Ape, Ttds, and Ppa; Xaa13 is Arg, Lys, Ape, Ttds, or arg; Xaa14 is Asp, Ala, asp, Lys, Ape, or Ttds; Xaa15 is Ttds, Ape, or Lys; Xaa16 is Lys or Ape, as needed, Xaa11 and Xaa12 together form a single amino acid selected from the group consisting of Gab, Pamb, Cmp, Pamb, and Mamb, and optionally Xaa10, Xaa11, and Xaa12 together form a single amino acid selected from the group consisting of Gab, Pamb, Cmp, Pamb, and Mamb; The compound according to embodiment 53, with the proviso that in the peptides of formulae (XXXa-f), Ape, if present, is the C-terminal building block. Embodiment 55. A compound according to any one of embodiments 53 to 54, wherein the amino acid attached to Xaa7 is Xaa10 of claim 46, preferably wherein the amino acid attached to Xaa7 is Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf, Lys, Ape, Ttds, or Bhk. Embodiment 56 The compound of any one of embodiments 53 to 55, wherein the Z group is covalently attached to the peptide, preferably to the C-terminal amino acid of the peptide, and wherein the Z group comprises a chelator and optionally a linker. Embodiment 57. The compound of embodiment 56, wherein the Z group is covalently attached to the C-terminal amino acid of the peptide, preferably to the C-terminal amino acid of any one of the peptides of formula (XXXa), (XXXb), (XXXc), (XXXd), (XXXe), and (XXXf). Embodiment 58 The compound of any one of embodiments 53, 54, and 55, wherein the Z group is covalently attached to the amino acid attached to Xaa7, and said Z group comprises a chelator and optionally a linker. Embodiment 59. The compound of any one of embodiments 53, 54, 55, 56, 57, and 58, wherein the Z group comprises a linker that covalently links the chelator to the amino acid attached to Xaa7, preferably when the peptide is not attached to Xaa7, or that covalently links the chelator to the C-terminus of the peptide, preferably to the C-terminal amino acid of any one of the peptides of formula (LI), (LII), (LIII), and (LIV). Embodiment 60 The compound of embodiment 59, wherein the covalent linkage is an amide bond. Embodiment 61. The compound of any one of embodiments 59 to 60, wherein the chelator is covalently linked to the linker, and the covalent linkage is selected from the group consisting of an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage, a sulfonamide linkage, a triazole linkage, and a disulfide linkage. Embodiment 62. The compound of any one of embodiments 59, 60, and 61, wherein the linker is selected from the group consisting of Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12, and other PEG-amino acids. Embodiment 63 The compound of embodiment 62, wherein the linker is selected from the group consisting of Ttds, O2Oc, Apac, 4Amc, PEG6, and PEG12. Embodiment 64. The compound of any one of embodiments 56, 57, and 58, wherein the chelator is covalently linked to the amino acid attached to Xaa7, or the chelator is covalently linked to the C-terminal amino acid of the peptide, preferably the C-terminal amino acid of any one of the peptides of formula (LI), (LII), (LIII), and (LIV). Embodiment 65. The compound of embodiment 64, wherein the chelator is linked directly to the amino acid attached to Xaa7 or to the C-terminal amino acid of the peptide, preferably the C-terminal amino acid of any one of the peptides of formula (LI), (LII), (LIII), and (LIV). Embodiment 66 The compound of any one of embodiments 64 to 65, wherein the Z group lacks any linker. Embodiment 67. The compound of any one of embodiments 64, 65, and 66, wherein the covalent linkage between the chelator and the amino acid attached to Xaa7 and the covalent linkage between the chelator and the C-terminal amino acid of the peptide, preferably the C-terminal amino acid of any one of the peptides of Formulae (LI), (LII), (LIII), and (LIV), is an amide bond. Embodiment 68. The chelator is DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcofagin, FSC, NETA, H4octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic, 99m The compound of any one of embodiments 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, and 67, which is selected from the group consisting of Tc(CO)3-chelators, more preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4, most preferably DOTA, DOTAGA, NOTA, and NODAGA. Embodiment 69:

[0095] [ka]

[0096] and diastereomers of the formula

[0097] [ka]

[0098] 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, and 168, wherein the non-stereochemically specified stereocenters (marked with an asterisk) are individually and independently of one another R- or S-configured. Embodiment 70:

[0099] [ka]

[0100] Compounds of H-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-Ttds-Lys(Bio)-NH2 (3BP-2881), The following formula

[0101] [ka]

[0102] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-2974),

[0103] [ka]

[0104] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-2975), The following formula

[0105] [ka]

[0106] The compound H-met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-2976), The following formula

[0107] [ka]

[0108] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-Ttds-Lys(DOTA)-NH2 (3BP-3105), The following formula

[0109] [ka]

[0110] The compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3168), The following formula

[0111] [ka]

[0112] The compound DOTA-Ttds-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3169), The following formula

[0113] [ka]

[0114] The compound DOTA-Ttds-Leu-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3172), The following formula

[0115] [ka]

[0116] The compound Ac-Met-[cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3175), The following formula

[0117] [ka]

[0118] The compound Ac-met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3187), The following formula

[0119] [ka]

[0120] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Nmf-Arg-Asp-NH2 (3BP-3188), The following formula

[0121] [ka]

[0122] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Tic-Arg-Asp-NH2 (3BP-3189), The following formula

[0123] [ka]

[0124] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Aic-Arg-Asp-NH2 (3BP-3190), The following formula

[0125] [ka]

[0126] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ppa-Arg-Asp-NH2 (3BP-3191), The following formula

[0127] [ka]

[0128] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Mpa-Arg-Asp-NH2 (3BP-3192), The following formula

[0129] [ka]

[0130] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Thi-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3193), The following formula

[0131] [ka]

[0132] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Ala-Phe-Arg-Asp-NH2 (3BP-3195), The following formula

[0133] [ka]

[0134] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ala-Arg-Asp-NH2 (3BP-3196), The following formula

[0135] [ka]

[0136] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Ala-NH2 (3BP-3198), The following formula

[0137] [ka]

[0138] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-NH2 (3BP-3200), The following formula

[0139] [ka]

[0140] The compound Ac-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3202), The following formula

[0141] [ka]

[0142] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Amf-Arg-Asp-NH2 (3BP-3203), The following formula

[0143] [ka]

[0144] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-his-Phe-Arg-Asp-NH2 (3BP-3210), The following formula

[0145] [ka]

[0146] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-phe-Arg-Asp-NH2 (3BP-3211), The following formula

[0147] [ka]

[0148] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-arg-Asp-NH2 (3BP-3212), The following formula

[0149] [ka]

[0150] The compound Ac-Met-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-asp-NH2 (3BP-3213), The following formula

[0151] [ka]

[0152] The compound Ac-Met-[Cys(3MeBn)-Gly-Pro-Thr-Glu-Phe-Cys]-Asp-His-Phe-Arg-Asp-NH2 (3BP-3214), The following formula

[0153] [ka]

[0154] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Nmf-Arg-Ttds-Lys(DOTA)-NH2 (3BP-3275), The following formula

[0155] [ka]

[0156] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-phe-Arg-Ttds-Lys(DOTA)-NH2 (3BP-3276), The following formula

[0157] [ka]

[0158] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-His-Ppa-arg-Ttds-Lys(DOTA)-NH2 (3BP-3277), The following formula

[0159] [ka]

[0160] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH2 (3BP-3288), The following formula

[0161] [ka]

[0162] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Arg-NH2 (3BP-3299), The following formula

[0163] [ka]

[0164] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Gab-Arg-NH2 (3BP-3300), The following formula

[0165] [ka]

[0166] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Pamb-Arg-NH2 (3BP-3301), The following formula

[0167] [ka]

[0168] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Cmp-Arg-NH2 (3BP-3302) The following formula

[0169] [ka]

[0170] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Pamb-Arg-NH2 (3BP-3303), The following formula

[0171] [ka]

[0172] The compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-NH2 (3BP-3319), The following formula

[0173] [ka]

[0174] The compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-NH2 (3BP-3320), The following formula

[0175] [ka]

[0176] The compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Pamb-Arg-NH2 (3BP-3321), The following formula

[0177] [ka]

[0178] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Mamb-Arg-NH2 (3BP-3324), The following formula

[0179] [ka]

[0180] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3349), The following formula

[0181] [ka]

[0182] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Bal-OH (3BP-3371), The following formula

[0183] [ka]

[0184] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-3395), The following formula

[0185] [ka]

[0186] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-3396), The following formula

[0187] [ka]

[0188] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA)-OH (3BP-3397), The following formula

[0189] [ka]

[0190] The compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (3BP-3398), The following formula

[0191] [ka]

[0192] The compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3401), The following formula

[0193] [ka]

[0194] the compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ape(DOTA) (3BP-3403), The following formula

[0195] [ka]

[0196] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Ape(DOTA) (3BP-3404), The following formula

[0197] [ka]

[0198] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Otf-Cys]-NH2 (3BP-3409), The following formula

[0199] [ka]

[0200] The compound pentylNH-urea-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3425), The following formula

[0201] [ka]

[0202] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3426), The following formula

[0203] [ka]

[0204] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3476), The following formula

[0205] [ka]

[0206] The compound Hex-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Bhk(DOTA-Ttds)-OH (3BP-3489), The following formula

[0207] [ka]

[0208] The compound pentyl-SO2-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3514), The following formula

[0209] [ka]

[0210] The compound Hex-[Cys(2Lut)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3518), The following formula

[0211] [ka]

[0212] The compound Hex-[Cys(3Lut)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3519), The following formula

[0213] [ka]

[0214] The compound Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3555), The following formula

[0215] [ka]

[0216] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-1Ni-Cys]-OH (3BP-3650), The following formula

[0217] [ka]

[0218] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-OH (3BP-3651), The following formula

[0219] [ka]

[0220] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3652), The following formula

[0221] [ka]

[0222] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu-Phe-Cys]-NH2 (3BP-3653), The following formula

[0223] [ka]

[0224] the compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-AET] (3BP-3654), The following formula

[0225] [ka]

[0226] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Gly-OH (3BP-3656), The following formula

[0227] [ka]

[0228] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Gab-OH (3BP-3657), The following formula

[0229] [ka]

[0230] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Ser-OH (3BP-3658), The following formula

[0231] [ka]

[0232] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Nmg-OH (3BP-3659), The following formula

[0233] [ka]

[0234] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Bhf-OH (3BP-3660), The following formula

[0235] [ka]

[0236] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Mpa-Cys]-OH (3BP-3664), The following formula

[0237] [ka]

[0238] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-OH (3BP-3665), The following formula

[0239] [ka]

[0240] The compound Hex-[Cys(tMeBn(DOTA-AET))-Nmg-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3678), The following formula

[0241] [ka]

[0242] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Hyp-Thr-Gln-Phe-Cys]-OH (3BP-3679), The following formula

[0243] [ka]

[0244] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Otf-Cys]-OH (3BP-3680), The following formula

[0245] [ka]

[0246] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-asp-NH2 (3BP-3681), The following formula

[0247] [ka]

[0248] The compound pentyl-SO2-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3690), The following formula

[0249] [ka]

[0250] The compound pentyl-SO2-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-3691), The following formula

[0251] [ka]

[0252] The compound pentyl-SO2-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3692), The following formula

[0253] [ka]

[0254] The compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3712), The following formula

[0255] [ka]

[0256] the compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-AET] (3BP-3713), The following formula

[0257] [ka]

[0258] The compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Gly-OH (3BP-3714), The following formula

[0259] [ka]

[0260] The compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Nmg-OH (3BP-3715), The following formula

[0261] [ka]

[0262] The compound Hex-[Cys(tMeBn(InDOTA-AET))-Nmg-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3716), The following formula

[0263] [ka]

[0264] The compound pentyl-SO2-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3717), The following formula

[0265] [ka]

[0266] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Bal-NH2 (3BP-3736), The following formula

[0267] [ka]

[0268] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Nmg-NH2 (3BP-3737), The following formula

[0269] [ka]

[0270] The compound Hex-[Cys(tMeBn(DOTA-AET))-Nmg-Pro-Thr-Gln-Phe-Cys]-NH2 (3BP-3744), The following formula

[0271] [ka]

[0272] the compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cysol] (3BP-3767), The following formula

[0273] [ka]

[0274] The compound Hex-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3770), The following formula

[0275] [ka]

[0276] The compound Hex-[Cys(tMeBn(DOTA-PP))-Nmg-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3771), The following formula

[0277] [ka]

[0278] The compound Hex-[Cys-(tMeBn(H-O2Oc-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3967), The following formula

[0279] [ka]

[0280] The compound H-Ahx-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3980), The following formula

[0281] [ka]

[0282] The compound Hex-[Cys-(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3981), The following formula

[0283] [ka]

[0284] The compound Hex-[Cys-(tMeBn(H-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-4003), The following formula

[0285] [ka]

[0286] The compound H-Ahx-Ttds-Nle-[Cys-(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-4004), The following formula

[0287] [ka]

[0288] The compound Hex-[Cys-(tMeBn(N4Ac-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4063), The following formula

[0289] [ka]

[0290] The compound Hex-[Cys-(tMeBn(N4Ac-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4088), The following formula

[0291] [ka]

[0292] The compound Hex-[Cys-(tMeBn(H-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4089), The following formula

[0293] [ka]

[0294] The compound Hex-[D-Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4109), The following formula

[0295] [ka]

[0296] The compound N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4161), The following formula

[0297] [ka]

[0298] The compound Hex-[Cys-(tMeBn(NODAGA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4162), The following formula

[0299] [ka]

[0300] The compound Hex-[Cys-(tMeBn(N4Ac-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4168), The following formula

[0301] [ka]

[0302] The compound Hex-[Cys-(tMeBn(N4Ac-O2Oc-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4169), The following formula

[0303] [ka]

[0304] The compound Hex-[Cys-(tMeBn(Bio-Ttds-Ttds-Ttds-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4170), The following formula

[0305] [ka]

[0306] The compound Hex-[Cys-(tMeBn(H-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4181), The following formula

[0307] [ka]

[0308] The compound Hex-[Cys(tMeBn(ATTO488-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4182), The following formula

[0309] [ka]

[0310] The compound Hex-[Cys-(tMeBn(GaNODAGA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4184), The following formula

[0311] [ka]

[0312] The compound Hex-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4186), The following formula

[0313] [ka]

[0314] The compound Hex-[Cys-(tMeBn(DTPA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4214), The following formula

[0315] [ka]

[0316] The compound N4Ac-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4219), The following formula

[0317] [ka]

[0318] the compound N4Ac-PEG6-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4221), The following formula

[0319] [ka]

[0320] The compound N4Ac-Glu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4222), The following formula

[0321] [ka]

[0322] The compound Hex-[Cys-(tMeBn(DTPA-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4224), The following formula

[0323] [ka]

[0324] The compound N4Ac-Efa-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4243), The following formula

[0325] [ka]

[0326] The compound N4Ac-gGlu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4245), The following formula

[0327] [ka]

[0328] The compound N4Ac-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4246), The following formula

[0329] [ka]

[0330] The compound N4Ac-gGlu-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4247), The following formula

[0331] [ka]

[0332] The compound N4Ac-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4249), The following formula

[0333] [ka]

[0334] The compound Hex-[Cys-(tMeBn(DOTA-AET))-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4250), The following formula

[0335] [ka]

[0336] The compound Hex-[Cys-(tMeBn(NODAGA-O2Oc-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4251), The following formula

[0337] [ka]

[0338] The compound N4Ac-Glu(AGLU)-Glu(AGLU)-Ttds-Nle-[Cys-(3MeBn)-Pro-Pro-Thr-Glu-Phe-Cys]-OH (3BP-4266), The following formula

[0339] [ka]

[0340] The compound Hex-[Cys-(tMeBn(N4Ac-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4299), The following formula

[0341] [ka]

[0342] the compound Hex-[Cys-(tMeBn(N4Ac-PEG6-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4300), The following formula

[0343] [ka]

[0344] the compound Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4301), The following formula

[0345] [ka]

[0346] The compound Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4302), The following formula

[0347] [ka]

[0348] the compound Hex-[Cys-(tMeBn(H-Asp-Asp-Cys-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4303), The following formula

[0349] [ka]

[0350] The compound Hex-[Cys-(tMeBn(H-SAc-Ser-Ser-Ser-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4308), The following formula

[0351] [ka]

[0352] The compound Hex-[Cys-(tMeBn(DTPA2-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4309), The following formula

[0353] [ka]

[0354] The compound Hex-[Cys-(tMeBn(NOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4310), The following formula

[0355] [ka]

[0356] The compound Hex-[Cys-(tMeBn(H-HYNIC-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4342), The following formula

[0357] [ka]

[0358] The compound Hex-[Cys-(tMeBn(NOTA-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4344), The following formula

[0359] [ka]

[0360] The compound Hex-[Cys-(tMeBn(DTPA2-Ttds-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4352), The following formula

[0361] [ka]

[0362] The compound Hex-[Cys-(tMeBn(DTPA2-PEG6-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4353), The following formula

[0363] [ka]

[0364] The compound Hex-[Cys-(tMeBn(DTPABzl-Glutar-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4366), The following formula

[0365] [ka]

[0366] The compound Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Gab-Arg-Ttds-Lys(AF488)-NH2 (3BP-4372), The following formula

[0367] [ka]

[0368] The compound Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Gab-Arg-Ttds-Ttds-Ttds-Lys(AF488)-NH2 (3BP-4373), The following formula

[0369] [ka]

[0370] The compound Hex-[Cys-(tMeBn(H-HYNIC-Ttds--AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4376), The following formula

[0371] [ka]

[0372] The compound Hex-[Cys-(tMeBn(PCTA--AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4379), The following formula

[0373] [ka]

[0374] The compound Hex-[Cys-(tMeBn(NOPO--AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4380), The following formula

[0375] [ka]

[0376] The compound Hex-[Cys-(tMeBn(HBED--AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4381), The following formula

[0377] [ka]

[0378] The compound Hex-[Cys-(tMeBn(DATA--AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4382), The following formula

[0379] [ka]

[0380] The compound DOTA-Ttds-Nle-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4386), The following formula

[0381] [ka]

[0382] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-4391), The following formula

[0383] [ka]

[0384] the compound DOTA-Ttds-Nle-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-4392), and The following formula

[0385] [ka]

[0386] Compound DOTA-Ttds-Nle-[Cys(3MeBn)-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-Ttds-Lys(DOTA)-NH2 (3BP-4393) 70. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, and 69, selected from the group consisting of: Embodiment 71. The following formula:

[0387] [ka]

[0388] The compound Hex-[Cys(tMeBn(DOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3554) and The following formula

[0389] [ka]

[0390] The compound Hex-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70, wherein the compound is different from a compound selected from the group consisting of (3BP-3407). Embodiment 72. Any S atom that can be oxidized, preferably an S atom of a thioether group, is present as -S-, -S(O)-, or -S(O2)-, or a mixture thereof, as in any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 11 7, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, and 71. Embodiment 73. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, which is capable of binding to fibroblast activation protein (FAP). Embodiment 74. The compound of any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, and 73, comprising a diagnostically active nuclide or a therapeutically active nuclide. Embodiment 75:

[0391] [ka]

[0392] The compound Hex-[Cys(tMeBn(InDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3590), The following formula

[0393] [ka]

[0394] The compound Hex-[Cys(tMeBn(LuDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3591), The following formula

[0395] [ka]

[0396] The compound Hex-[Cys(tMeBn(GaDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3592), The following formula

[0397] [ka]

[0398] The compound Hex-[Cys(tMeBn(EuDOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-Asp-NH2 (3BP-3661), The following formula

[0399] [ka]

[0400] The compound Hex-[Cys(tMeBn(InDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3623), The following formula

[0401] [ka]

[0402] The compound Hex-[Cys(tMeBn(LuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3624), The following formula

[0403] [ka]

[0404] the compound Hex-[Cys(tMeBn(EuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3662), and The following formula

[0405] [ka]

[0406] The compound Hex-[Cys(tMeBn(GaDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-3949), The following formula

[0407] [ka]

[0408] The compound Hex-[Cys-(tMeBn(CuDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4293), The following formula

[0409] [ka]

[0410] The compound Hex-[Cys-(tMeBn(ZnDOTA-AET))-Pro-Pro-Thr-Gln-Phe-Cys]-OH (3BP-4343) The compound of embodiment 74, which is different from a compound selected from the group consisting of: Embodiment 76 The compound of any one of embodiments 74 and 75, wherein the diagnostically active nuclide is a diagnostically active radionuclide. Embodiment 77. The diagnostically active radionuclide is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, preferably 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, most preferably 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18F, 123 I, and 124 The compound of embodiment 76, selected from the group consisting of I. Embodiment 78 The compound of embodiment 76, wherein the therapeutically active nuclide is a therapeutically active radionuclide. Embodiment 79. The therapeutically active radionuclide is 47 Sc, 67 Cu, 89 Sr, 90 Y, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I, 211 At, preferably 47 Sc, 67 Cu, 90 Y, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I, 211 At, most preferably 90 Y, 177 Lu, 225 Ac, 227 Th, 131 I, and 211 The compound of embodiment 78, selected from the group consisting of At. Embodiment 80. A method according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 2, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, and 79, wherein the amino acid sequence of the homolog has at least 85% identity with the amino acid sequence of SEQ ID NO:1. Embodiment 81 The compound of embodiment 80 which is an inhibitor of fibroblast activation protein (FAP). Embodiment 82. Any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, having a pIC50 value against the human FAP of SEQ ID NO: 1 of 6.0 or more, preferably 7.0 or more, and most preferably 8.0 or more. 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, and 81. Embodiment 83. The method of any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, for use in a method for the diagnosis of a disease. 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82. Embodiment 84. A compound for use according to embodiment 83, wherein the disease is a disease involving upregulated expression of fibroblast activation protein (FAP), preferably fibroblast activation protein (FAP). Embodiment 85. The compound for use according to any one of embodiments 83 to 84, wherein the disease involves diseased tissues comprising cells exhibiting upregulated expression of fibroblast activation protein (FAP), preferably cells exhibiting upregulated expression of fibroblast activation protein (FAP), more preferably a disease involving fibroblasts associated with a tumor. Embodiment 86. A compound for use according to any one of embodiments 83 to 85, wherein the disease is a neoplasm, preferably a cancer or tumor. Embodiment 87. The compound for use according to embodiment 86, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, and thyroid cancer. Embodiment 88. The compound for use according to embodiment 87, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising breast cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma. Embodiment 89. The compound for use according to any one of embodiments 83 to 85, wherein the disease is selected from the group comprising inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases. Embodiment 90 The compound for use according to embodiment 89, wherein the disease is an inflammatory disease. Embodiment 91. A compound for use according to embodiment 90, wherein the disease is atherosclerosis, arthritis, or rheumatoid arthritis. Embodiment 92 The compound for use according to embodiment 91, wherein the disease is a cardiovascular disease. Embodiment 93. A compound for use according to embodiment 92, wherein the disease is a cardiovascular disease associated with atherosclerotic plaques. Embodiment 94. A compound for use according to embodiment 93, wherein the disease is an atherosclerotic lesion caused by plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis, or vascular occlusion. Embodiment 95 The compound for use according to embodiment 83, wherein the disease is a fibrotic disease. Embodiment 96. The compound for use according to embodiment 95, wherein the disease is selected from the group comprising idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis. Embodiment 97. The compound for use according to any one of embodiments 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, and 96, comprising a diagnostically active nuclide, preferably a diagnostically active radionuclide. Embodiment 98. The diagnostically active nuclide 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb,18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, preferably 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, more preferably 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18 F, 123 I, and 124 The compound for use according to embodiment 97, selected from the group comprising I. Embodiment 99 The compound for use according to any one of embodiments 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, and 98, wherein the method for diagnosis is an imaging method. Embodiment 100. The compound for use according to embodiment 98, wherein the imaging method is selected from the group consisting of scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET). Embodiment 101. The compound for use according to any one of embodiments 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100, wherein the method comprises administering a diagnostically effective amount of the compound to a subject, preferably a mammal, wherein the mammal is selected from the group comprising humans, companion animals, pets, and livestock, more preferably the subject is selected from the group comprising humans, dogs, cats, horses, and cows, and most preferably the subject is a human. Embodiment 102. The compound of any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, for use in a method for treating a disease. 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82. Embodiment 103. A compound for use according to embodiment 102, wherein the disease is a fibroblast activation protein (FAP), preferably a disease in which upregulated expression of fibroblast activation protein (FAP) is involved. Embodiment 104. A compound for use according to any one of embodiments 102 to 103, wherein the disease involves cells exhibiting upregulated expression of fibroblast activation protein (FAP), preferably diseased tissue comprising cells exhibiting upregulated expression of fibroblast activation protein (FAP), more preferably a disease involving fibroblasts associated with a tumor. Embodiment 105. A compound for use according to any one of embodiments 102 to 104, wherein the disease is a neoplasm, preferably a cancer or tumor. Embodiment 106. The compound for use according to embodiment 105, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, and thyroid cancer. Embodiment 107. The compound for use according to embodiment 106, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising breast cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma. Embodiment 108. The compound for use according to any one of embodiments 102, 103, and 104, wherein the disease is selected from the group comprising inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases. Embodiment 109 The compound for use according to embodiment 108, wherein the disease is an inflammatory disease. Embodiment 110. A compound for use according to embodiment 109, wherein the disease is atherosclerosis, arthritis, or rheumatoid arthritis. Embodiment 111 The compound for use according to embodiment 108, wherein the disease is a cardiovascular disease. Embodiment 112. A compound for use according to embodiment 111, wherein the disease is a cardiovascular disease associated with atherosclerotic plaques. Embodiment 113. A compound for use according to embodiment 112, wherein the disease is an atherosclerotic lesion caused by plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis, or vascular occlusion. Embodiment 114 The compound for use according to embodiment 108, wherein the disease is a fibrotic disease. Embodiment 115. A compound for use according to embodiment 114, wherein the disease is selected from the group comprising idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis. Embodiment 116. A compound for use according to any one of embodiments 102, 103, 104, and 105, comprising a therapeutically active nuclide, preferably a therapeutically active radionuclide. Embodiment 117. The therapeutically active nuclide is 47 Sc, 67 Cu, 89 Sr, 90 Y, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I, 211 At, preferably 47 Sc, 67 Cu, 90 Y, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I, 211 At, most preferably 90 Y, 177 Lu, 225 Ac, 227 Th, 131 I, and 211 The compound for use according to embodiment 116, selected from the group comprising At. Embodiment 118. The compound for use according to any one of embodiments 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, and 117, wherein the method comprises administering a therapeutically effective amount of the compound to a subject, preferably a mammal, wherein the mammal is selected from the group comprising humans, companion animals, pets, and livestock, more preferably the subject is selected from the group comprising humans, dogs, cats, horses, and cattle, and most preferably the subject is a human. Embodiment 119. Any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 for use in a method for identifying a subject. 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82, wherein the subject is likely to respond or not likely to respond to treatment of a disease, and the method for identifying a subject is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 , 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 and 82, preferably comprising a step of performing a method for the diagnosis of a disease described in any one of embodiments 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 and 101. Embodiment 120. The method of any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 for use in a method for selecting a subject from a group of subjects. 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82, wherein the subject is likely to respond or not likely to respond to treatment of a disease, and the method for selecting a subject from a group of subjects comprises the steps of: , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 , 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 and 82, preferably comprising a step of performing a method for the diagnosis of a disease described in any one of embodiments 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 and 101. Embodiment 113. Any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 for use in a method for stratifying a group of subjects into subjects likely to respond to treatment of a disease and subjects not likely to respond to treatment of a disease. 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82, wherein the method for stratifying a group of subjects comprises the steps of: 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 , 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 and 82, preferably comprising a step of performing a method for the diagnosis of a disease described in any one of embodiments 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 and 101. Embodiment 122 The compound for use according to any one of embodiments 119, 120 and 121, wherein the disease is a disease involving upregulated expression of fibroblast activation protein (FAP), preferably fibroblast activation protein (FAP). Embodiment 123. The compound for use according to any one of embodiments 119, 120, 121, and 122, wherein the disease involves diseased tissues comprising cells that exhibit upregulated expression of fibroblast activation protein (FAP), preferably cells that exhibit upregulated expression of fibroblast activation protein (FAP), more preferably a disease involving tumor-associated fibroblasts. Embodiment 124. A compound for use according to any one of embodiments 119, 120, 121, 122, and 123, wherein the disease is a neoplasm, preferably a cancer or tumor. Embodiment 125. The compound for use according to embodiment 124, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, and thyroid cancer. Embodiment 126. The compound for use according to embodiment 125, wherein the neoplasms, cancers, and tumors are each individually selected from the group consisting of breast cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma. Embodiment 127. The compound for use according to any one of embodiments 119, 120, 121, 122, and 123, wherein the disease is selected from the group comprising inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases. Embodiment 128 The compound for use according to embodiment 127, wherein the disease is an inflammatory disease. Embodiment 129. A compound for use according to embodiment 128, wherein the disease is atherosclerosis, arthritis, or rheumatoid arthritis. Embodiment 130. A compound for use according to embodiment 129, wherein the disease is a cardiovascular disease. Embodiment 131. A compound for use according to embodiment 130, wherein the disease is a cardiovascular disease associated with atherosclerotic plaques. Embodiment 132. A compound for use according to embodiment 131, wherein the disease is an atherosclerotic lesion caused by plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis, or vascular occlusion. Embodiment 133 The compound for use according to embodiment 127, wherein the disease is a fibrotic disease. Embodiment 134. A compound for use according to embodiment 1335, wherein the disease is selected from the group comprising idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis. Embodiment 135 The compound for use according to any one of embodiments 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, and 134, wherein the method of diagnosis is an imaging method. Embodiment 136 The compound for use according to embodiment 135, wherein the imaging method is selected from the group comprising scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET). Embodiment 137. The compound for use according to any one of embodiments 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, and 136, comprising a diagnostically active nuclide, preferably a diagnostically active radionuclide. Embodiment 138. The diagnostically active nuclide is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb,18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, preferably 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, most preferably 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18 F, 123 I, and 124 The compound for use according to embodiment 137, selected from the group comprising I. Embodiment 139. The method of any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, for use in a method for delivering an effector to a fibroblast activation protein (FAP), preferably a human fibroblast activation protein (FAP). 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82, wherein the effector is selected from the group comprising diagnostically active agents and therapeutically active agents. Embodiment 140 The compound for use according to embodiment 139, wherein the effector is selected from the group comprising diagnostically active nuclides and therapeutically active nuclides. Embodiment 141 The compound for use according to embodiment 140, wherein the diagnostically active nuclide is a diagnostically active radionuclide. Embodiment 142. The diagnostically active radionuclide is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, preferably 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, most preferably 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18 F, 123 I, and 124 The compound for use according to embodiment 141, selected from the group consisting of I. Embodiment 143. The compound for use according to any one of embodiments 139, 140, 141 and 142, wherein the fibroblast activation protein (FAP) is expressed by a cell, preferably a fibroblast, mesenchymal stem cell, smooth muscle cell, cell of epithelial origin, or endothelial cell, more preferably a human fibroblast, mesenchymal stem cell, smooth muscle cell, cell of epithelial origin, or endothelial cell, most preferably a human fibroblast, mesenchymal stem cell, smooth muscle cell, cell of epithelial origin, or endothelial cell, each of which exhibits upregulated expression of fibroblast activation protein (FAP). Embodiment 144. The compound for use according to embodiment 143, wherein the cell is contained in or is part of a tissue, preferably a diseased tissue of a subject suffering from a disease. Embodiment 145. A compound for use according to embodiment 144, wherein the disease involves cells that exhibit upregulated expression of fibroblast activation protein (FAP), preferably diseased tissues that contain cells that exhibit upregulated expression of fibroblast activation protein (FAP), more preferably a disease involving fibroblasts associated with a tumor. Embodiment 146. A compound for use according to any one of embodiments 144 to 145, wherein the disease is a neoplasm, preferably a cancer or tumor. Embodiment 147. The compound for use according to embodiment 146, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, and thyroid cancer. Embodiment 148. The compound for use according to embodiment 147, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising breast cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and squamous cell carcinoma. Embodiment 149. A compound for use according to any one of embodiments 144 to 145, wherein the disease is selected from the group comprising inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases. Embodiment 150 The compound for use according to embodiment 149, wherein the disease is an inflammatory disease. Embodiment 151. A compound for use according to embodiment 150, wherein the disease is atherosclerosis, arthritis, or rheumatoid arthritis. Embodiment 152 The compound for use according to embodiment 149, wherein the disease is a cardiovascular disease. Embodiment 153. A compound for use according to embodiment 152, wherein the disease is a cardiovascular disease associated with atherosclerotic plaques. Embodiment 154. A compound for use according to embodiment 153, wherein the disease is an atherosclerotic lesion caused by plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis, or vascular occlusion. Embodiment 155 The compound for use according to embodiment 149, wherein the disease is a fibrotic disease. Embodiment 156. A compound for use according to embodiment 155, wherein the disease is selected from the group comprising idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis. Embodiment 157 The compound for use according to embodiment 140, wherein the therapeutically active nuclide is a therapeutically active radionuclide. Embodiment 158. The therapeutically active radionuclide is 47 Sc, 67 Cu, 89 Sr, 90 Y, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I, 211 At, preferably47 Sc, 67 Cu, 90 Y, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I, 211 At, most preferably 90 Y, 177 Lu, 225 Ac, 227 Th, 131 I, and 211 The compound for use according to embodiment 157, selected from the group consisting of At. Embodiment 159. The compound for use according to any one of embodiments 157 to 158, wherein the fibroblast activation protein (FAP) is expressed by a cell, preferably a fibroblast, mesenchymal stem cell, smooth muscle cell, cell of epithelial origin, or endothelial cell, more preferably a human fibroblast, mesenchymal stem cell, smooth muscle cell, cell of epithelial origin, or endothelial cell, most preferably a human fibroblast, mesenchymal stem cell, smooth muscle cell, cell of epithelial origin, or endothelial cell that exhibits upregulated expression of fibroblast activation protein (FAP). Embodiment 160 The compound for use according to embodiment 159, wherein the cell is contained in or is part of a tissue, preferably a diseased tissue of a subject suffering from a disease. Embodiment 161. A compound for use according to embodiment 160, wherein the disease involves cells exhibiting upregulated expression of fibroblast activation protein (FAP), preferably diseased tissue comprising cells exhibiting upregulated expression of fibroblast activation protein (FAP), more preferably a disease involving fibroblasts associated with a tumor. Embodiment 162. A compound for use according to any one of embodiments 159, 160, and 161, wherein the disease is a neoplasm, preferably a cancer or tumor. Embodiment 163. The compound for use according to embodiment 162, wherein the neoplasms, cancers, and tumors are each individually selected from the group comprising solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, and thyroid cancer. Embodiment 164. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82, and a pharmaceutically acceptable excipient. Embodiment 165. The composition of embodiment 164 for use in any method defined in any of the preceding claims. Embodiment 166. A method for diagnosing a disease in a subject, comprising administering to a subject a diagnostically effective amount of any one of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 , 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82 to the subject. Embodiment 167 The method of embodiment 166, wherein the compound comprises a diagnostically active agent, which agent is preferably a radionuclide. Embodiment 168. A method for treating a disease in a subject, comprising administering a therapeutically effective amount of any of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82 to the subject. Embodiment 169 The method of embodiment 168, wherein the compound comprises a therapeutically active agent, the agent preferably being a radionuclide. Embodiment 170 The method of any one of embodiments 166, 167, 168, and 169, wherein the disease is a disease associated with upregulated expression of fibroblast activation protein (FAP), preferably fibroblast activation protein (FAP). Embodiment 171. The method of any one of embodiments 166, 167, 168, 169, and 170, wherein the disease involves diseased tissue containing cells that exhibit upregulated expression of fibroblast activation protein (FAP), preferably cells that exhibit upregulated expression of fibroblast activation protein (FAP), more preferably a disease involving tumor-associated fibroblasts. Embodiment 172. The method of any one of embodiments 166, 167, 168, 169, 170, and 171, wherein the disease is selected from the group comprising neoplasia, preferably cancer or tumor, as well as inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases. Embodiment 173. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 10. A kit comprising a compound according to any one of claims 6, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82, optionally one or more excipients, and optionally one or more devices, wherein the devices are selected from the group comprising a labeling device, a purification device, a handling device, a radiation protection device, an analytical device, or an administration device. Embodiment 174. A kit according to embodiment 173 for use in any method defined in any of the preceding claims.

[0411] More specifically, the problem underlying the present invention is that in a first aspect: Formula (I)

[0412] [ka]

[0413] Cyclic peptides and an N-terminal modification group A attached to Xaa1, the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction; Xaa1 is a compound represented by formula (II)

[0414] [ka]

[0415] is a residue of an amino acid R 1a is -NH-, R1b is H or CH3, n=0 or 1, the N-terminal modification group A is covalently bound to the nitrogen atom of Xaa1; The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2, The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether, Xaa2 is represented by formula (III), (IV), or (XX)

[0416] [ka]

[0417] is a residue of an amino acid R 2a , R 2b , R 2c are each independently selected from the group consisting of (C1-C2)alkyl and H, and the (C1-C2)alkyl is optionally substituted with a substituent selected from the group consisting of OH, NH2, halogen, and (C5-C7)cycloalkyl; p=0, 1, or 2; v=1 or 2, w=1, 2, or 3, the amino acid of formula (IV) is optionally substituted at positions 3 and 4 of the indicated ring with one or two substituents selected from the group consisting of methyl, OH, NH, and F; Xaa3 is a compound of formula (V) or (XX)

[0418] [ka]

[0419] is a residue of an amino acid X 3 CH2, CF2, CH-R 3b , S, O, and NH; p=1 or 2, v=1 or 2, w=1, 2, or 3, R 3a is H, methyl, OH, NH2, or F, R 3b is methyl, OH, NH2, or F, Xaa4 is a compound represented by formula (VI)

[0420] [ka]

[0421] is a residue of an amino acid R 4a H, OH, COOH, CONH2, X 4 , and -NH-CO-X 4 and X is selected from the group consisting of 4 is selected from the group consisting of (C1-C6) alkyl, (C5-C6) aryl, and (C5-C6) heteroaryl; and X 4 is optionally substituted by one or two substituents selected from the group consisting of methyl, CONH2, halogen, NH2, and OH; q=1, 2, or 3; one or two hydrogen atoms of said one, two, or three CH— groups are optionally and independently replaced by methyl, ethyl, (C-C)aryl, or (C-C)heteroaryl; R 4b is methyl or H, Xaa5 is structure (VII)

[0422] [ka]

[0423] is a residue of an amino acid R 5 is selected from the group of OH and NH; r=1, 2, or 3, Xaa6 is an amino acid selected from the group consisting of aromatic L-α-amino acids and heteroaromatic L-α-amino acids, Xaa7 is a compound represented by formula (IX)

[0424] [ka]

[0425] is an aminothiol or amino acid residue of R 7a -CO-, -COOH, -CONH2, -CH2-OH, -(CO)-NH-R 7b , -(CO)-(NR 7c )-R 7b , or H and R 7b and R 7c are each independently (C1-C4) alkyl; t is 1 or 2, Yc is the formula (X)

[0426] [ka]

[0427] The S atom of Xaa1 is linked to the S atom of Xaa7 through the formation of two thioether linkages, thereby forming a structure of formula (XXI)

[0428] [ka]

[0429] forming a ring structure of the substitution pattern of the aromatic group of formula (X) is ortho, meta, or para; n=0 or 1, t=1 or 2, Y 1 is CH or N, Y 2 is N or CR c1 and R c1 is H or CH2-R c2 and R c2is of formula (XI), (XII), or (XXII)

[0430] [ka]

[0431] The structure is R c3 and R c4 are each independently selected from the group consisting of H and (C1-C4) alkyl; u=1, 2, 3, 4, 5, or 6, x and y are each independently 1, 2, or 3; X=O or S, In formulas (XI) and (XXII), one of the nitrogen atoms is R c1 In formula (XII), -X- is bonded to -CH2- in R c1 is bonded to -CH2- the N-terminal modification group A is a blocking group AbI or an amino acid Aaa; This is solved by compounds.

[0432] More specifically, in a second aspect the problem underlying the present invention is solved by a compound according to the first aspect, including any embodiment, for use in a method for the diagnosis of a disease.

[0433] More particularly, in a third aspect the problem underlying the present invention is solved by a compound according to the first aspect, including any embodiment, for use in a method for the treatment of a disease.

[0434] More particularly, in a fourth aspect the problem underlying the present invention is solved by a compound according to the first aspect including any embodiment for use in a method for identifying a subject, wherein the subject is likely to respond or not to respond to treatment of a disease, the method for identifying a subject comprising performing a method of diagnosis using a compound according to the first aspect including any embodiment.

[0435] More particularly, in a fifth aspect the problem underlying the present invention is solved by a compound according to the first aspect including any embodiment for use in a method of selecting subjects from a population of subjects, wherein the subjects are likely to respond or not to respond to treatment of a disease, the method of selecting subjects from a population of subjects comprising performing a method of diagnosis using a compound according to the first aspect including any embodiment.

[0436] More particularly, in a sixth aspect the problem underlying the present invention is solved by a compound according to the first aspect including any embodiment for use in a method of stratifying a population of subjects into subjects likely to respond to treatment of a disease and subjects unlikely to respond to treatment of a disease, wherein the method for stratifying subjects comprises performing a method of diagnosis using a compound according to the first aspect including any embodiment.

[0437] More specifically, in a seventh aspect, the problem underlying the present invention is solved by a composition, preferably a pharmaceutical composition, comprising a compound according to the first aspect, including any embodiment, and a pharmaceutically acceptable excipient.

[0438] More particularly, in an eighth aspect the problem underlying the present invention is solved by a method for diagnosing a disease in a subject, the method comprising administering to the subject a diagnostically effective amount of a compound according to the first aspect, including any embodiment.

[0439] More particularly, in a ninth aspect the problem underlying the present invention is solved by a method for the treatment of a disease in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a compound according to the first aspect, including any embodiment.

[0440] More particularly, in a tenth aspect the problem underlying the present invention is solved by a kit comprising a compound according to the first aspect including any embodiment, one or more optional excipient(s), and optionally one or more device(s), wherein the device(s) are selected from the group comprising a labelling device, a purification device, a manipulation device, a radioprotection device, an analytical device or an administration device.

[0441] One of ordinary skill in the art will recognize that a compound or compounds of the present invention is any compound disclosed herein, including, but not limited to, any compound described in any of the above embodiments and any of the following embodiments.

[0442] One of ordinary skill in the art will recognize that a method or methods of the present invention is any method disclosed herein, including, but not limited to, any method described in any of the above embodiments and any of the following embodiments.

[0443] Those of ordinary skill in the art will recognize that a composition or compositions of the present invention is any composition disclosed herein, including, but not limited to, any composition described in any of the above embodiments and any of the following embodiments.

[0444] Those skilled in the art will recognize that a kit or kits of the present invention is any kit disclosed herein, including, but not limited to, any kit described in any of the above embodiments and any of the following embodiments.

[0445] Because no cyclic peptide-based inhibitors specific for fibroblast activation proteins (FAPs) with nanomolar affinity have been previously described, the present invention is based on the inventors' surprising discovery that the compounds of the present invention, and more particularly the cyclic peptides thereof, provide highly specific binding of compounds comprising such cyclic peptides to FAPs.

[0446] Furthermore, the present invention is based on the surprising discovery that a chelator can be attached to the cyclic peptide at three different positions, directly or indirectly, i.e., using a linker. The first position is Yc having the structure of formula (X), which connects the S atom of Xaa1 and the S atom of Xaa7, thus forming two thioether linkages; the second position is Aaa attached to Xaa1 of the cyclic peptide of formula (I), and the third position is an amino acid or peptide attached to Xaa7. Surprisingly, the attachment of such a chelator does not significantly affect the binding of the compounds of the present invention to FAPs and the inhibitory properties of the compounds of the present invention against FAPs, respectively. In one embodiment, the present invention relates to a cyclic peptide of formula (I) in which a chelator (Z group) is attached to only one of the first, second, or third positions defined above. It is also within the scope of the present invention that a chelator is attached to the cyclic peptide of formula (I) at any combination of the first, second, and third positions defined above. More specifically, the present invention also relates to compounds of formula (I) in which a Z group is attached at both the first and second positions as defined above, compounds of formula (I) in which a Z group is attached at both the first and third positions as defined above, compounds of formula (I) in which a Z group is attached at both the second and third positions as defined above, and compounds of formula (I) in which a Z group is attached at the first, second, and third positions as defined above. These compounds containing two or three Z groups can be realized in any embodiment of the invention disclosed herein.

[0447] Finally, the present inventors have found that the compounds of the present invention are surprisingly stable in plasma, surprisingly useful as imaging agents, and effective in shrinking tumors. The term "alkyl" preferably used herein refers to saturated, straight-chain or branched hydrocarbon groups, and usually includes a modifier that specifies the number of carbon atoms that it can contain.For example, the term (C1-C6) alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, 3-methylbutyl, 1,2-dimethylpropyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1,1-dimethylbutyl, and any other isoform of alkyl groups that contain 6 saturated carbon atoms.

[0448] In certain embodiments, as preferably used herein, (C1-C2) alkyl refers, respectively and independently, to either methyl and ethyl. In certain embodiments, and as preferably used herein, (C1-C3) alkyl refers to, respectively and independently, methyl, ethyl, n-propyl, and isopropyl.

[0449] In certain embodiments, and as preferably used herein, (C1-C4) alkyl refers to any of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0450] In certain embodiments, as preferably used herein, (C1-C6) alkyl each and independently includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methyl-butyl, 3-methyl-butyl, 3-pentyl, 3-methyl-but-2-yl, 2-methyl-but-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 2-methyl, -pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 3-hexyl, 2-ethyl-butyl, 2-methyl-pent-2-yl, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 3-methyl-pent-2-yl, 4-methyl-pent-2-yl, 2,3-dimethyl-butyl, 3-methyl-pent-3-yl, 2-methyl-pent-3-yl, 2,3-dimethyl-but-2-yl and 3,3-dimethyl-but-2-yl.

[0451] In certain embodiments, as preferably used herein, (C1-C8) alkyl refers to a saturated or unsaturated, straight or branched chain hydrocarbon group having from 1 to 8 carbon atoms. Representative (C1-C8) alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methyl-butyl, 3-methyl-butyl, 3-pentyl, 3-methyl-but-2-yl, 2-methyl-but-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl , 3-hexyl, 2-ethyl-butyl, 2-methyl-pent-2-yl, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 3-methyl-pent-2-yl, 4-methyl-pent-2-yl, 2,3-dimethyl-butyl, 3-methyl-pent-3-yl, 2-methyl-pent-3-yl, 2,3-dimethyl-but-2-yl, 3,3-dimethyl-but-2-yl, n-heptyl, 2-heptyl, 2-methyl-hexyl, 3-methyl-hexyl, 4-methyl hexyl, 5-methylhexyl, 3-heptyl, 2-ethylpentyl, 3-ethylpentyl, 4-heptyl, 2-methylhex-2-yl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 3-methylhex-2-yl, 4-methylhex-2-yl, 5-methylhex-2-yl, 2,3-dimethylpentyl, 2,4-dimethyl ethyl-pentyl, 3,4-dimethyl-pentyl, 3-methyl-hex-3-yl, 2-ethyl-2-methyl-butyl, 4-methyl-hex-3-yl, 5-methyl-hex-3-yl, 2-ethyl-3-methyl-butyl, 2,3-dimethyl-pent-2-yl, 2,4-dimethyl-pent-2-yl, 3,3-dimethyl-pent-2-yl, 4,4-dimethyl-pent-2-yl, 2,2,3-trimethyl-butyl, 2,3,3-trimethyl-butyl, 2,3,3-trimethyl-but-2-yl, n-octyl, 2-octyl, 2-methyl-heptyl, 3-methyl-heptyl, 4-methyl-heptyl, 5-methyl-heptyl, 6-methyl-heptyl, 3-octyl, 2-ethyl-hexyl, 3-ethyl-hexyl, 4-ethyl-hexyl, 4-octyl, 2-propyl-pentyl, 2-methyl-hept-2-yl, 2,2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 5,5-dimethyl-hexyl, 3-methyl-hept-2-yl, 4-methyl-hept-2-yl, 5 -Methyl-hept-2-yl, 6-methyl-hept-2-yl, 2,3-dimethyl-hex-1-yl, 2,4-dimethyl-hex-1-yl, 2,5-dimethyl-hex-1-yl, 3,4-dimethyl-hex-1-yl, 3,5-dimethyl-hex-1-yl, 3,5-dimethyl-hex-1-yl, 3-methyl-hept-3-yl, 2-ethyl-2-methyl-1-yl, 3-ethyl-3-methyl-1-yl, 4-methyl-hept-3-yl, 5-methyl-hept-3-yl, 6-methyl-hept-3-yl, 2-ethyl-3-methyl-pentyl , 2-ethyl-4-methyl-pentyl, 3-ethyl-4-methyl-pentyl, 2,3-dimethyl-hex-2-yl, 2,4-dimethyl-hex-2-yl, 2,5-dimethyl-hex-2-yl, 3,3-dimethyl-hex-2-yl, 3,4-dimethyl-hex-2-yl, 3,5-dimethyl-hex-2-yl, 4,4-dimethyl-hex-2-yl, 4,5-dimethyl-hex-2-yl, 5,5-dimethyl-hex-2-yl, 2,2,3-trimethyl-pentyl, 2,2,4-trimethyl-pentyl, 2,3,3-trimethyl-pentyl butyl, 2,3,4-trimethylpentyl, 2,4,4-trimethylpentyl, 3,3,4-trimethylpentyl, 3,4,4-trimethylpentyl, 2,3,3-trimethylpent-2-yl, 2,3,4-trimethylpent-2-yl, 2,4,4-trimethylpent-2-yl, 3,4,4-trimethylpent-2-yl, 2,2,3,3-tetramethylbutyl, 3,4-dimethylhex-3-yl, 3,5-dimethylhex-3-yl, 4,4-dimethylhex-3-yl, 4,5-dimethylhex-3-yl, 5,and any of 5-dimethyl-hex-3-yl, 3-ethyl-3-methyl-pent-2-yl, 3-ethyl-4-methyl-pent-2-yl, 3-ethyl-hex-3-yl, 2,2-diethyl-butyl, 3-ethyl-3-methyl-pentyl, 4-ethyl-hex-3-yl, 5-methyl-hept-3-yl, 2-ethyl-3-methyl-pentyl, 4-methyl-hept-4-yl, 3-methyl-hept-4-yl, 2-methyl-hept-4-yl, 3-ethyl-hex-2-yl, 2-ethyl-2-methyl-pentyl, 2-isopropyl-pentyl, 2,2-dimethyl-hex-3-yl, 2,2,4-trimethyl-pent-3-yl, and 2-ethyl-3-methyl-pentyl. The (C-C) alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, (C-C) alkyl, -O-[(C-C) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH, -CO-NHR', -CO-NR', -NH-CO-R', -SO-R', -SO-R', -OH, -halogen, -N, -NH, -NHR', -NR' and -CN, where each R' is independently selected from -(C-C) alkyl and aryl.

[0452] The term "alkylidene" as used herein preferably refers to a saturated straight or branched hydrocarbon group in which two substitution points are specified. Simple alkyl chains in which the two substitution points are at the maximum distance from each other, such as methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl, are also called methylene (also called methane-1,1-diyl), ethylene (also called ethane-1,2-diyl), propylene (also called propane-1,3-diyl), butylene (also called butane-1,4-diyl) and pentylene (also called pentane-1,5-diyl).

[0453] In an embodiment, preferably as used herein, (C1-C 10) Alkylidene means, each and independently, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,2-diyl, 2-methyl-propane-1,3-diyl, pentane-1,5-diyl, pentane-1,4-diyl, pentane-1,3-diyl, pentane-1,2-diyl, pentane-2 ...5-diyl, pentane-1,4-diyl, pentane-1,3-diyl, pentane-1,2-diyl, pentane-2,3-diyl, pentane-1,5-diyl, pentane-1,5-diyl, pentane-1,5-diyl, pentane-1,5-diyl, pentane-1,5-diyl, pentane-1,5-diyl hexane-2,4-diyl, any other isomer having 5 carbon atoms, hexane-1,6-diyl, any other isomer having 6 carbon atoms, heptane-1,7-diyl, any other isomer having 7 carbon atoms, octane-1,8-diyl, any other isomer having 8 carbon atoms, nonane-1,9-diyl, any other isomer having 9 carbon atoms, decane-1,10-diyl and any other isomer having 10 carbon atoms, preferably (C1-C 10 ) Alkylidene means, each and independently, any of methylene, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, and decane-1,10-diyl. (C1-C 10 ) Alkylidene groups can be unsubstituted or substituted with one or more groups including, but not limited to, (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2 and -CN, where each R' is independently selected from -(C1-C8) alkyl and aryl.

[0454] In certain embodiments, and as preferably used herein, (C3-C8)cycloalkyl means each and independently any of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0455] In certain embodiments, and as preferably used herein, (C5-C7)cycloalkyl means, each and independently, any of cyclopentyl, cyclohexyl, and cycloheptyl.

[0456] In certain embodiments, as preferably used herein, a (C3-C8)carbocycle refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbon ring. Representative (C3-C8)carbocycles include, but are not limited to, any of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cyclooctadienyl. A (C3-C8) carbocyclic group can be unsubstituted or substituted with one or more groups including, but not limited to, (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2 and -CN, where each R' is independently selected from -(C1-C8) alkyl and aryl.

[0457] In certain embodiments, and as preferably used herein, (C-C)carbocyclo refers to a (C-C) carbocyclic group as defined above, in which one of the carbocyclic group hydrogen atoms is replaced with a bond.

[0458] In certain embodiments, and as preferably used herein, "aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0459] In certain embodiments, as preferably used herein, (C5-C6)aryl refers to a carbocyclic aromatic group containing 5 or 6 carbon atoms. The carbocyclic aromatic group can be unsubstituted or substituted with, but not limited to, -(C1-C8)alkyl, -O-[(C1-C8)alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2 and -CN, where each R' is independently selected from -(C1-C8)alkyl and aryl.

[0460] In certain embodiments, and as preferably used herein, "heteroaryl" refers to a heterocyclic aromatic group. Examples of heteroaryl groups include, but are not limited to, furan, thiophene, pyridine, pyrimidine, benzothiophene, benzofuran, and quinoline.

[0461] In certain embodiments, as preferably used herein, (C5-C6)heteroaryl refers to a heteroaromatic group consisting of 5 or 6 ring atoms, at least one of which is different from carbon, preferably nitrogen, sulfur, or oxygen. The heteroaromatic group can be unsubstituted or substituted with one or more groups, including but not limited to -(C1-C8)alkyl, -O-[(C1-C8)alkyl], aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH2, -CO-NHR', -CO-NR'2, -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH2, -NHR', -NR'2, and -CN, wherein each R' is independently selected from -(C1-C8)alkyl and aryl.

[0462] In certain embodiments, as preferably used herein, (C-C)heterocyclo refers to a (C-C)heterocyclic group as defined above, in which one of the hydrogen atoms of the carbocyclic group is replaced with a bond. The (C-C)heterocyclo can be unsubstituted or substituted with up to six groups, including (C-C)alkyl, -O-[(C-C)alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH, -CO-NHR', -CO-NR', -NH-CO-R', -SO-R', -SO-R', -OH, -halogen, -N, -NH, -NHR', -NR', and -CN, where each R' is independently selected from -(C-C)alkyl and aryl.

[0463] In certain embodiments, as preferably used herein, arylene refers to a group having two covalent bonds and having the following structure:

[0464] [ka]

[0465] wherein the phenyl group can be unsubstituted or substituted with up to four groups including, but not limited to, (C-C) alkyl, -O-[(C-C) alkyl], -aryl, -CO-R', -O-CO-R', -CO-OR', -CO-NH, -CO-NHR', -CO-NR', -NH-CO-R', -SO-R', -SO-R', -OH, -halogen, -N, -NH, -NHR', -NR' and -CN, where each R' is independently selected from -(C-C) alkyl and aryl.

[0466] In some embodiments, as used herein, preferably, in any structural formula or in any context of this specification, including claims, an atom with an unspecified atomic mass number is either an unspecified isotopic composition, a naturally occurring isotopic mixture, or an individual isotope.This particularly applies to carbon, oxygen, nitrogen, sulfur, phosphorus, halogen and metal atoms, such as, but not limited to, C, O, N, S, F, P, Cl, Br, At, Sc, Cr, Mn, Co, Fe, Cu, Ga, Sr, Zr, Y, Mo, Tc, Ru, Rh, Pd, Pt, Ag, In, Sb, Sn, Te, I, Pr, Pm, Dy, Sm, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Sn, Re, Rd, Os, Ir, Au, Pb, Bi, Po, Fr, Ra, Ac, Th and Fm.

[0467] In certain embodiments, as preferably used herein, a chelating agent is a compound capable of forming a chelate, whereby the chelating agent is a compound, preferably a cyclic compound, in which a metal or moiety having an electron gap or lone pair participates in the formation of a ring. More preferably, the chelating agent is a compound of this type in which a single ligand occupies more than one coordination site at the central atom.

[0468] In certain embodiments, as preferably used herein, a diagnostically active compound is a compound that is suitable or useful in the diagnosis of disease. In certain embodiments, as preferably used herein, a diagnostic agent or diagnostically active agent is a compound that is suitable or useful in the diagnosis of disease.

[0469] In certain embodiments, as preferably used herein, a therapeutically active compound is a compound that is suitable or useful in the treatment of a disease. In certain embodiments, a therapeutic agent or therapeutically active agent, as preferably used herein, is a compound suitable or useful in the treatment of a disease.

[0470] In certain embodiments, as preferably used herein, a diagnostically therapeutically active compound is a compound that is suitable or useful for both the diagnosis and treatment of a disease. In certain embodiments, as preferably used herein, a diagnostic therapeutic agent or diagnostic therapeutically active agent is a compound that is suitable or useful for both the diagnosis and treatment of a disease.

[0471] In certain embodiments, diagnostic therapeutics, as preferably used herein, is a method for the combined diagnosis and treatment of a disease, preferably wherein the combined diagnostically and therapeutically active compounds used in the diagnostic therapeutics are radiolabeled.

[0472] In certain embodiments, treatment of a disease, as used herein, is treatment and / or prevention of a disease. In certain embodiments, as preferably used herein, a disease involving a FAP refers to a disease in which cells, including but not limited to fibroblasts, that express a FAP, preferably in an upregulated manner, and tissues containing or comprising cells, such as fibroblasts, that express a FAP, or that express a FAP, preferably in an upregulated manner, respectively, are the sole cause of the disease and / or symptoms of the disease, or are part of the underlying pathology of the disease. A preferred FAP-expressing cell is a cancer-associated fibroblast (CAF). In disease embodiments, preferably when used in connection with disease treatment, treating, and / or therapy, the effect on the cells, tissue, and pathology, respectively, results in a cure, treatment, or amelioration of the disease and / or symptoms of the disease. In disease embodiments, preferably when used in connection with disease diagnosis and / or therapy, labeling of FAP-expressing cells and / or FAP-expressing tissues can distinguish or differentiate the cells and / or tissues from healthy or non-FAP-expressing cells and / or healthy or non-FAP-expressing tissues. More preferably, such discrimination or differentiation forms the basis of the above-mentioned diagnosis and diagnosing, respectively. In that embodiment, labeling refers to the interaction of a detectable label, directly or indirectly, with FAP-expressing cells and / or FAP-expressing tissues or tissues containing such FAP-expressing cells, and more preferably, such interaction involves or is based on the interaction of a label or a compound bearing such a label with the FAP.

[0473] In one embodiment, as preferably used herein, a target cell is a cell that expresses a FAP and is the sole or sole cause of a disease and / or symptoms of a disease, or is part of the underlying pathology of a disease.

[0474] In one embodiment, and preferably as used herein, a non-target cell is a cell that does not express a FAP and / or is not the sole or sole cause of the disease and / or symptoms of the disease, or is not part of the underlying pathology of the disease.

[0475] In certain embodiments, as preferably used herein, a neoplasm is an abnormal new growth of cells. Cells in a neoplasm proliferate more rapidly than normal cells and continue to proliferate if not treated. Neoplasms can be benign or malignant.

[0476] In certain embodiments, a tumor, as preferably used herein, is a mass lesion that can be benign or malignant. In certain embodiments, cancer, as preferably used herein, is a malignant neoplasm.

[0477] In certain embodiments, as preferably used herein, a linkage is the attachment of two atoms of two independent moieties. A preferred linkage is a chemical bond or multiple chemical bonds. More preferably, the chemical bond is a covalent bond or multiple chemical bonds. Most preferably, the linkage is a covalent bond or multiple coordinate bonds. As preferably used herein, an embodiment of a coordinate bond is the bond or bonds realized when a metal is bound by a chelating agent. Depending on the type of atoms connected and their atomic environment, different types of linkages are created. These types of linkages are defined by the type of atomic arrangement created by the linkage. For example, the linkage between an amine-containing moiety and a carboxylic acid-containing moiety results in a linkage called an amide (also referred to as an amide linkage, -CO-N-, -N-CO-). Those skilled in the art will recognize that the following examples of creating this and other linkages are merely prototypical examples and in no way limit the scope of this application. Those skilled in the art will recognize that the combination of an amine-containing moiety with an isothiocyanate-containing moiety results in a thiourea (also referred to as a thiourea linkage, -N-CS-N-), and the combination of a C-atom-containing moiety with a thiol group (-C-SH) results in a thioether (also referred to as a thioether linkage, -CSC-). A non-limiting list of linkages preferably used in connection with the chelators and linkers of the present invention, and their characteristic types of atomic arrangements, is provided in Table 2.

[0478] [Table 2]

[0479] In some embodiments of the present invention, examples of reactive groups used to form linkages between chelators and linkers, or to form direct bonds between chelators and compounds of the present invention, are summarized in Table 3. However, it will be understood by those skilled in the art that the linkages that can be achieved in embodiments for forming conjugates of the present invention are not limited to those in Table 3, nor are the reactive groups that form such linkages limited.

[0480] [Table 3]

[0481] The following are reactive groups and functional groups that are utilized or suitable for forming linkages between moieties or structures used in embodiments of the conjugates of the present invention. Primary or secondary amino, carboxylic acid, activated carboxylic acid, chloro, bromo, iodo, sulfhydryl, hydroxyl, sulfonic acid, activated sulfonic acid, sulfonate esters like mesylate or tosylate, Michael acceptors, trans cyclooctene, isocyanate, isothiocyanate, azide, alkyne and strained alkenes like tetrazine.

[0482] As preferably used herein, the term "activated carboxylic acid" refers to a carboxylic acid group having the general formula -CO-X, where X is a leaving group. For example, activated forms of the carboxylic acid group can include, but are not limited to, acyl chlorides, symmetrical or asymmetrical anhydrides, and esters. In some embodiments, the activated carboxylic acid group is an ester with pentafluorophenol, nitrophenol, benzotriazole, azabenzotriazole, thiophenol, or N-hydroxysuccinimide (NHS) as the leaving group.

[0483] As preferably used herein, the term "activated sulfonic acid" refers to a sulfonic acid group having the general formula -SO2-X, where X is a leaving group. For example, activated forms of sulfonic acid can include, but are not limited to, sulfonyl chloride or sulfonic acid anhydride. In some embodiments, the activated sulfonic acid group is a sulfonyl chloride containing chloride as a leaving group.

[0484] In an embodiment, as preferably used herein, the term "mediate linkage" means that a linkage or linkage type is established, preferably a linkage between two moieties. In preferred embodiments, the linkage and linkage type are as defined herein.

[0485] In this application, the numbers are designated by lower and higher integers, e.g., 1 to 4. Within the scope of the ranges mentioned, such ranges include the lower integer, the higher integer, and any integer between the lower and higher integers. To that extent, the range is actually a separate disclosure of the integers. In the above example, the range 1 to 4 means 1, 2, 3, and 4.

[0486] The compounds of the present invention typically comprise the amino acid sequences provided herein. Conventional amino acids, also called natural amino acids, are identified according to their standard three-letter and one-letter abbreviations, as set forth in Table 4.

[0487] [Table 4]

[0488] Unconventional amino acids, also called unnatural amino acids, are any type of non-oligomeric compound that contains an amino group and a carboxyl group and is not a conventional amino acid. Examples of unconventional amino acids and other building blocks used in the construction compounds of the present invention are identified according to their abbreviations or names found in Table 5. The structures of some building blocks are described with exemplary reagents for introducing the building block into a peptide (e.g., carboxylic acid-like), or these building blocks are shown as residues fully attached to another structure, such as a peptide or amino acid. Amino acid structures are shown as explicit amino acids, not as residues of amino acids, as they will appear after implementation into a peptide sequence. Some larger chemical moieties consisting of more than one moiety are also shown for clarity.

[0489] [Table 5-1]

[0490] [Table 5-2]

[0491] [Table 5-3]

[0492] [Table 5-4]

[0493] [Table 5-5]

[0494] [Table 5-6]

[0495] [Table 5-7]

[0496] [Table 5-8]

[0497] [Table 5-9]

[0498] [Table 5-10]

[0499] [Table 5-11]

[0500] [Table 5-12]

[0501] [Table 5-13]

[0502] [Table 5-14]

[0503] The amino acid sequence of peptide provided herein is written in typical peptide sequence format, as understood by those skilled in the art.For example, the three-letter designation of conventional amino acid, or the designation of non-conventional amino acid, or the abbreviation of additional component indicates that amino acid or component exists at a specific position in peptide sequence.Each amino acid designation or component is connected to the designation or component of the next and / or previous amino acid in sequence by a hyphen (typically representing amide linkage).

[0504] Where an amino acid contains more than one amino acid and / or carboxy group, all orientations of this amino acid are in principle possible, although in α-amino acids, utilization of the α-amino and α-carboxy groups is preferred; otherwise, the preferred orientation is explicitly specified.

[0505] For amino acids, in their abbreviations, the first letter indicates the stereochemistry of the C-α atom, if applicable, e.g., a capitalized first letter indicates that the L-form of the amino acid is present in the peptide sequence, while a lowercase first letter indicates that the D-form of the corresponding amino acid is present in the peptide sequence.

[0506] In one embodiment, as preferably used herein, an aromatic L-α-amino acid is , any kind of L-α-amino acid containing an aryl group. In one embodiment, as preferably used herein, a heteroaromatic L-α-amino acid is any type of L-α-amino acid that contains a heteroaryl group.

[0507] Those skilled in the art will recognize whether a stereocenter exists in the compounds disclosed herein, regardless of whether such stereocenter is part of an amino acid moiety or any other part or moiety of the compound of the present invention. Thus, the present invention encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. The ability to resolve the final product, intermediate, or starting material can be affected by any suitable method known in the art. For example, see "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0508] In this application, the structural formula of a compound may, in some cases, for convenience, represent a certain type of isomer, but the present invention includes all isomers such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, etc. In this specification, the structural formula of a compound may, in some cases, for convenience, represent a certain type of isomer, but the present invention includes all isomers such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, etc.

[0509] Unless otherwise indicated, amino acid sequences are presented herein in an N-terminal to C-terminal direction. Derivatives of the amino acids that make up the peptides of the present invention may be listed in Table 6. In any embodiment, one or more amino acids of the compounds of the present invention are substituted with a derivative of the corresponding preferred amino acid.

[0510] [Table 6-1]

[0511] [Table 6-2]

[0512] Linear peptides A typical linear peptide is typically written from N- to C-terminus as shown below: NT-Xaa1-Xaa2-Xaa3-Xaa4-...Xaan-CT; There, 1. Xaax is the abbreviation, descriptor or symbol for the amino acid or component at a particular sequence position x, as shown in Table 5; 2. NT is the N-terminal group, e.g., "H" (hydrogen for the free N-terminal amino group), or an abbreviation for a particular terminal carboxylic acid, such as "Ac" for acetic acid, or other chemical group or structural formula of a chemical group linked via a hyphen to the N-terminal amino acid designation (Xaa1), and 3. CT is an abbreviation for the C-terminal group, typically "OH" or "NH2" (as the terminal carboxylic acid or amide), or a specific terminal amine (Xaan) linked to the C-terminal amino acid designation via a hyphen. Branched peptides with side chains modified by specific building blocks or peptides A typical linear branched peptide is described from N- to C-terminus as follows: NT-Xaa1-Xaa2-Xaa3(NT-Xab1-Xab2-......Xabn)-......Xaan-CT There, the explanations 1.-3. for the description of linear peptides apply to the specification of Xaax, NT and CT in the backbone of branched peptides.

[0513] The position of the branching is specified in parentheses after the Xaax abbreviation. The branching typically occurs at a lysine (Lys) residue (or similar), which means that the branching is attached to the ε-amino function of the lysine side chain via an amide bond.

[0514] The contents in brackets describe the sequence / structure of the peptide branch "NT-Xab1-Xab2-......Xabn", where: 1. Xabx is an abbreviation, descriptor or symbol for the amino acid or building block at a particular sequence position x of the branch, as shown in Table 3; 2. NT is the N-terminal group, e.g., an abbreviation for a particular terminal carboxylic acid, such as "Ac" for acetic acid, or another chemical group or structural formula of a chemical group linked via a hyphen to the N-terminal amino acid designation (Xab1); and 3. The final component of the branched Xabn, which forms an amide bond with the side chain amino function of a lysine (or similar residue) and its own carboxyl function, thereby forming the branching base. Components that link together in a chain. Cyclic peptides An exemplary generic cyclic peptide, written from N- to C-terminal, is shown below: NT-Xaa1-[Xaa2-Xaa3-Xaa4-......Xaan]-CT; where the specifications of Xaax, NT and CT in the backbone of the cyclic peptide are as per clarifications 1.-3. of the description of linear peptides. The characteristics of the peptide cycle are indicated in square brackets.

[0515] 1. Open square brackets indicate the building block with the side chain where the cycle begins (cycle-start residue), 2. The closed square brackets indicate the building block with the side chain that ends the cycle (cycle-ending residue).

[0516] The chemical nature of the connection between these two residues is as follows: 1. an amide bond, where one of the residues shown contains an amino function in its side chain (e.g., Lys) while the other contains a carboxyl function in its side chain (e.g., Glu), or 2. Disulfide bonds when the indicated residue / amino acid contains a sulfhydryl moiety (e.g., Cys). Cyclic peptides containing cycloaddition elements (Yc) A typical extended cyclic peptide, written from N- to C-terminal, is shown below: NT-Xaa1-[Xaa2(Yc)-Xaa3-Xaa4-...Xaan]-CT; The specifications of Xaax, NT, and CT in the backbone of a cyclic peptide are as described in 1.-3. for the description of linear peptides. Additionally, Yc is the cyclization element. As in cyclic peptides, the cycle features are identified by square brackets indicating the cycle start and cycle end residues.

[0517] The brackets adjacent to the cycle-starting residue identify the cyclization element Yc in the extended peptide cycle. The Yc element is linked to the side chain of that residue. In turn, the Yc element is linked to the side chain of the cycle-ending residue. The chemical nature of the linkage between any of these residues and the Yc element depends on the side chain functionality of the corresponding amino acid Xaan. If the side chain of Xaan contains a sulfhydryl group (e.g., Cys), the linkage is a thioether.

[0518] As a non-limiting example, the structure of Ac-[Cys(tMeBn(DOTA-PP))-Pro-Pro-Thr-Gln-Phe-Cys]-OH is depicted below.

[0519] [ka]

[0520] There, 1. Ac corresponds to NT in the general formula. 2. Cys, Pro, Pro, Thr, Gln, Phe, and Cys correspond to Xaa1 to Xaa7 in the general formula.

[0521] 3.OH corresponds to CT in the general formula. 4. An open square bracket (,[') adjacent to the N-terminal cysteine ​​in the sequence indicates that the cycle begins at this residue (cycle start residue).

[0522] 5. A closed square bracket (,]') adjacent to the N-terminal cysteine ​​in the sequence indicates that the cycle ends at this residue (cycle-ending residue). 6. The tMeBn in parentheses adjacent to the Cys indicated as the start residue identifies the cyclization element Yc, which in turn binds to the Cys indicated as the cycle end residue. The Yc element is linked to the above residue via a thioether linkage.

[0523] 7. The remaining attachment point of the tMeBn residue is the DOTA chelator via a PP linker. Explicit terms such as "Cys(tMeBn(DOTA-PP)" are included in the list of chemical structures in Table 2.

[0524] In an embodiment of the invention, an amino acid or peptide is attached to Xaa7, the majority of the amino acids of the peptide are charged or polar, and the net charge of the peptide is −2, −1, 0, +1 or +2.

[0525] In calculating peptide net charge, negatively charged amino acids are those that have an acidic group such as -COOH or -SO3H in their side chain, and their net charge corresponds to the number of acidic groups; for example, Asp or Glu have a net charge of -1.

[0526] In this calculation, positively charged amino acids are those that have a basic group, such as amino or -guanidino, in their side chain, and their net charge corresponds to the number of basic groups, e.g., Lys or Arg have a net charge of +1.

[0527] Polar amino acids are amino acids that have polar groups in their side chains, such as CONH, OH, F, Cl, CN, and heterocycles such as imidazole in histidine.

[0528] Polar amino acids have a net charge of 0. It is recognized that some nitrogen-containing heterocycles are protonated at equilibrium and therefore carry a degree of positive charge depending on the pH of the environment, but are considered to have a net charge of 0 for calculation purposes.

[0529] The majority of the amino acids in this peptide (over 50%) are charged or polar. Preferably, the positive or negative charges may be separated by polar or non-polar amino acids.

[0530] In some embodiments, the presence of a negatively charged amino acid is preferred at XaalO. In some embodiments, the presence of a positively charged amino acid is preferred at Xaa13, preferably Arg and arg.

[0531] According to the present invention, the compound of the present invention can comprise a Z group. The Z group comprises a chelator and optionally a linker. When preferably used, the linker is an element, moiety, or structure that separates two parts of a molecule. In the present invention, the linker group forms a covalent bond with both the chelator group and the respective part of the compound of the present invention to which Z is attached. In principle, the linker group can be any chemical group that can form a bond at a specific position with both the chelator group and the part of the compound of the present invention.

[0532] An important property or characteristic of the linker is that it separates the chelator and cyclic peptide portions of the compounds of the invention. This is particularly important when the target binding ability of the cyclic peptide is compromised by the proximity of the chelator. However, the overall linker length in its most extended conformer should not exceed 200 Å, preferably 150 Å or less, and most preferably 100 Å or less.

[0533] In a preferred embodiment, the linker is -[X] a -, a is an integer from 1 to 10, and each X is an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, Each moiety is independently connected to its neighbor in the sequence by a functional group selected from those including a bond, an ether linkage, a thioether linkage, a sulfonamide, a triazole, and a disulfide linkage.

[0534] X1 is connected to the chelator, if present, to X2, or to the compound of the invention at a specific position. a If present, X a-1 and is connected to the compound of the present invention at a specific position.

[0535] A more preferred class of linker groups is -[X] a -, where a is an integer from 1 to 10, preferably 1 to 8, 1 to 6, 1 to 5, 1 to 4, or 1 to 3, and each X is an individual component independently connected to its neighbor in the sequence by a functional group selected from the group including an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage, a sulfonamide linkage, a triazole linkage, and a disulfide linkage.

[0536] In some embodiments, component X is represented by the general formula (8):

[0537] [ka]

[0538] wherein: Fragment Lin if present 2 , and the fragment Lin if present 3 are each individually and independently -CO-, -NR 10 -, -S-, -CO-NR 10 -,-CS-NR 10 -, -O-, -succinimide and -CH2-CO-NR 10 -; with the proviso that Lin 2 or Lin 3 At least one of R has a carbon atom 9 and the nitrogen atoms of all nitrogen-containing fragments are linked to R 9 Concatenated to; R 10 is selected from the group consisting of hydrogen and (C1-C4) alkyl; and R 9 is -(C1-C 10 ) alkylidene-, -(C3-C8) carbocyclo-, -arylene-, -(C1-C 10 ) alkylidene-arylene-, -arylene-(C1-C 10 ) alkylidene-, -(C1-C10 ) alkylidene-arylene-(C1-C 10 ) alkylidene-, -(C1-C 10 ) alkylidene-(C3-C8)carbocyclo-, -(C3-C8)carbocyclo-(C1-C 10 ) alkylidene-, -(C1-C 10 )Alkylidene-(C3-C8)carbocyclo-(C1-C 10 ) alkylidene-, -(C3-C8) heterocyclo-, (C1-C 10 ) alkylidene-(C3-C8)heterocyclo-, -(C3-C8)heterocyclo-(C1-C 10 ) alkylidene-, -(C1-C 10 ) alkylidene-(C3-C8)heterocyclo-(C1-C 10 ) Alkylidene-, -(CH2CH2O) r - and -(CH2) s -(CH2CH2O) r -(CH2) t -Selected from; r is any integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s is any integer from 0, 1, 2, 3, and 4; t is any integer from 0, 1, 2, 3, and 4.

[0539] Preferably, apart from the linkage between X1 and the chelating agent, the linkages are amide linkages. More preferably, components X2 to X a are independently selected from the group consisting of amino acids, dicarboxylic acids and diamines, and each linkage is an amide.

[0540] In one embodiment, components X2 to X ais preferably an amino acid, selected from the group consisting of conventional and unconventional amino acids. In one embodiment, the amino acid is selected from the group consisting of β-amino acids, γ-amino acids, δ-amino acids, ε-amino acids, and ω-amino acids. In a further embodiment, the amino acid is a cyclic amino acid or a linear amino acid. It will be understood by those skilled in the art that in the case of amino acids with asymmetric centers, all stereoisomeric forms can be used in component X.

[0541] In one embodiment, components X2 to X a is preferably an amino acid, which is selected from a group comprising amino acids which differ in terms of the spacing of the amino group from the carboxyl group. Amino acids of this type are generally the following:

[0542] [ka]

[0543] It can be expressed as follows. It is within the scope of the present invention that such amino acids are not further substituted. However, it is also within the scope of the present invention that such amino acids are further substituted, preferably where such substitutions are CO-NH and / or Ac-NH-.

[0544] Representative of this class of amino acids (structure 32) that can be used as building block X are glycine (Gly), β-alanine (Bal), γ-aminobutyric acid (GABA), aminopentanoic acid, aminohexanoic acid, and homologs with up to 10 CH groups.

[0545] Representatives of this type of amino acid (structure 33) which are more preferably used as building block X are 3-aminomethylbenzoic acid, 4-aminomethylbenzoic acid, anthranilic acid, 3-aminobenzoic acid and 4-aminobenzoic acid.

[0546] Related building blocks are diamines derived from amino acids (structures 32+33) by replacing NH2 with COOH, which are preferably used as building block X: diaminoethane, 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, 3-aminomethyl-aniline, 4-aminomethyl-aniline, 1,2-diaminobenzene, 1,3-diaminobenzene and 1,4-diaminobenzene.

[0547] Related building blocks are dicarboxylic acids derived from amino acids (structures 32+33) by replacing COOH with NH2, with those more preferably used as building block X being malonic acid, succinic acid, glutaric acid, adipic acid, phthalic acid, terephthalic acid, isophthalic acid and 2, 3 or 4 carboxyphenylacetic acid.

[0548] In a further embodiment, the amino acid is preferably an amino acid containing a polyether as a backbone. Preferably, such a polyether is polyethylene glycol and consists of up to 30 monomer units. Preferably, such polyether-containing amino acids exhibit increased hydrophilicity compared to amino acids that do not contain such polyether. Component X, and ultimately the linker group [X] a Incorporation into typically results in increased hydrophilicity. Preferred embodiments of this type of amino acid are described below, and such amino acids may contain 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene oxide moieties:

[0549] [ka]

[0550] It is recognized that the Preferred ethylene glycol containing amino acids are Ttds (N-(3-{2-[2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propyl)-succinic acid) and O2Oc ([2-(2-(2-amino-ethoxy)-ethoxy]-acetic acid), The formula is as follows:

[0551] [ka]

[0552] In a preferred embodiment, the linker comprises an oligomer or monomer of only one specific amino acid selected from the group Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb, Pamb, Ppac, 4Amc, Inp, Sni, Rni, Nmg, Cmp, PEG6, PEG12, PEG-amino acid, more preferably the linker is monomeric.

[0553] In another preferred embodiment, the linker comprises one component X2 selected from the group consisting of Ttds, O2Oc, Apac, Gly, Bal, Gab, Mamb Pamb, PEG6, PEG12, and PEG-amino acid, and a second component X1 bonded directly to the amino-nitrogen of X2 and attached directly to the chelator by a linkage selected from the group consisting of an amide linkage, a urea linkage, a carbamate linkage, an ester linkage, an ether linkage, a thioether linkage, a sulfonamide linkage, a triazole linkage, and a disulfide linkage. X1, in this case, acts as an adapter mediating the linkage of different types of attachment functional groups provided by the chelator to the nitrogen atom of amino acid X2, in the sense that X1 provides a complementary functional group associated with the linkage of the chelator.

[0554] However, the use of a linker usually depends on the purpose. In some situations, it is necessary to free up a larger portion of the molecule separate from the bioactive molecule to maintain high bioactivity. In other situations, the introduction of a linker opens up the opportunity to adjust the physicochemical properties of the molecule by introducing polarity or multiple charges. In certain situations, it can be advantageous and rewarding if a chelating agent can be combined with a bioactive compound without the need for such a linker. In particular, compounds of the present invention in which a chelating agent is attached to Yc of formula (X), which connects the S atom of Xaa1 and the S atom of Xaa7 through the formation of two thioether linkages, typically exhibit excellent performance without the use of any dedicated linker.

[0555] In certain embodiments, the compounds of the present invention include a chelator. Preferably, the chelator is part of the compound of the present invention, whereby the chelator is attached directly or indirectly, such as by a linker, to the compound of the present invention. Preferred chelators are those that form metal chelates, preferably containing at least one radiometal. The at least one radiometal is preferably useful in diagnostic and / or therapeutic and / or diagnostic-therapeutic uses, or more preferably useful or suitable for imaging and / or radiotherapy.

[0556] In principle, chelating agents useful and / or suitable for the practice of the present invention, including the diagnosis and / or treatment of disease, are known to those skilled in the art. A wide variety of respective chelating agents are available, see, for example, Banerjee et al. (Banerjee et al., Dalton Trans 2005, 24:3886), and references therein (Price et al., Chem Soc Rev 2014, 43:260; Wadas et al., Chem Rev 2010, 110:2858). Such chelating agents include, but are not limited to, linear, cyclic, macrocyclic, tetrapyridine, N3S, N2S2, and N4 chelating agents disclosed in U.S. Pat. Nos. 5,367,080A, 5,364,613A, 5,021,556A, 5,075,099A, and 5,886,142A.

[0557] Representative chelating agents and their derivatives include, but are not limited to, AAZTA, BAT, CDTA, DTA, DTPA, CY-DTA, DTCBP, CTA, cyclam, cyclen, TETA, sarcofadin, CPTA, TEAMA, cyclen, DO3A, DO2A, TRITA, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H4octapa, H2dedpa, H5decapa, H2azapa, H2CHX DEDPA, DFO-Chx-MAL, DFO-p-SCN, DFO-1AC, DFO-BAC, p-SCN-Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, diphosphine, DOTA, DOTAGA, DOTA-MFCO, DOTAM-monoacid, nitro-DOTA, nitro-PA-DOTA, p-NCS-Bz- DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-DOTA, DOTMA, NB-DOTA, H4NB-DOTA, H4TCE-DOTA, 3,4,3-(Li-1,2-HOPO), TREN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOXP, p-NCS-DOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-mono-amide-DOTA, BCN-DOTA, butyne-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2A(trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)ethanamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOT A-NHS-ester, maleimide-DOTA-GA, maleimide-mono-amine-DOTA, maleimide-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone-benzothiazole, thiosemicarbazone-styrylpyridine tetradentate ligand H2L, 2-4 , HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, Deferiprone, THP, HYNIC Dorazinonicotinamide), NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(Tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIM A, IAM B, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, Macropa, Macropaquin, Macroquin-SO3, N x S 4-x、N2S2、N3S、N4、MAG3B、NOTE、NODAGA、SCN-Bz-NOTE-R、NOT-P(NOTMP) NOTAM, p-NCS-NOTE, TACN, TACN-TM, NETA, NETA-モノアン, p-SCN-PhPr-NE 3TA、C-NE3TA-NCS、C-NETA-NCS、3p-C-NETA、NODASE、NOPO、NODA、NO2A、 N-KNOT-NODA, C-NOTE, BCNOT-KNOT-KNOT-KNOT-KNOT-NOTE, NO2A-KNOT, N O2A-Butyne, NO2AP, NO3AP, N-NOTE, Oxo-DO3A, p-NH2-Bn-NOTE, p-NH2-Bn-oxo-DO3A, p-NO2-Bn-Cyclen, p-SCN-Bn-NOTE, p-SCN-Bn-oxo-DO3 A, TRAP, PEPA, BF-PEPA, Pycup, Pycup2A, pycup1A1Bn, pycup2Bn, SarAr -R, Diamsar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me) TAM A、TAM B, TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PC B-TE1A1P、TETA-NHS、CPTA、CPTA-NHS、CB-TE1K1P、CB-TE2A、TE2A、H2CB-TE2A、TE2P CB-TE2P、MM-TE2A、DM-TE2A、2C-TETA、6C-TETA、BAT、BAT-6、NHS-BAT Packaging: SSBAT, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-KN, p-BZ-HTCPP.

[0558] HYNIC, DTPA, EDTA, DOTA, TETA, bisaminobisthiol (BAT) based chelators as disclosed in U.S. Pat. No. 5,720,934; desferrioxamine (DFO) as disclosed in (Doulias et al., Free Radic Biol Med, 2003, 35:719); tetrapyridine and N3S, N2S2 and N4 chelators as disclosed in U.S. Pat. No. 5,367,080A, U.S. Pat. No. 5,364,613A, U.S. Pat. No. 5,021,556A, U.S. Pat. No. 5,075,099A, U.S. Pat. No. 5,886,142A, all of which references are incorporated herein by reference in their entireties; 6-amino-6-methylperhydro-1,4-diazepine-N,N',N'',N'''-tetraacetic acid (AAZTA) as disclosed in Pfister et al. (Pfister et al., EJNMI Res, 2015, 5:74), Deferiprone, 1,2-dimethyl-3,4-hydroxypyridinone and hexadentate tris(3,4-hydroxypyridinone)THP are disclosed by Cusnir et al. (Cusnir et al., Int J Mol Sci, 2017, 18), monoamine-monoamide dithiol (MAMA) based chelators are disclosed by Demoin et al. (Demoin et al., Nucl Med Biol, 2016, 43:802), MACROPA and analogs are disclosed by Thieler et al. (Thiele et al., Angew Chem Int Ed Engl 2017, 56:14712), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N'',N''',N'''',N''''-hexaacetic acid (HEHA) and PEPA analogs are disclosed by Price and Orvig (Price et al., Chem Soc Rev 2014, 43:260), and Pycup and analogs are disclosed by Boros et al. (Boros et al., Mol Pharm, 2014, vol. 11:617), and includes N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCM), 2-[(carboxymethyl)]-[5-(4-nitrophenyl-1-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)-amino]acetic acid (3p-C-DEPA), CB-TE2A, TE2A, TE1A1P, Diamsar, 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]- Eicosane-1,8-diamine (SarAr), NETA, N,N0,N00, tris(2-mercaptoethyl)-1,4,7-triazacyclononane (TACN-TM), {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NETA), diethylenetriaminepentaacetic acid (DTP), 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy-phosphinoylmethyl]-[1,4,7]triazonan-1-ylmethyl}-hydroxy-phosphinoyl)-propionic acid (TRAP), NOPO, H4octapa, SHBED, BPCA, 3,6,9,15-tetraazabicyclo[9.3.1]-Pentadeca-1(15), 11,13-triene-3,6,9,-triacetic acid (PCTA), 1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA) are disclosed by Price and Orvig (Price et al., Chem Soc Rev, 2014, 43:260), and 1-hydroxy-2-pyridone ligand (HOPO) is disclosed by Allott et al. (Allott et al., Chem Commun (Camb), 2017, 53:8529), [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepam-1-yl]-acetic acid (DATA) was disclosed by Tornesello et al. (Tornesello et al., Molecules, 2017, 22:1282), and tetrakis(aminomethyl)methane (TAM) and analogs were disclosed by McAuley 1988 (McAuley et al., C. Canadian Journal of Chemistry, 1989, 67:1657), and hexadentate tris(3,4-hydroxypyridinone) (THP) and analogs are disclosed in Ma et al. (Ma et al., Dalton Trans, 2015, 44:4884).

[0559] The diagnostic and / or therapeutic uses of some of the above chelating agents have been described in the prior art. For example, 2-hydrazinonicotinamide (HYNIC) 99m Tc and 186,188 It has been widely used in the presence of co-ligands for the incorporation of Re (Schwartz et al., Bioconjug Chem, 1991, 2:333; Babich et al., J Nucl Med, 1993, 34:1964; Babich et al., Nucl Med Biol, 1995, 22:25); DTPA 111It has been used in Octreoscan® for the complexation of In, and several modifications have been described in the literature (Li et al., Nucl Med Biol, 2001, 28:145; Brechbiel et al., Bioconjug Chem, 1991, 2:187); DOTA-type chelators for radiotherapy applications have been reported by Tweedle et al. (U.S. Pat. No. 4,885,363); other polyazamacrocycles for complexing trivalent isotope metals have been reported by Eisenwiener et al. (Eisenwiener et al., Bioconjug Chem, 2002, 13:530); and 99m N4-chelators, such as Tc-N4-chelators, have been used to label peptides, such as minigastrins, to target the CCK-2 receptor (Nock et al., J Nucl Med 2005, 46:1727).

[0560] In certain embodiments, metal chelators include, but are not limited to, DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcofadin, FSC, NETA, H4octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic, 99m Tc(CO)3-chelators, and analogs thereof; DOTA stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTAGA stands for 1,4,7,10-tetraazacyclodosecane, 1-(glutaric acid)-4,7,10-triacetic acid; NOTA represents 1,4,7-triazacyclononanetriacetic acid, NODAGA stands for 1,4,7-triazacyclononane-N-glutaric acid-N',N''-diacetic acid; NODA-MPAA stands for 1,4,7-triazacyclononane-1,4-diacetate-methylphenylacetic acid; HBED stands for bis(2-hydroxybenzyl)ethylenediaminediacetic acid; TETA represents 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid; CB-TE2A represents 4,11-bis-(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane; DTPA stands for diethylenetriaminepentaacetic acid, DFO represents a desferal or desferrioxamine type group of chelating agents, a non-limiting example chemical name is N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide.

[0561] Macropa represents N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown; HOPO represents an octadentate hydroxypyridinone type group of the chelating agent, and a non-limiting example structure is shown below.

[0562] TRAP is a 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy- {1,4,7]triazonan-1-ylmethyl}-hydroxy-phosphinoyl)-propionic acid, THP stands for hexadentate tris(3,4-hydroxypyridinone); DATA stands for [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid; NOTP stands for 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic) acid; Sarcofazine represents 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane; FSC stands for 3,15,27-triamino-7,19,31-trihydroxy-10,22,34-trimethyl-1,13,25-trioxa-7,19,31-triaza-cyclohexatriaconta-9,21,33-triene-2,8,14,20,26,32-hexane; NETA represents {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid; H4octap represents N,N'-(6-carboxy-2-pyridylmethyl)-N,N'-diacetic acid-1,2-diaminoethane; Pycup represents 1,8-(2,6-pyridinedimethylene)-1,4,8,11-tetraazacyclotetradecane; N x S 4-x (N4, N2S2, N3S) represent a group of tetradentate chelators with an N atom (basic amine or non-basic amide) and a thiol as donors to stabilize Tc complexes, especially Tc(V)-oxo complexes. The structure of one representative, non-limiting example, MAG3, is shown below.

[0563] MAG3 represents {2-[2-(3-mercapto-propionylamino)-acetylamino]-acetylamino}-acetic acid; HYNIC stands for 6-hydrazino-nicotinic acid; 99m Tc(CO)3- chelator refers to a bi- or tridendate chelator capable of forming a stable complex with technetium tricarbonyl fragments; Their chemical structures are as follows:

[0564] [ka]

[0565] [ka]

[0566] In preferred embodiments, the metal chelator is selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4 and analogs thereof.

[0567] In a more preferred embodiment, the metal chelator is selected from the group consisting of DOTA, DOTAGA, NOTA, N4Ac and NODAGA, and analogs thereof. Those skilled in the art will recognize that chelating agents can in principle be used regardless of whether the compounds of the present invention are used or suitable for diagnosis or therapy, and such principles are outlined, inter alia, in WO 2009 / 109332 A1.

[0568] Furthermore, those skilled in the art will recognize that the presence of a chelating agent in a compound of the invention, unless specifically stated, includes the possibility that the chelating agent may be complexed to any metal complexing partner, i.e., in principle, any metal that can be complexed by a chelating agent. The explicitly stated chelating agent of a compound of the invention or the general term chelating agent in relation to a compound of the invention may refer to the chelating agent not so complexed, or to any metal complexing partner. The term "metal chelator complex" refers to a chelator having a metal complex partner bound thereto, wherein the metal complex partner is either a radioactive or non-radioactive metal complex partner. Preferably, the metal chelator complex, i.e., the chelator to which the metal complex partner is bound, is a stable metal chelator complex.

[0569] Non-radioactive metal chelator complexes have several uses, for example, for assessing properties such as stability or activity that are otherwise difficult to determine. One aspect is that cold variants of radioactive versions of metal complex partners (e.g., non-radioactive gallium, lutetium, or indium complexes described in the Examples) can act as surrogates for radioactive compounds. Furthermore, they are valuable tools for identifying metabolites in vitro or in vivo, as well as for assessing the toxicity properties of compounds of the invention. In addition, metal chelator complexes can be used in binding assays that take advantage of the fluorescent properties of some metal complexes with different ligands (e.g., europium salts).

[0570] Chelating agents can be synthesized with a wide variety of (possibly already activated) groups for conjugation to peptides or amino acids, or are commercially available. Direct conjugation of chelating agents to the amino-nitrogen of each compound of the present invention is fully possible for chelating agents selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, DATA, sarcofadin, N4, MAG3 and Hynic, preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, CB-TE2A and N4. In this regard, the preferred linkage is an amide linkage.

[0571] Functional groups on chelators that are ideal precursors for direct conjugation to the amino-nitrogen of a chelator are known to those skilled in the art and include, but are not limited to, carboxylic acids, activated carboxylic acids, such as active esters, e.g., NHS-esters, pentafluorophenol-esters, HOBt-esters and HOAt-esters, isothiocyanates.

[0572] Functional groups on chelators that are ideal precursors for direct conjugation of the chelator to the carboxyl group of a peptide are known to those skilled in the art and include, but are not limited to, alkylamino and arylamino nitrogens, for which several chelator reagents are commercially available, e.g., for DOTA, which has either an alkylamino or arylamino nitrogen.

[0573] It will be appreciated by those skilled in the art that the radionuclide to be coupled or attached to the compounds of the present invention will be selected having regard to the particularities of the disease to be treated and / or diagnosed, respectively, and / or the patient population and patient group to be treated and diagnosed, respectively.

[0574] In embodiments of the present invention, radioactive nuclei are also referred to as radionuclides. Radioactive decay is the process by which the nuclei of unstable atoms lose energy by emitting ionizing particles (ionizing radiation). There are various types of radioactive decay. Decay, i.e., energy loss, occurs when an atom with one type of nucleus, called the parent radionuclide, is transformed into an atom with a different nucleus state or into a different nucleus containing a different number of protons and neutrons. Both of these products are called daughter nuclei. In some decays, the parent and daughter are different chemical elements, and therefore, the decay process results in nuclear transmutation (the creation of atoms of new elements). For example, radioactive decay can be alpha decay, beta decay, and gamma decay. Alpha decay occurs when a nucleus emits an alpha particle (helium nucleus). This is the most common process of emitting nucleons, but in rarer types of decay, the nucleus emits protons or specific nuclei of other elements (in a process called cluster decay). Beta decay occurs when a nucleus loses electrons (β - -decay) or positron (β +-decay) and releases a type of neutrino. In contrast, there are radioactive decay processes that do not produce mutations. can be emitted as gamma rays in gamma decay, or can be used to eject orbital electrons by interaction with an excited nucleus in a process called internal conversion, or can be used to absorb an inner atomic electron from an electron shell, thereby changing a nuclear proton into a neutron, which can cause the emission of an electron neutrino in a process called electron capture (EC), or can be emitted without changing the number of protons and neutrons in a process called isomeric transition (IT). Another form of radioactive decay, spontaneous fission (SF), is found only in very heavy chemical elements, resulting in the spontaneous decomposition into smaller nuclei and a few isolated nuclear particles.

[0575] In a preferred embodiment of the present invention, radionuclides may be used to label the compounds of the present invention. In an embodiment of the present invention, the radionuclide is suitable for complexation with a chelating agent to provide a radionuclide chelate complex.

[0576] In further embodiments, one or more atoms of the compounds of the invention are of non-natural isotopic composition; preferably, these atoms are radionuclides, more preferably radionuclides of carbon, oxygen, nitrogen, sulfur, phosphorus and the halogens; these radioactive atoms are typically part of amino acids, optionally halogen-containing amino acids, and / or components, and optionally halogenated components of each of the compounds of the invention.

[0577] In a preferred embodiment of the invention, the radionuclide has a half-life that allows for diagnostic and / or therapeutic medical use, specifically a half-life of between 1 minute and 100 days. In a preferred embodiment of the present invention, the radionuclides have decay energies that allow for diagnostic and / or therapeutic medical use. Specifically, for gamma-emitting isotopes, the decay energies are 0.004 to 10 MeV, preferably 0.05 to 4 MeV, for diagnostic use. For positron-emitting isotopes, the decay energies are 0.6 to 13.2 MeV, preferably 1 to 6 MeV, for diagnostic use. For particle-emitting isotopes, the decay energies are 0.039 to 10 MeV, preferably 0.4 to 6.5 MeV, for therapeutic use.

[0578] In a preferred embodiment of the present invention, the radionuclide is industrially produced for medical use, specifically the radionuclide is available in GMP quality. In a preferred embodiment of the present invention, the daughter nuclide(s) after radioactive decay of the radionuclide are compatible with diagnostic and / or therapeutic medical use. Furthermore, the daughter nuclide(s) are stable or further decay in a manner that does not interfere with or even support diagnostic and / or therapeutic medical use. Representative radionuclides that can be used in connection with the present invention are summarized in Table 7.

[0579] [Table 7-1]

[0580] [Table 7-2]

[0581] [Table 7-3]

[0582] [Table 7-4]

[0583] [Table 7-5]

[0584] Table 7-6

[0585] Table 7-7

[0586] Table 7-8

[0587] Table 7-9

[0588] Table 7-10

[0589] Table 7-11

[0590] Table 7-12

[0591] Table 7-13

[0592] Table 7-14

[0593] Table 7-15

[0594] Table 7-16

[0595] Table 7-17

[0596] Table 7-18

[0597] Table 7-19

[0598] Table 7-20

[0599] Table 7-21

[0600] Table 7-22

[0601] Table 7-23

[0602] Table 7-24

[0603] Table 7-25

[0604] [Table 7-26]

[0605] [Table 7-27]

[0606] [Table 7-28]

[0607] [Table 7-29]

[0608] [Table 7-30]

[0609] [Table 7-31]

[0610] [Table 7-32]

[0611] [Table 7-33]

[0612] [Table 7-34]

[0613] In an embodiment of the present invention, the radionuclide is used for diagnostic purposes. Preferably, the radioisotope is, but not limited to, 43 Sc, 44 Sc, 51 Mn, 52 Mn,64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 177 Lu, 201 Tl, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I. More preferably, the radionuclide is selected from the group comprising: 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I. Even more preferably, the radionuclide is selected from the group comprising: 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18 F, 123 I, and 124 I. However, the use of these radionuclides is limited to diagnostic purposes. It will also be recognized by those skilled in the art that the term "antibody" is not intended to be limiting and encompasses their use in therapeutic and diagnostic therapeutics when conjugated to the compounds of the present invention.

[0614] In an embodiment of the invention, a radionuclide is used in therapy. Preferably, the radioisotope is: 47 Sc, 67 Cu,89 Sr, 90 Y, 111 In, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I, 211 More preferably, the radioisotope is selected from the group including At. 47 Sc, 67 Cu, 90 Y, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I, 211 Even more preferably, the radionuclide is selected from the group comprising: 90 Y, 177 Lu, 225 Ac, 227 Th, 131 I and 211 However, it will also be appreciated by those skilled in the art that the use of the above radionuclides is not limited to therapeutic purposes, but also encompasses their use in diagnostics and diagnostic therapeutics when conjugated to the compounds of the present invention.

[0615] In certain embodiments, the compounds of the present invention are present as pharmaceutically acceptable salts. The "pharmaceutically acceptable salts" of the compounds of the present invention are preferably acid or base salts generally considered in the art to be suitable for use in contact with human or animal tissues without undue toxicity or carcinogenicity, and preferably without irritation, allergic reactions, or other problems or complications. Such salts include mineral and organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The compounds of the present invention can form internal salts that are also pharmaceutically acceptable salts.

[0616] Suitable pharmaceutically acceptable salts include, but are not limited to, hydrochloric acid, phosphoric acid, bromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acid, such as acetic acid, HOOC-(CH2) n Examples of pharmaceutically acceptable salts include salts of acids such as -COOH (n is any integer from 0 to 4, i.e., 0, 1, 2, 3, or 4). Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those of ordinary skill in the art will recognize additional pharmaceutically acceptable salts for the compounds provided herein. In general, pharmaceutically acceptable acid or base salts can be synthesized from parent compounds containing a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Generally, the use of nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred.

[0617] A "pharmaceutically acceptable solvate" of a compound of the present invention is preferably a solvate of a compound of the present invention formed by the association of one or more solvent molecules with one or more molecules of a compound of the present invention. Preferably, the solvent is one generally considered in the art to be suitable for use in contact with human or animal tissues without undue toxicity or carcinogenicity, preferably without irritation, allergic reaction, or other problems or complications. Such solvents include organic solvents such as alcohols, ethers, esters, and amines.

[0618] The "hydrate" of the compound of the present invention is formed by the association of one or more water molecules with one or more molecules of the compound of the present invention. Such hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and tetrahydrate. Regardless of the hydrate composition, all hydrates are generally considered to be pharmaceutically acceptable.

[0619] The compounds of the present invention have high binding affinity to FAP and high inhibitory activity against FAP. Because of this high binding affinity, the compounds of the present invention are effective, useful, and / or suitable as targeting agents, and when conjugated to another moiety, as targeting moieties.Preferably, the targeting agent herein is a drug that interacts with the target molecule, which is the FAP in this case.Therefore, with respect to the cells and tissues targeted by the compounds of the present invention, any cells and tissues that express the FAP can be targeted or targeted, respectively.

[0620] In certain embodiments, the compound interacts with a fibroblast activation protein (FAP), preferably a human FAP having the amino acid sequence of SEQ ID NO: 1, or a homolog thereof, wherein the amino acid sequence of the homolog has at least 85% identity to the FAP of SEQ ID NO: 1. In preferred embodiments, the identity is 90%, preferably 95%, 96%, 97%, 98% or 99%.

[0621] The identity between two nucleic acid molecules can be determined as known to those skilled in the art.More specifically, sequence comparison algorithms can be used to calculate the percent sequence homology of test sequence(s) to reference sequence based on designated program parameters.Test sequence is preferably the sequence or protein or polypeptide that is said to be identical to different protein or peptide, or should be tested to see whether it is identical, and if so, how identical it is, and therefore this different protein or polypeptide is also called reference sequence, and is preferably wild-type protein or polypeptide, more preferably human FAP of SEQ ID NO: 1.

[0622] Optimal alignment of sequences for comparison can be achieved, for example, by the local homology algorithm of Smith & Waterman (Smith et al., Advances in Applied Mathematics, 1981, 2:482), by the Needleman & Wunsch (Needleman et al., J Mol Biol, 1970, 48:443), by the search for similarity method of Pearson & Lipman (Pearson et al., Proc Natl Acad Sci USA, 1988, 85:24444), or by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection.

[0623] An example of an algorithm suitable for determining percent sequence identity is the algorithm used in the Basic Local Alignment Search Tool (hereinafter referred to as "BLAST"). See, for example, Altschul et al., 1990 (Altschul et al., J Mol Biol, 1990, 215:403) and Altschul et al., 1997 (Altschul et al., Nucleic Acids Res, 1997, 25:3389). Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (hereinafter referred to as "NCBI"). The default parameters used in determining sequence identity using software available from NCBI, such as BLASTN (for nucleotide sequences) and BLASTP (for amino acid sequences), are described in McGinnis et al. (McGinnis et al., Nucleic Acids Res, 2004, 32:W20).

[0624] It is within the scope of the present invention that the compounds of the present invention are used or intended for use in a method for treating the diseases disclosed herein. Such a method preferably comprises administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. Such a method includes, but is not limited to, curative or adjuvant cancer treatment. It is used as a palliative treatment when a cure is not possible and the purpose is to control the disease locally or to alleviate symptoms, or as a therapeutic treatment when the therapy has a survival benefit and may be curative.

[0625] The methods for treating diseases disclosed herein include those described herein, including tumors and cancers. The compounds of the present invention can be used as the first therapy, or as the second, third, fourth, or last therapy, including the treatment of the disclosed diseases.It is also within the scope of the present invention to combine the compounds of the present invention with additional therapeutic approaches.Those skilled in the art will be aware that the exact treatment intent, including the intent of curative, adjuvant, neoadjuvant, therapeutic, or palliative treatment, depends on the type, location, and stage of the tumor, as well as the general health of the patient.

[0626] In an embodiment of the invention, the disease is selected from the group consisting of neoplasms not otherwise specified, benign neoplasms, neoplasms of unknown benign or malignant nature, malignant neoplasms, metastatic neoplasms, neoplasms of unknown primary or metastatic nature, benign tumor cells, tumor cells of unknown benign or malignant nature, malignant tumor cells, malignant small cell tumors, malignant giant cell tumors, malignant spindle cell tumors, epithelial neoplasms of unspecified nature, benign epithelial tumors, carcinoma in situ of unspecified nature, metastatic carcinoma of unspecified nature, carcinomatosis, benign epithelioma, malignant epithelioma, large cell carcinoma of unspecified nature, undifferentiated carcinoma of unspecified nature, atypical carcinoma of unspecified nature, pleomorphic carcinoma, giant cell and spindle cell carcinoma, giant cell carcinoma, spindle cell carcinoma, pseudosarcomatous carcinoma, pleomorphic cell carcinoma, spheroid cell carcinoma, multiple small tumors, small cell carcinoma of unspecified nature, oat cell carcinoma, small cell carcinoma, spindle cell type, papillary and squamous neoplasm, papilloma of unspecified nature, in Papillary carcinoma in situ, papillary carcinoma not otherwise specified, verrucous papilloma, verrucous carcinoma not otherwise specified, squamous cell papilloma, squamous cell carcinoma, inverted papilloma, papillomatosis not otherwise specified, squamous cell carcinoma in situ not otherwise specified, squamous cell carcinoma not otherwise specified, metastatic squamous cell carcinoma not otherwise specified, squamous cell carcinoma, keratinizing type not otherwise specified, large cell nonkeratinizing squamous cell carcinoma, small cell nonkeratinizing squamous cell carcinoma, spindle cell squamous cell carcinoma, adenoid squamous cell carcinoma, in cases where stromal invasion is suspected Squamous cell carcinoma in situ, Microinvasive squamous cell carcinoma, Queyrat's erythroplasia, Bowen's disease, Lymphoepithelial carcinoma, Basal cell neoplasm, Basal cell tumor, Basal cell carcinoma not otherwise specified, Multicentric basal cell carcinoma, Localized scleroderma basal cell carcinoma, Fibroepithelial basal cell carcinoma, Basosquamous cell carcinoma, Transforming carcinoma, Yadazoline intraepithelioma, Trichoepithelioma, Trichofolliculoma, Trichilemmomas, Calcifying epithelioma, Transitional cell papilloma and carcinoma, Transitional cell papilloma not otherwise specified, Urothelial papilloma, Transitional cell carcinoma in situ, Transitional cell carcinoma not otherwise specified, Schneiderian papilloma, Inverted transitional cell papilloma, Schneiderian carcinoma, Spindle cell transitional cell carcinoma, Basaloid carcinoma, Cloacal carcinoma, Papillary transitional cell carcinoma, Adenoma and adenocarcinoma, Adenoma not otherwise specified, Bronchial adenoma not otherwise specified, InAdenocarcinoma in situ, Adenocarcinoma not otherwise specified, Metastatic adenocarcinoma not otherwise specified, Scirrhous adenocarcinoma, Fibrofibrosis gastritis, Superficial spreading adenocarcinoma, Intestinal adenocarcinoma, Diffuse carcinoma, Monomorphic adenoma, Basal cell adenoma, Islet cell adenoma, Islet cell carcinoma, Insulinoma not otherwise specified, Malignant insulinoma, Glucagonoma not otherwise specified, Malignant glucagonoma, Gastrinoma not otherwise specified, Malignant gastrinoma, Mixed islet cell and exocrine adenocarcinoma, Bile duct adenoma, Cholangiocarcinoma, Bile duct cystadenoma, Cholangiocarcinoma, Hepatocellular adenoma, Hepatocellular carcinoma not otherwise specified, Benign hepatocellular cholangiocarcinoma, Mixed hepatocellular carcinoma and cholangiocarcinoma, Trabecular adenoma, Trabecular adenocarcinoma, Embryonic adenoma, Exocrine carcinoma Phosphocutaneous cylindroma, adenoid cystic carcinoma, cribriform carcinoma, adenomatous polyp not otherwise specified, adenocarcinoma in adenomatous polyp, tubular adenoma not otherwise specified, tubular adenocarcinoma, adenomatous polyposis colon, adenocarcinoma in adenomatous polyposis colon, multiple adenomatous polyps, solid carcinoma not otherwise specified, simple carcinoma, carcinoid tumor not otherwise specified, malignant carcinoid tumor, argyrophilic carcinoid tumor not otherwise specified, malignant argyrophilic carcinoid tumor, non-argyrophilic carcinoid tumor not otherwise specified, malignant non-argyrophilic carcinoid tumor, malignant mucinous carcinoid tumor, composite carcinoid, pulmonary adenomatosis, bronchiolo-alveolar adenocarcinoma, alveolar adenoma , hydatid adenocarcinoma, unspecified papillary adenoma, unspecified papillary adenocarcinoma, unspecified villous adenoma, adenocarcinoma in villous adenoma, villous adenocarcinoma, tubular villous adenoma, pigment chromophobe adenoma, chromophobe carcinoma, eosinophilic adenoma, eosinophilic carcinoma, eosinophilic-basophilic mixed adenoma, eosinophilic-basophilic mixed carcinoma, eosinophilic adenoma, eosinophilic adenocarcinoma, Basic adenoma, basophilic carcinoma, clear cell adenoma, clear cell adenocarcinoma unspecified, adrenal-like tumor, renal cell carcinoma, clear cell adenofibroma, granular cell carcinoma, principal cell adenoma, watery clear cell adenoma, watery clear cell adenocarcinoma, mixed cell adenoma, mixed cell adenocarcinoma, lipoadenoma, follicular adenoma, follicular adenocarcinoma unspecified, well differentiated follicular adenocarcinoma, cord-like Small follicular adenocarcinoma, small follicular adenoma, large follicular adenoma, papillary and follicular adenocarcinoma, non-encapsulated sclerosing carcinoma, multiple endocrine adenoma, juxtaglomerular tumor, adrenocortical adenoma not otherwise specified, adrenocortical cell carcinoma, compact cell adrenocortical adenoma, heavily pigmented atypical adrenocortical adenoma, clear cell adrenocortical adenoma, glomerular cell adrenocortical adenoma, mixed cell adrenocortical adenoma, endometrioid adenoma not otherwise specified, endometrioid adenoma, borderline malignant tumor, endometrioid carcinoma, endometrioid adenofibroma not otherwise specified, borderline malignant endometrioid adenofibroma, malignant endometrioid adenofibroma, skin adnexal neoplasm, skin adnexal adenoma, skin adnexal carcinoma, hidradenoma, not otherwise specifiedFunctional sweat gland tumors, sweat gland adenocarcinomas, apocrine adenomas, apocrine adenocarcinomas, eccrine acrosyringomas, eccrine syringomas, sweat gland cysts, papillary hidradenomas, papillary sweat gland tumors, specific non-functional syringomas, sebaceous adenomas, sebaceous adenocarcinomas, ceruminous gland adenomas, ceruminous gland adenocarcinomas, mucosal epidermoid neoplasms, mucosal epidermoid tumors, cystic, mucinous, and serous neoplasms of mucosal epidermoid carcinomas, specific non-functional cystadenomas, specific non-functional cystadenocarcinomas, specific non-functional serous cystadenomas, serous cystadenomas with borderline malignancy, specific non-functional serous cystadenocarcinomas, specific non-functional papillary cystadenomas, papillary cystadenomas with borderline malignancy, specific non-functional papillary cystadenocarcinomas, specific non-functional papillary serous cystadenomas, papillary serous cystadenomas with borderline malignancy, papillary serous cystadenocarcinomas, specific non-functional serous surface papillomas, serous surface papillomas with borderline malignancy, serous surface papillocarcinomas, specific non-functional mucinous cystadenomas, mucinous cystadenomas with borderline malignancy, specific non-functional mucinous cystadenocarcinomas, specific non-functional papillary mucinous cystadenomas, papillary mucinous cystadenomas with borderline malignancy, papillary mucinous cystadenocarcinomas, mucinous adenomas, mucinous adenocarcinomas, peritoneal pseudomyxoma, mucin-producing adenocarcinomas, signet ring cell carcinomas, metastatic signet ring cell carcinomas, tubular, lobular, and medullary neoplasms, specific non-functional non-invasive intraductal carcinomas, invasive ductal carcinomas, comedocarcinomas, specific non-functional non-invasive comedocarcinomas, juvenile breast carcinomas, intraductal papillomas, non-invasive intraductal papillary adenocarcinomas, intracystic papillary adenomas, non-invasive intracystic carcinomas, specific non-functional intraductal papillomatosis of the lactiferous ducts, subareolar lactiferous duct papillomatosis, specific non-functional medullary carcinomas, amyloid stroma-associated medullary carcinomas, lymphocyte stroma-associated medullary carcinomas, in situ lobular carcinomas, specific non-functional lobular carcinomas, invasive ductal carcinomas, inflammatory carcinomas, mammary Paget's disease, Paget's disease and invasive ductal carcinomas, extramammary Paget's disease, acinar cell neoplasms, acinar cell adenomas, acinar cell tumors, acinar cell carcinomas, compound epithelial neoplasms, adenoid squamous carcinomas, adenolymphomas, squamous metaplasia adenocarcinomas, chondroid metaplasia and osteoid metaplasia adenocarcinomas, spindle cell metaplasia adenocarcinomas, apocrine metaplasia adenocarcinomas, benign thymomas, malignant thymomas, specific sex gland neoplasms, sex cord-stromal tumors, specific non-functional thecomas, thecoma carcinomas, specific non-functional luteomas, specific non-functional granulosa cell tumors, malignant granulosa cell tumors, granulosa cell-theca cell tumors, benign male germ cell tumors, specific non-functional male germ cell tumors, malignant male germ cell tumors, Sertoli-Leydig cell tumors, ovarian male germ cell tumors, specific non-functional tubular male germ cell tumors, Sertoli cell carcinomas, lipid-storing tubular male germ cell tumors, benign Leydig cell tumors, specific non-functional Leydig cell tumors, malignant Leydig cell tumors, hilus cell tumors, ovarian lipoid cell tumors, adrenal rest tumorsParaganglioma and glomus tumor, paraganglioma not otherwise specified, malignant paraganglioma, sympathetic paraganglioma, parasympathetic paraganglioma, jugular body tumor, aortic body tumor, carotid bulb tumor, extra-adrenal paraganglioma not otherwise specified, malignant extra-adrenal paraganglioma, pheochromocytoma not otherwise specified, malignant pheochromocytoma, hemangiosarcoma, glomus tumor, glomus angioma, nevi and melanoma, pigmented nevi not otherwise specified, malignant melanoma not otherwise specified, nodular melanoma, balloon cell nevus, balloon cell melanoma, halo nevus, fibrous papule of the nose, nerve nevus, giant cell nevus, non-pigmented nevi, amelanotic melanoma, junctional nevus, junctional nevus Malignant melanoma in bleb, Precancerous melanosis not otherwise specified, Malignant melanoma in precancerous melanosis, Hutchinson's melanoma, Malignant melanoma in Hutchinson's melanoma, Superficial spreading melanoma, Intradermal nevi, Compound nevi, Giant pigmented nevi, Malignant melanoma in giant pigmented nevi, Epithelioid nevi and spindle cell nevi, Epithelioid melanoma, Spindle cell melanoma not otherwise specified, Spindle cell melanoma type a, Spindle cell melanoma type b, Mixed epithelioid and spindle cell melanoma, Blue nevi not otherwise specified, Malignant blue nevi, Cellular proliferative blue nevi, Soft tissue tumors and sarcomas not otherwise specified, Benign soft tissue tumors, Sarcoma not otherwise specified, Specified Sarcomatosis unspecified, spindle cell sarcoma, giant cell sarcoma, small cell sarcoma, epithelioid cell sarcoma, fibromatous neoplasm, fibroma not otherwise specified, fibrosarcoma not otherwise specified, myxofibroma, fibromyxoblastic sarcoma, periosteal fibroma, periosteal fibrosarcoma, fascial fibroma, fascial fibrosarcoma, infantile fibrosarcoma, elastoma, aggressive fibromatosis, abdominal fibromatosis, dendrofibroma, fibrous histiocytoma not otherwise specified, atypical fibrous histiocytoma, malignant fibrous histiocytoma, fibroxanthoma not otherwise specified, atypical fibroxanthoma, malignant fibroxanthoma, dermatofibroma not otherwise specified, dermatofibroma protuberans, dermatofibroma not otherwise specified, myxomatous neoplasm, myxoma not otherwise specified, myxoma Lipomatous neoplasm, lipoma not otherwise specified, liposarcoma not otherwise specified, fibrolipoma, well-differentiated liposarcoma, fibromyxoid lipoma, myxoid liposarcoma, round cell liposarcoma, pleomorphic liposarcoma, mixed liposarcoma, intramuscular lipoma, spindle cell lipoma, angiomyolipoma, angiomyoliposarcoma, angiolipoma not otherwise specified, invasive angiolipoma, myelolipoma, hibernation adenoma, lipoblastomatosis, leiomyomatous neoplasm, leiomyoma not otherwise specified, intravascular leiomyomatosis, leiomyosarcoma not otherwise specified, epithelioid leiomyoma, epithelioid leiomyosarcoma, cellular leiomyoma, transforming leiomyoma, angiomyoma, angiomyosarcoma, myoma, sarcoma, rhabdomyoma not otherwise specified,Unspecified striations, Myosarcoma, Pleomorphic rhabdomyosarcoma, Mixed rhabdomyosarcoma, Embryonal rhabdomyosarcoma, Adult rhabdomyosarcoma, Embryonal rhabdomyosarcoma, Alveolar rhabdomyosarcoma, Complex mixed and stromal neoplasm, Endometrial stromal sarcoma, Endolymphatic stromal endometriosis, Adenomyoma, Pleomorphic adenoma, Malignant mixed tumor not otherwise specified, Müllerian mixed tumor, Mesodermal mixed tumor, Mesodermal nephroma, Nephroblastoma not otherwise specified, Epithelial nephroblastoma, Mesenchymal nephroblastoma, Hepatoblastoma, Carcinosarcoma not otherwise specified, Embryonal carcinosarcoma, Myoepithelioma, Benign mesenchymoma, Mesenchymoma not otherwise specified, Malignant mesenchymoma, Embryonal sarcoma, Fibroepithelial neoplasm, Brenner tumor not otherwise specified, Brenner tumor Borderline malignant tumor, malignant Brenner tumor, fibroadenoma not otherwise specified, intraductal fibroadenoma not otherwise specified, periductal fibroadenoma, adenofibroma not otherwise specified, serous adenofibroma, myxoid adenofibroma, cellular intracanalicular fibroadenoma, cystosarcoma phyllodes not otherwise specified, malignant cystosarcoma phyllodes not otherwise specified, juvenile fibroadenoma, synovial neoplasm, benign synovial tumor, synovial sarcoma not otherwise specified, spindle cell synovial sarcoma, epithelioid cell synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma of tendons and aponeuroses, mesothelial neoplasm, benign mesothelioma, malignant mesothelioma, benign fibrous mesothelioma, malignant fibrous mesothelioma, benign epithelioid mesothelioma, malignant epithelioid mesothelioma, benign biphasic mesothelioma, malignant biphasic mesothelioma tumor, adenoid tumor not otherwise specified, germ cell neoplasm, dysgerminoma, seminoma not otherwise specified, undifferentiated seminoma, spermatocytic seminoma, germ cell tumor, embryonal carcinoma not otherwise specified, endodermal sinus tumor, polyembryoma, gonadoblastoma, benign teratoma, teratoma not otherwise specified, malignant teratoma not otherwise specified, teratocarcinoma, undifferentiated malignant teratoma, intermediate malignant teratoma, dermoid cyst, malignant transformed dermoid cyst, thyroid ovarian thyroid not otherwise specified, malignant thyroid ovarian thyroid, goiter carcinoid, trophoblastic neoplasm, hydatidiform mole not otherwise specified, invasive hydatidiform mole, choriocarcinoma, choriocarcinoma with teratoma, malignant trophoblastic teratoma, mesonephroma, benign mesonephroma, mesonephric tumor, malignant mesonephroma, endosalpingioma, vascular tumor, hemangioma not otherwise specified, angiosarcoma, cavernous hemangioma, venous hemangioma, vine hemangioma, Kupffer cell sarcoma, benign hemangioendothelioma, hemangioendothelioma not otherwise specified, malignant hemangioendothelioma, capillary hemangioma, intramuscular hemangioma, Kaposi's sarcoma, angiokeratoma, angiokeratoma verrucosa, benign hemangiopericytoma, hemangiopericytoma not otherwise specified, malignant hemangiopericytoma, angiofibroma not otherwise specified, hemangioblastoma, lymphangioma, lymphangiomas, lymphangiosarcoma, capillary lymphangioma, cavernous lymphangioma, cystic lymphangioma, lymphangioleiomyomatosis, lymphangioleiomyomatosis, angiolymphangioma,Osteoma and osteosarcoma, osteoma not otherwise specified, osteosarcoma not otherwise specified, chondroblastic osteosarcoma, fibroblastic osteosarcoma, telangiectatic osteosarcoma, osteosarcoma in Paget's disease of bone, parosteal osteosarcoma, osteoid osteoma not otherwise specified, osteoblastoma, chondrogenic neoplasm, osteochondroma, osteochondromatosis not otherwise specified, chondroma not otherwise specified, chondrosarcoma not otherwise specified, parosteal chondrosarcoma, parosteal chondrosarcoma, chondroblastoma not otherwise specified, malignant chondroblastoma, mesenchymal chondrosarcoma, chondromyxoid fibroma, giant cell tumor, giant cell tumor of bone not otherwise specified, malignant giant cell tumor of bone, giant cell tumor of soft tissue not otherwise specified, malignant giant cell tumor of soft tissue, mixed Bone tumor, Ewing's sarcoma, long bone adamantinoma, ossifying fibroma, odontogenic tumor, benign odontogenic tumor, odontogenic tumor not otherwise specified, malignant odontogenic tumor, dentoma, cementoma not otherwise specified, benign cementoblastoma, cementogenic fibroma, giant cementoma, odontoma not otherwise specified, aggregate odontoma, complex odontoma, ameloblastic fibro-odontoma, ameloblastic sarcoma, adenoid odontogenic tumor, calcifying odontogenic cyst, ameloblastoma not otherwise specified, malignant ameloblastoma, odontoid ameloblastoma, flat odontogenic tumor, odontogenic myxoma, odontogenic fibroma not otherwise specified, ameloblastic fibroma, ameloblastic Dermofibrosarcoma, odontogenic calcific epithelioma, mixed tumor, craniopharyngioma, pinealgioma, pineocytoma, pineoblastoma, melanotic neuroectodermal tumor, chordoma, glioma, malignant glioma, gliomatosis cerebri, mixed glioma, subependymal glioma, subependymal giant cell astrocytoma, choroid plexus papilloma unspecified , malignant choroid plexus papilloma, ependymoma unspecified, anaplastic ependymoma, papillary ependymoma, myxopapillary ependymoma, astrocytoma unspecified, anaplastic astrocytoma, plasmid astrocytoma, mastocytic astrocytoma, fibrous astrocytoma, pilocytic astrocytoma, spongoblastoma unspecified, polar spongoblast. tumor, astroblastoma, glioblastoma not otherwise specified, giant cell glioblastoma, glioblastoma with sarcomatous elements, primitive polar spongioblastoma, oligodendroglioma not otherwise specified, anaplastic oligodendroglioma, oligodendroglioma, medulloblastoma not otherwise specified, desmoplastic medulloblastoma, medullomyoblastoma, cerebellar sarcoma not otherwise specified, teratocyte sarcoma, pseudoepithelioma neoplasm, ganglioneuroma, ganglioneuromatosis, neuroblastoma not otherwise specified, medulloepithelioma not otherwise specified, teratoid medulloepithelioma, neuroepithelioma not otherwise specified, spongioneuroma, ganglioglioma, neurocytoma, Pacinian tumor, retinoblastoma not otherwise specified, differentiated retinoblastoma,Undifferentiated omental budding cells, olfactory... Nerve tumor, sensory neurocytoma, nasal neuroblastoma, olfactory neuroepithelioma, meningioma, meningioma not otherwise specified, meningiomatosis not otherwise specified, malignant meningioma, meningioma, fibrous meningioma, psammomatous meningioma, angiomatous meningioma, hemangioblastic meningioma, hemangiopericytic meningioma, transitional meningioma, papillary meningioma, meningeal sarcomatosis, nerve sheath tumor, neurofibroma not otherwise specified, neurofibromatosis not otherwise specified, neurofibrosarcoma, melanotic neurofibroma, plexiform neurofibroma, schwannoma not otherwise specified, schwannomatosis, malignant schwannoma, neuroma not otherwise specified, granular cell tumor and alveolar soft part sarcoma, granular cell tumor not otherwise specified, malignant granular cell lymphoma, alveolar soft part sarcoma, unspecified or diffuse lymphoma, benign lymphoma-like tumor, malignant lymphoma not otherwise specified, non-Hodgkin's lymphoma, undifferentiated malignant lymphoma not otherwise specified, stem cell malignant lymphoma, unspecified rotational cell malignant lymphoma not otherwise specified, lymphosarcoma not otherwise specified, lymphoplasmacytic malignant lymphoma, immunoblastic malignant lymphoma, mixed lymphocytic-histiocytic malignant lymphoma not otherwise specified, centroblastic-centrocytic diffuse malignant lymphoma, follicular-centrocytic malignant lymphoma not otherwise specified, well-differentiated lymphocytic malignant lymphoma not otherwise specified, moderately differentiated lymphocytic malignant lymphoma not otherwise specified, Centrocytic lymphoma, unspecified, follicular-centered lymphoma, poorly differentiated lymphocytic lymphoma, unspecified, prolymphocytic lymphosarcoma, centroblastic lymphoma, unspecified, non-cleaved follicular-centered lymphoma, unspecified, reticulum cell sarcoma, reticulum cell sarcoma, unspecified, pleomorphic reticulum cell sarcoma, nodular reticulum cell sarcoma, Hodgkin's disease, Hodgkin's disease not otherwise specified, lymphocyte-predominant Hodgkin's disease, mixed-cell Hodgkin's disease, lymphocyte-depleted Hodgkin's disease not otherwise specified, lymphocyte-depleted diffuse fibromatosis-type Hodgkin's disease, lymphocyte-depleted reticular Hodgkin's disease, nodular sclerosing Hodgkin's disease not otherwise specified , cytoplasmic nodular sclerosing Hodgkin's disease, Hodgkin's granuloma, Hodgkin's granuloma, Hodgkin's sarcoma, nodular lymphoma or follicular nodular lymphoma not otherwise specified, nodular mixed lymphocytic-histiocytic malignant lymphoma, centroblastic-centrocytic follicular malignant lymphoma, nodular well-differentiated lymphocytic malignant lymphoma, nodular moderately differentiated lymphocytic malignant lymphoma, follicular cleaved follicular-centrocytic malignant lymphoma, nodular poorly differentiated lymphocytic malignant lymphoma, follicular non-cleaved follicular-centrocytic malignant lymphoma, mycosis fungoides, mycosis fungoides, Sézary's disease, mixed reticuloendothelial neoplasm,Microglioma, malignant histiocytosis, histiocytic medullary reticulosis, Letterer-Siwe disease, plasma cell neoplasm, plasma cell myeloma, benign plasma cell neoplasm, plasmacytoma not otherwise specified, malignant plasma cell neoplasm, mast cell tumor, mast cell tumor not otherwise specified, mast cell sarcoma, malignant mastocytosis, Burkitt tumor, Burkitt tumor, leukemia group, leukemia group not otherwise specified, leukemia not otherwise specified, acute leukemia not otherwise specified, unspecified Subacute leukemia, chronic leukemia not otherwise specified, nonleukemic leukemia not otherwise specified, combined leukemia group, combined leukemia, lymphocytic leukemia group, lymphocytic leukemia not otherwise specified, acute lymphocytic leukemia, subacute lymphocytic leukemia, chronic lymphocytic leukemia, nonleukemic lymphocytic leukemia, prolymphocytic leukemia, plasma cell leukemia group, plasma cell leukemia, erythroleukemia group, erythroleukemia, acute erythremia, chronic erythremia, lymphoma Myeloid leukemia group, lymphosarcoma cell leukemia, myeloid leukemia group, myeloid leukemia not otherwise specified, acute myeloid leukemia, subacute myeloid leukemia, chronic myeloid leukemia, non-leukemic myeloid leukemia, neutrophilic leukemia, acute promyelocytic leukemia, basophilic leukemia group, basophilic leukemia, eosinophilic leukemia group, eosinophilic leukemia, monocytic leukemia group, monocytic leukemia not otherwise specified, acute monocytic leukemia, subacute The leukemia is selected from the group consisting of myeloid monocytic leukemia, chronic monocytic leukemia, non-leukemic monocytic leukemia, mixed leukemia complex, mast cell leukemia, megakaryocytic leukemia, megakaryocytic myelopathy, myeloid sarcoma, hairy cell leukemia, mixed myeloproliferative lymphoproliferative disorder, polycythemia vera, acute panmyelosis, chronic myeloproliferative disorder, myelosclerosis complicated by myeloid metaplasia, idiopathic thrombocythemia, and chronic lymphoproliferative disorder.

[0627] In an embodiment of the invention, the disease is selected from the group consisting of pancreatic tumors, pancreatic adenocarcinoma, tumors of the head of the pancreas, pancreatic body, pancreatic tail, pancreatic duct, islets of Langerhans, tumors of the pancreatic neck, prostate tumors, prostate cancer, prostate, neuroendocrine tumors, breast cancer, tumors of the central breast, upper inner quadrant of the breast, lower inner quadrant of the breast, upper outer quadrant of the breast, lower outer quadrant of the breast, axillary process of the breast, tumors of double lesions of the breast, early-onset breast cancer, parathyroid tumors, myeloma, lung cancer, small cell lung cancer, non-small cell lung cancer, tumors of the main bronchus, upper lobe of the lung, middle lobe of the lung, lower lobe of the lung, colorectal cancer, ascending colon, hepatic flexure of the colon, transverse colon, splenic flexure of the colon, descending colon, sigmoid colon, double lesions of the colon, tumors of the small intestine, liver tumors, hepatocellular adenoma, hepatocellular carcinoma, hepatocellular cholangiomas, mixed hepatocellular carcinoma and cholangiocarcinoma, hepatoblastoma, ovarian cancer, Sarcoma, osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor, gastrointestinal tract, gastric cancer, thyroid cancer, medullary thyroid carcinoma, thyroid gland, renal cell carcinoma, renal pelvis, bladder tumor, bladder cancer, tumor of the bladder trigone, bladder dome, lateral bladder wall, posterior bladder wall, ureteral orifice, urachal tumor, overlapping lesions of the bladder, basal cell carcinoma, basal cell neoplasm, basal cell tumor, basal cell carcinoma, multicentric basal cell carcinoma, basaloid carcinoma, basal cell adenoma, squamous cell carcinoma, oral squamous cell carcinoma, laryngeal squamous cell carcinoma, cervical cancer, ectocervix, overlapping lesions of the cervix, tumors of the uterine isthmus, uterine tumor, ovarian tumor, cervical esophagus, thoracic esophagus, abdominal esophagus, upper third of the esophagus, middle third of the esophagus, lower third of the esophagus, tumors of overlapping lesions of the esophagus, endometrial cancer, head and neck cancer, lymphoma, malignant mesothelial tumor, mesothelial neoplasm, mesothelioma, fibrous mesothelioma, fibrous mesothelioma, epithelioid mesothelioma, epithelial mesothelioma, duodenal carcinoma, neuroendocrine tumor, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, neuroendocrine tumor of the foregut, neuroendocrine tumor of the midgut, neuroendocrine tumor of the hindgut, gastroenteropancreatic neuroendocrine tumor, neuroendocrine carcinoma, neuroendocrine tumor of the breast, neuroendocrine tumor of the ovary, testicular cancer, thymic carcinoma, tumor of the stomach, fundus, body, antrum, pylorus, lesser curvature, greater curvature, gastric overlap lesion, paraganglioma, ganglioneuroma, melanoma, malignant melanoma, nodular melanoma, amelanotic melanoma, superficial spreading melanoma, epithelioid cell melanoma, spindle cell melanoma, mixed epithelioid cell and spindle cell melanoma.

[0628] In further embodiments, the condition is lateral upper lip, lateral lower lip, lateral lip unspecified, upper lip mucosa, lower lip mucosa, labial mucosa unspecified, labial commissure, overlapping lesions of lip, base of tongue unspecified, dorsal surface of tongue unspecified, tongue border, ventral surface of tongue unspecified, anterior two-thirds of tongue unspecified, lingual tonsil, overlapping lesions of tongue, tongue unspecified, upper gingiva, lower gingiva, gingiva unspecified, anterior floor of mouth, lateral floor of mouth, overlapping lesions of floor of mouth, floor of mouth unspecified, hard palate, soft palate unspecified, uvula, overlapping lesions of palate, palate unspecified, buccal mucosa, oral vestibule, retromolar area, overlapping lesions of other and unspecified parts of oral cavity, oral cavity unspecified, ear Submandibular gland, sublingual gland, major salivary gland overlap lesion, major salivary gland unspecified, tonsil fossa, tonsil pillar, tonsil overlap lesion, tonsil unspecified, fossa, anterior surface of epiglottis, lateral oropharyngeal wall, posterior oropharyngeal wall, branchial clefts, oropharynx overlap lesion, oropharynx unspecified, superior nasopharynx wall, posterior nasopharynx wall, lateral nasopharynx wall, anterior nasopharynx wall, nasopharynx unspecified, pyriform sinus, postcricoid surface, hypopharyngeal surface of aryepiglottic fold, posterior hypopharyngeal wall, hypopharyngeal overlap lesion, hypopharynx unspecified, pharynx unspecified, laryngopharynx, Waldeyer's ring, lip, oral and pharyngeal overlap lesion, cervical esophagus, thoracic esophagus, abdominal esophagus, esophagus upper third of the esophagus, middle third of the esophagus, lower third of the esophagus, esophageal duplication, esophagus not otherwise specified, cardia not otherwise specified, fundus, body, antrum, pylorus, lesser curvature of the stomach not otherwise specified, greater curvature of the stomach not otherwise specified, gastric duplication, stomach not otherwise specified, duodenum, jejunum, ileum, Meckel's diverticulum, small intestinal duplication, small intestine not otherwise specified, cecum, appendix, ascending colon, hepatic flexure of the colon, transverse colon, splenic flexure of the colon, descending colon, sigmoid colon, colonic duplication, colon not otherwise specified, rectosigmoid junction, rectum not otherwise specified, anus not otherwise specified, anal canal, cloacal layer, anorectal and anal canal duplication, liver , intrahepatic bile duct, gallbladder, extrahepatic bile duct, ampulla of Vater, biliary duplication, biliary tract unspecified, head of pancreas, body of pancreas, tail of pancreas, pancreatic duct, islets of Langerhans, pancreatic neck, pancreatic duplication, pancreas unspecified, intestinal tract unspecified, digestive system duplication, gastrointestinal tract unspecified, nasal cavity, middle ear, maxillary sinus, ethmoid sinus, frontal sinus, sphenoid sinus, accessory sinus duplication, accessory sinus unspecified, glottis, supraglottis, subglottis, laryngeal cartilage, laryngeal duplication, larynx unspecified, trachea, main bronchus, upper lobe of lung, middle lobe of lung, lower lobe of lung, lung duplication, lung unspecified, thymus, heart, anterior mediastinum, posterior mediastinum, mediastinum unspecified, pleura unspecified,Overlapping lesions of heart mediastinum and pleura, upper respiratory tract unspecified, respiratory system and intrathoracic organs unspecified, airway unspecified, upper limb long bone joints, upper limb short bone joints, lower limb long bone joints, lower limb short bone joints, limb bone joints and articular cartilage overlapping lesions, limb bones unspecified, skull and facial bones, mandible, vertebral column, ribs, sternum, clavicle, pelvic bone, bone joints and articular cartilage overlapping lesions, bone unspecified, blood, bone marrow, spleen, reticuloendothelial system unspecified, hematopoietic system unspecified, skin unspecified lips, eyelids unspecified, external Ear, facial skin, scalp and neck skin, trunk skin, upper limb skin, lower limb skin, peripheral nerves of the head and neck, peripheral nerves of the shoulders and arms, peripheral nerves of the legs, peripheral nerves of the chest, peripheral nerves of the abdomen, peripheral nerves of the pelvis, peripheral nerves of the trunk, overlapping lesions of peripheral nerves and autonomic nervous system, autonomic nervous system unspecified, retroperitoneum, peritoneum, unspecified peritoneum, overlapping lesions of retroperitoneum and peritoneum, connective tissue of the head, connective tissue of the arms, connective tissue of the legs, connective tissue of the chest, connective tissue of the abdomen, connective tissue of the pelvis, trunk unspecified, Connective tissue, subcutaneous connective tissue and other soft tissue overlapping lesions, connective tissue unspecified, nipple, central breast, upper inner quadrant of breast, lower inner quadrant of breast, upper outer quadrant of breast, lower outer quadrant of breast, axillary process of breast, overlapping lesions of breast, breast unspecified, labia majora, labia minora, clitoris, overlapping lesions of vulva, vulva unspecified, vagina unspecified, cervix, ectocervix, overlapping lesions of cervix, uterine isthmus, endometrium, myometrium, fundus, overlapping lesions of uterine body, uterine body, uterus unspecified, Ovary, Fallopian tube, Broad ligament of uterus, Round ligament, Parametrium, Uterine adnexa, Wolffian body, Female genital tract overlap, Female genital tract unspecified, Foreskin, Glans penis, Body of penis, Penile overlap, Penile unspecified, Prostate, Cryptorchidism, Descended testis, Testis unspecified, Epididymis, Spermatic cord, Scrotum unspecified, Tunica vaginalis testis, Male genital tract overlap, Male genital tract unspecified, Kidney unspecified, Renal pelvis, Ureter, Trigone, Bladder dome, Lateral bladder wall, Posterior bladder wall, Uretinal orifice, Urachus, Bladder overlap, Bladder unspecified, Urethra, Paraurethra Ductal glands, urinary overlap lesions, urinary system unspecified, conjunctiva, cornea unspecified, retina, choroid, ciliary body, lacrimal gland, orbit unspecified, ocular and adnexal overlap lesions, eye unspecified, meninges, spinal meninges unspecified, meninges unspecified, cerebrum, frontal lobe, temporal lobe, parietal lobe, occipital lobe, ventricles unspecified, cerebellum unspecified, brain stem, brain overlap lesions, brain unspecified, spinal cord, cauda equina, olfactory nerve, optic nerve, auditory nerve, cranial nerves unspecified, brain and central nervous system overlap lesions, nervous system unspecified, thyroid, adrenal cortex, adrenal medulla, adrenal glands unspecified, parathyroid glands, inferior It may arise in organs and tissues selected from the group including: pituitary gland, craniopharyngeal duct, pineal gland, carotid body, aortic body, overlapping lesions of endocrine glands and related structures, unspecified endocrine glands, unspecified face or neck, unspecified chest, unspecified abdomen, unspecified pelvis, unspecified upper extremities, unspecified lower extremities, other unspecified location, overlapping lesions of unspecified location, facial-head-and-neck lymph nodes, intrathoracic lymph nodes, intra-abdominal lymph nodes, axillary-arm lymph nodes, inguinal-leg lymph nodes, pelvic lymph nodes, lymph nodes in multiple regions, unspecified lymph nodes, unknown primary site.

[0629] Subjects treated with the compounds disclosed and claimed herein can be treated in combination with other non-surgical anti-proliferative (e.g., anti-cancer) drug therapies. In one embodiment, the compounds may be administered in combination with an anti-cancer compound, such as a cytostatic compound. A cytostatic compound is a compound (e.g., a small molecule, nucleic acid, or protein) that inhibits cell growth and / or proliferation. In some embodiments, the cytostatic compound is directed against malignant cells of a tumor. In yet other embodiments, the cytostatic compound inhibits the growth and / or proliferation of vascular smooth muscle cells or fibroblasts.

[0630] Suitable antiproliferative or cytostatic compounds for use in conjunction with the compounds disclosed and claimed herein include anti-cancer drugs. Some anti-cancer drugs that can be used are well known and include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; ciloremycin; cisplatin; cladribine ;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Dactinomycin;Daunorubicin hydrochloride;Decitabine;Dexormaplatin;Dezaguanine;Dezaguanine mesylate;Diaziquone;Docetaxel;Doxorubicin;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine Benzalkonium chloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizine; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; F Osquidone; Fostriecin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Irmofosine; Interferon alfa-2a; Interferon alfa-2b; Interferon alfa-n1; Interferon alfa-n3; Interferon beta-1a; Interferon gamma-1b; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride Salts;Masoprocol;Maytansine;Mechlorethamine hydrochloride;Megestrol acetate;Melengestrol acetate;Melphalan;Menogaril;Mercaptopurine;Methotrexate;Methotrexate sodium;Metoprine;Meturedepa;Mitindomide;Mitocalcin;Mitochromine;Mitogillin;Mitomarcin;Mitomycin;Mitospar;Mitotane;Mitoxantrone hydrochloride;Mycophenolic acid;Niraparib;Nocodazole;Nogalamycin;Olparib;Ormaplatin;Oxisuran;Paclitaxel;Pegaspargase;Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Rogletimide; Rucaparib; Safingol; Safingol hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonig Phosphate;Streptozocin;Sulofenur;Talazoparib;Tallysomycin;Taxol;Taxotere;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposide;Teroxilon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Topotecan hydrochloride;Toremifene citrate;Trestron acetate;Triciribine phosphate;Trimetrexate;Trimetrexate glucuronate;Tubrozole hydrochloride;Uracil mustard;Uredep;Vapreotide;Veraparib;Verteporfin;Vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0631] Other anti-cancer drugs include, but are not limited to, 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; acylfulvene; adecipenol; adozelesin; ALL-TK antagonists; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1 (anti-dorsalizing morphogenetic protein-1) protein-1); antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulaculin; atamestane; atlimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxins; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporines; beta-lactam derivatives; beta-arretin; betaclamycin B; betulinic acid; bFGF inhibitors; bisaziridinylspermine; bisnafide; bisstraten A; brefullate; budotitanium; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamido-aminotriazoles; carboxyamidotriazoles; CaRest M3; CARN 700; cartilage-derived inhibitors; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamides; cicaprost; cis-porphyrins; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; kelp Retastatin analogs; conagenin; crambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentaanthraquinone; cycloplatam; cypemycin; cytarabine ocphosphate; cytolytic factors; cytostatin; dacliximab; dehydrodidemnin B; deslorelin; dexphosphamide; dexrazoxane; dexverapamil; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dihydrotaxol; dihydrotaxol Xamixamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluridine; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflomitine; Elemene; Emiteflu; Epirubicin; Epristeride; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Filgrastim; Finasteride; Flavopiridol; Flezelastine; Fluasterone; Fludarabine; Fluorodauronil nitrite Acid salts; Forfenimex; Formestane; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Glutathione inhibitors; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idoxifene; Idramanton; Ilmofosine; Ilomastat; Imidazoacridone; Imiquimod; Immunostimulatory peptides; Insulin-like growth factor-I receptor inhibitors; Interferon agonists; Interferons; Interleukins; Iobengane; Iododoxorubicin Syn; 4-ipomeanol (ipomeanol, 4-); irinotecan; ilopract; irsogladine; isobengazole; isohomohalichondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds;Lisoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lutotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; mervalone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; Mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mofalotene; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A + mycobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressor 1-based therapy; mustard anticancer compounds; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; naglestip; naloxone + pentazocine; napavine; na Futerpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrulline; O6-benzylguanine; Octreotide; Oxenon; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Osateron; Oxaliplatin; Oxaunomycin; Paclitaxel analogs; Paclitaxel derivatives; Palauamine; Palmitoylrhizoxin; Pamidronate; Panaxytri All;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecin;Pentosan polysulfate sodium;Pentostatin;Pentrozole;Perflubron;Perfosfamide;Perillyl alcohol;Phenazinomycin;Phenylacetate;Phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Prasetin A;Prasetin B;Plasminogen activator inhibitors;Platinum complexes;Platin compounds;Platin-triamine complexes;Porfimer sodium;Porfiromycin;Propylbis-acridone;Prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors; microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridines; pyridoxylated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated reteri Putin; Rhenium etidronate (Re186); Rhizoxin; Ribozyme; RII retinamide; Rohitukin; Romurtide; Roquinimex; Rubiginone B1; Ruboxil; Saitopine; SarCNU; Saclophytol A; Sargramostim; Sdi1 mimetic; Senescence-derived inhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Single-chain antigen binding protein; Sizofuran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Sorbetol; Somatomedin-binding protein; Sonermin; Spa Sulfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongistatin 1; Squalamine; Stem cell inhibitors; Stem cell division inhibitors; Stipiamide; Stromelysin inhibitors; Sulfinosine; Superactive vasoactive intestinal peptide antagonists; Sladista; Suramin; Swainsonine; Synthetic glycosaminoglycans; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Terlapyrylium; Telomerase inhibitors; Temozolomide; Tetrachlorodecaoxide; Tetrazomine; Talib Lastin; Thalidomide; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfasin; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Ethyl etiopurinse; Titanocene dichloride; Topsentin; Toremifene; Totipotent stem cell factor; Translation inhibitors; Tretinoin; Triacetyluridine; Triciribine; Tropisetron; Turosteride; Tyrosine kinase inhibitors; Tyrphostin; UBC inhibitors; Ubenimex; Urogenital sinus-derived growth inhibitory factor; Urokinase receptor antagonists; Variolin B;Vector-based, red blood cell gene therapy; Veraresol; Veramine; Verudine; Vinorelbine; Vinoxacin; Vitaxin; Zanoterone; Zilascorub; and Zinostatin stimalamer.

[0632] The compounds disclosed and claimed herein may also be used in combination with any of the following treatments: Therapy in combination with inhibitors of poly(ADP-ribose) polymerase (PARP), a class of chemotherapy drugs that target cancers with defective DNA damage repair (Yuan et al., Expert Opin Ther Pat, 2017, 27:363). Such PARP inhibitors include, but are not limited to, olaparib, rupacarib, velaparib, niraparib, talazoparib, pamiparib, iniparib, E7449, and A-966492.

[0633] For example, nuclear factor-kappa B signal transduction therapy is combined with inhibitors of signal transduction pathways and mechanisms that lead to the repair of DNA single-strand and double-strand breaks (Pilie et al., Nat Rev Clin Oncol, 2019, 16:81; Zhang et al., Chin J Cancer, 2012, 31:359). Such inhibitors include, but are not limited to, inhibitors of ATM and ATR kinase, checkpoint kinase 1 and 2, DNA-dependent protein kinase, and WEE1 kinase (Pilie et al., Nat Rev Clin Oncol, 2019, 16:81).

[0634] Immunomodulators (Khalil et al., Nat Rev Clin Oncol, 2016, 13:394), cancer vaccines (Hollingsworth et al., NPJ Vaccines, 2019, 4:7), immune checkpoint inhibitors (e.g., PD-1, PD-L1, CTLA-4 inhibitors) (Wei et al., Cancer Discov, 2018, 8:1069), cyclin D kinase 4 / 6 inhibitors (Goel et al., Trends Cell Biol, 2018, 28:911), antibodies that can bind to tumor cells and / or metastases and induce antibody-dependent cellular cytotoxicity (ADCC) (Kellne r et al., Transfus Med Hemother, 2017, 44:327), T cell or NK cell engagers (e.g., bispecific antibodies) (Yu et al., J Cancer Res Clin Oncol, 2019, 145:941), and cell therapy using expanded autologous or allogeneic immune cells (e.g., chimeric antigen receptor T (CAR-T) cells) (Khalil et al., Nat Rev Clin Oncol, 2016, 13:394). Immune checkpoint inhibitors include, but are not limited to, nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemiplimab.

[0635] According to the present invention, the compound can be administered before, simultaneously with, or after other anti-cancer compounds. The administration schedule can include administering different agents in an alternating manner. In other embodiments, the compound can be delivered before and during, during and after, or before and after treatment with other therapies. In some cases, the compound is administered more than 24 hours before the administration of other anti-proliferative treatments. In other embodiments, more than one anti-proliferative therapy can be administered to the subject. For example, the subject can receive the compound of the present invention in combination with both surgery and at least one other anti-proliferative compound. Alternatively, the compound can be administered in combination with more than one anti-cancer drug.

[0636] In some embodiments, the compounds of the present invention are used to detect cells and tissues that overexpress FAP, and such detection is achieved by conjugating a detectable label, preferably a detectable radionuclide, to the compounds of the present invention.In preferred embodiments, the cells and tissues to be detected are diseased cells and tissues, and / or are the sole cause of disease and / or disease symptoms, or are part of the underlying pathology of disease.In more preferred embodiments, the diseased cells and tissues cause and / or are part of oncological conditions (e.g., neoplasia, tumor, and cancer) or non-oncological conditions (e.g., inflammatory disease, cardiovascular disease, autoimmune disease, and fibrotic disease).

[0637] In another embodiment, the compounds of the present invention are used to treat cells and tissues that overexpress FAP. In a preferred embodiment, the treated cells and tissues are diseased cells and tissues, and / or are one or the only cause of disease and / or disease symptoms, or are part of the underlying pathology of disease. In a more preferred embodiment, the diseased cells and tissues cause and / or are part of oncological adaptations (e.g., neoplasia, tumor, and cancer), and therapeutic activity is achieved by conjugating a therapeutically active effector, preferably a therapeutically active radionuclide, to the compounds of the present invention. In a more preferred embodiment, the diseased cells and tissues cause and / or are part of non-oncological adaptations (e.g., inflammatory diseases, cardiovascular diseases, autoimmune diseases, and fibrotic diseases), and therapeutic activity is achieved by inhibiting the enzymatic activity of FAP.

[0638] In further embodiments, particularly when the disease is a non-tumor disease or non-tumor indication (e.g., inflammatory disease, cardiovascular disease, autoimmune disease, and fibrotic disease), the compounds of the present invention are administered in a therapeutically effective amount; preferably, the compounds of the present invention do not contain therapeutically active nuclides. An effective amount is the amount of compound administered that is sufficient to produce a therapeutically or medically desired result or effect in the subject to which the compound is administered. The effective amount will vary depending on the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of treatment, the nature of concurrent or concomitant therapy (if any), the particular route of administration, and factors within the knowledge and expertise of the medical professional. For example, in the context of a method for treating a subject with a condition characterized by abnormal cell proliferation, an effective amount for inhibiting proliferation would be an amount sufficient to reduce or completely stop abnormal cell proliferation, for example, to slow or stop the development or progression of a cell mass such as a tumor. As used in this embodiment, "inhibit" encompasses all of the above.

[0639] In other embodiments, a therapeutically effective amount will be the amount necessary to prolong the dormancy of micrometastases or stabilize remaining primary tumor cells following surgery or drug therapy. Generally, when using unconjugated compounds that do not contain a therapeutically active radionuclide, the therapeutically effective amount will vary depending on the age, condition, and sex of the subject, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art. Dosages can be adjusted by the individual physician or veterinarian, particularly in the event of complications. A therapeutically effective amount typically ranges from 0.1 μg / kg to about 2000 mg / kg, or 1.0 μg / kg to about 1000 mg / kg, or about 0.1 mg / kg to about 500 mg / kg, or about 1.0 mg / kg to about 100 mg / kg, administered in one or more doses per day for one or more days. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six, or more subdoses, for example, administered separately at appropriate intervals throughout the day, in unit dosage forms, as needed. In some embodiments, the compound is administered for more than 7 days, more than 10 days, more than 14 days, and more than 20 days. In still other embodiments, the compound is administered for several weeks or several months. In still other embodiments, the compound is delivered every other day. For example, the agent is delivered every 2 days, or every 3 days, or every 4 days, or every 5 days, or every 6 days, or every week, or every month.

[0640] In a preferred embodiment, the compounds of the invention are for use in the treatment and / or prevention of disease, whereby such treatment is radionuclide therapy. Preferably, radionuclide therapy utilizes or is based on different forms of radiation emitted by radionuclides. Such radiation includes, for example, photon radiation, but is not limited to, β -The radiation may be any one of electron radiation, including particle and Auger electron radiation, proton radiation, neutron radiation, positron radiation, alpha particle radiation or ion beam radiation.Depending on the type of particle or radiation emitted by the radionuclide, radionuclide therapy can be distinguished, for example, as photon-emitting nuclide therapy, electron-emitting nuclide therapy, proton-emitting nuclide therapy, neutron-emitting nuclide therapy, positron-emitting nuclide therapy, alpha particle-emitting nuclide therapy or ion beam radionuclide therapy.All these forms of radionuclide therapy are encompassed by the present invention, and all these forms of radionuclide therapy can be realized by the compound of the present invention, preferably under the condition that the radionuclide attached to the compound of the present invention, more preferably as an effector, provides this type of radiation.

[0641] Radionuclide therapy preferably works by damaging the DNA of cells. Damage is caused by photons, electrons, protons, neutrons, positrons, alpha particles, or ion beams, which directly or indirectly ionize the atoms that make up the DNA chain. Indirect ionization occurs as a result of the ionization of water, forming free radicals, particularly hydroxyl radicals, which then damage DNA.

[0642] In the most common forms of radionuclide therapy, many of the effects of radiation are due to free radicals. Because cells have mechanisms for repairing DNA damage, breaking DNA on both strands proves to be the most significant technique for altering cellular characteristics. Because cancer cells are generally undifferentiated and stem cell-like, they replicate more and have a reduced ability to repair sublethal damage compared to many healthy, differentiated cells. DNA damage is inherited through cell division, causing cancer cells to accumulate damage and die or replicate more slowly.

[0643] Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Therefore, the use of hyperbaric oxygen tanks, blood substitutes that deliver large amounts of oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cell toxins such as tirapazamine can be applied.

[0644] Other factors to consider when selecting the radioactive dose include whether the patient is receiving chemotherapy, whether the radiation therapy is administered before or after surgery, and the degree of success of the surgery.

[0645] The total radioactive dose can be fractionated, i.e., spread over time as one or more treatments, for several important reasons. Fractionation allows for the recovery of normal cells. Although this allows time for tumor cells to recover, tumor cells generally repair less efficiently between fractionated doses. Fractionation also allows tumor cells that were in a relatively radioresistant phase of the cell cycle during one treatment to cycle back into a sensitive phase of the cell before the next fractionated dose is given. Similarly, tumor cells that were chronically or acutely hypoxic and therefore more radioresistant may reoxidize between fractions, improving tumor cell killing.

[0646] It is generally known that different cancers respond differently to radiation therapy. The response of a cancer to radiation is described by its radiosensitivity. Cancer cells that are highly radiosensitive are rapidly killed by moderate doses of radiation. These include leukemia, many lymphomas, and germ cell tumors.

[0647] To some extent, it is important to distinguish the radiosensitivity of a particular tumor, a laboratory measurement, from the "cure potential" of the cancer with an internally delivered dose of radioactivity in actual clinical practice. For example, leukemia is generally not curable with radiation therapy because it is disseminated throughout the body. Lymphoma may be curable with radiation if localized to one area of ​​the body. Similarly, many common, moderately radioresponsive tumors can be treated with curative doses of radioactivity if they are in their early stages. This is true, for example, for non-melanoma skin cancer, head and neck cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer.

[0648] A tumor's response to radiation therapy is also related to its size. For complex reasons, very large tumors are less responsive to radiation than small tumors or microscopic disease. Various strategies are used to overcome this effect. The most common technique is surgical resection before radiation therapy. This is most commonly seen in the treatment of breast cancer with wide local excision or mastectomy, followed by adjuvant radiation therapy. Another method is to shrink the tumor using neoadjuvant chemotherapy before radionuclide therapy. A third technique is to enhance the cancer's radiosensitivity by administering certain drugs during the course of radiation therapy. Examples of radiosensitizing drugs include, but are not limited to, cisplatin, nimorazole, and cetuximab.

[0649] Intraoperative radiation therapy is a special type of radiation therapy delivered immediately after the surgical removal of the cancer. This method has been used in breast cancer (targeted intraoperative radiation therapy), brain tumors, and rectal cancer.

[0650] Radionuclide therapy itself is painless. Many low-dose palliative treatments are minimally or ineffective. Higher-dose treatments can cause side effects that vary during treatment (acute side effects), within months or years after treatment (long-term side effects), or even after further treatment (cumulative side effects). The nature, severity, and persistence of side effects depend on the organ receiving the radiation, the treatment itself (type of radionuclide, dose, fractionation, concurrent chemotherapy), and the patient.

[0651] It is within the scope of the present invention that each and any of the above strategies may be implemented, insofar as the methods for treating the diseases of the present invention are known as such in the art and constitute further embodiments of the present invention.

[0652] It is also within the scope of the present invention that the compounds of the present invention be used in methods for the diagnosis of the diseases disclosed herein, preferably comprising the step of administering a diagnostically effective amount of a compound of the present invention to a subject in need thereof.

[0653] According to the present invention, the imaging method is selected from the group consisting of scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET). In a preferred embodiment of the present invention, the compounds according to the present invention comprise a chelator from the N4 chelator family, more preferably a chelator that chelates Tc radionuclides, and are particularly suitable for use in methods and procedures using SPECT. In this embodiment, the chelator from the N4 chelator family is N4Ac.

[0654] In a preferred embodiment of the invention, compounds according to the invention that comprise a NODAGA chelator, more preferably that chelate Ga radionuclides, are particularly suitable for use in methods and procedures that employ PET.

[0655] Scintigraphy is the process by which radiopharmaceuticals are internalized by cells, tissues and / or organs. It is a form of diagnostic test or method used in nuclear medicine, in which a radiopharmaceutical is internalized in vivo, and the radiation emitted by the internalized radiopharmaceutical is captured by an external detector (gamma camera) to form and display a two-dimensional image.In contrast, SPECT and PET form and display a three-dimensional image.For this reason, SPECT and PET are classified as separate technologies from scintigraphy, but they also use a gamma camera to detect internal radiation.Scintigraphy is different from diagnostic X-ray, in which external radiation passes through the body to form an image.

[0656] Single-photon emission computed tomography (SPECT) scans are a type of nuclear imaging technique that uses gamma rays. They are very similar to traditional nuclear medicine 2D imaging using a gamma camera. Before a SPECT scan, the patient is injected with a radiolabeled chemical that emits gamma rays that can be detected by the scanner. A computer collects information from the gamma camera and converts it into 2D cross-sectional images. These cross-sectional images can be reconstructed to form a 3D image of the organ or tissue. SPECT involves the detection of gamma rays emitted by radionuclides provided by radiolabeled chemicals, both singly and sequentially. To acquire a SPECT image, the gamma camera rotates around the patient. Projection images are acquired at specified points during the rotation, typically every 3–6°. A full 360° rotation is often used to obtain an optimal reconstruction. The time required to acquire each projection image also varies, but 15–20 seconds is typical. This gives a total scan time of 15–20 minutes. Multi-headed gamma cameras are faster. SPECT acquisition is very similar to 2D gamma camera imaging, so the same radiopharmaceuticals can be used.

[0657] Positron emission tomography (PET) is a noninvasive diagnostic imaging technique for measuring the biochemical state or metabolic activity of cells in the human body. PET is unique because it produces images of basic biochemistry or function within the body. Traditional diagnostic techniques, such as X-rays, CT scans, or MRIs, produce images of the body's anatomy or structure. The premise of these techniques is that they can visualize changes in the structure or structure associated with disease. Biochemical processes are also altered by disease and may occur before overall changes in the anatomy. PET is an imaging technique that can visualize some of these early biochemical changes. PET scanners rely on radiation emitted by the patient to create images. Each patient is given a minute amount of a radiopharmaceutical that closely resembles a natural substance used by the body or that specifically binds to a receptor or molecular structure. As a radioisotope undergoes positron-emitting decay (also known as beta-plus decay), it emits a positron, the antiparticle counterpart of the electron. After traveling up to a few millimeters, the positron encounters an electron, annihilates, and generates a pair of counter-moving (gamma) photons. These are detected when they reach the scintillation material in the scanning device, producing a flash of light that is detected by a photomultiplier tube or silicon avalanche photodiode. The technique relies on the simultaneous or coincident detection of photon pairs. Photons that do not arrive as a pair, i.e., within a few nanoseconds of each other, are ignored. All coincidences are forwarded to an image processing unit, where the final image data is produced using an image reconstruction procedure.

[0658] SPECT / CT and PET / CT are the combination of SPECT and PET with computed tomography (CT). A key benefit of combining these modalities is improved reader confidence and accuracy. With traditional PET and SPECT, the limited number of photons emitted from abnormal regions results in very low levels of background that are difficult to anatomically localize to the region. The addition of CT helps determine the location of abnormal regions from an anatomical perspective and classify the likelihood that this represents disease.

[0659] It is within the scope of the present invention that the methods for diagnosis of disease of the present invention may implement each and any of the above strategies, insofar as they are known in the art as such and constitute further embodiments of the present invention.

[0660] The compounds of the present invention are useful for stratifying patients, i.e., determining how a patient responds to a given drug. Stratification is useful for creating subsets within a patient population that provide detailed information about whether a patient will respond to a novel therapy. Stratification can be an important component for converting clinical trials that originate with negative or neutral results into those with positive results by identifying subsets of the population that are most likely to respond to a novel therapy.

[0661] Stratification involves the identification of patient groups that share "biological" characteristics to select optimal management of patients and achieve the best possible outcomes in terms of risk assessment, risk prevention, and achieving optimal treatment outcomes.

[0662] The compounds of the invention can be used to assess or detect as early as possible a particular disease (which is a diagnostic use), the risk of developing the disease (which is a susceptibility / risk use), the progression of the disease, including indolent versus aggressive (which is a prognostic use), and can be used to predict the response and toxicity to a given treatment (which is a predictive use).

[0663] It is also within the scope of the present invention that the compounds of the present invention are used in diagnostic and therapeutic methods.The concept of diagnostic and therapeutic is to combine a therapeutic agent with a corresponding diagnostic test, which can increase the clinical use of the therapeutic agent.The concept of diagnostic and therapeutic is becoming increasingly attractive and is widely considered to be the key to improving the efficiency of drug treatment by identifying patients who will benefit from a given therapy, thus helping doctors to avoid unnecessary treatment.

[0664] The concept of diagnostic therapy is to combine a therapeutic agent with a diagnostic test that allows physicians to identify patients who will benefit most from a given therapy. In an embodiment, and as preferably used herein, the compounds of the present invention are used to diagnose patients, i.e., to identify and localize the primary tumor and potential local and distant metastases. Furthermore, tumor volume can be determined, particularly using three-dimensional diagnostic modalities such as SPECT or PET. Only patients who have FAP-positive tumor masses and therefore will benefit from a given therapy are selected for a specific therapy, thus avoiding unnecessary treatment. Preferably, such therapy is FAP-targeted therapy using the compounds of the present invention. In one particular embodiment, chemically identical tumor-targeted diagnosis, preferably imaging diagnosis for scintigraphy, PET, or SPECT, and radiotherapy are applied. Such compounds differ only in the radionuclide and therefore usually have very similar, if not identical, pharmacokinetic profiles. This can be achieved using chelators and diagnostic or therapeutic radiometals. Alternatively, this can be achieved using precursors for radiolabeling and radiolabeling with diagnostic or therapeutic radionuclides. In one embodiment, diagnostic imaging is preferably used by quantifying the radiation of the diagnostic radionuclide, followed by dosimetry as known to those skilled in the art and predicting drug concentration in the tumor relative to vulnerable side-effect organs. Thus, truly personalized drug administration therapy for the patient is achieved.

[0665] In embodiments, and as preferably used herein, diagnostic therapy is achieved using a single diagnostically and therapeutically active compound, such as a compound of the present invention labeled with a radionuclide that emits diagnostically detectable radiation (e.g., positrons or gamma rays) as well as therapeutically effective radiation (e.g., electrons or alpha particles).

[0666] The present invention also contemplates methods for intraoperatively identifying / disclosing diseased tissue expressing FAP in a subject. Such methods employ compounds of the present invention, whereby such compounds of the present invention preferably include a diagnostically active agent as an effector.

[0667] According to further embodiments of the present invention, the compounds of the present invention, particularly when complexed with radionuclides, are useful in treating many isolated solid cancers, including surgery as a first line method of treatment for many solid cancers; radiation therapy, including the use of ionizing radiation in attempts to cure or ameliorate cancer symptoms using enclosed internal or external sources in the form of brachytherapy; chemotherapy, such as alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumor agents; hormonal treatments that modulate the behavior of tumor cells without directly attacking these cells; targeted agents, including monoclonal antibodies and tyrosine kinase inhibitors, that directly target molecular abnormalities in certain types of cancer; angiogenesis inhibitors; immunotherapy; cancer vaccination; and physical, emotional, mental, and psychological treatments to improve the patient's quality of life. It can be used as an adjunct or adjuvant to any other oncology treatment, including palliative care, which includes activities to alleviate social suffering, and alternative treatments, which include a diverse group of products that are not part of the health care system, practice, and conventional medicine.

[0668] In an embodiment of the method of the present invention, the subject is a patient. In an embodiment, the patient is a subject who has been diagnosed with a disease, suspected of having a disease, or is at risk of having or developing a disease, whereby the disease is a disease described herein, preferably a disease including FAP.

[0669] The dosages used in the practice of the methods for treatment and diagnosis, respectively, in which radionuclides are used, more particularly those bound to or part of the compounds of the present invention, will vary depending, for example, on the particular condition to be treated, e.g., the known radiosensitivity of the tumor type, the tumor volume, and the desired therapy. Generally, the dose is calculated based on the radioactivity distribution to each organ and the observed target uptake. The gamma-emitting complex may be administered once or several times for diagnostic imaging. In animals, the indicated dose range is, for example, 1 to 200 MBq. 111 In or 89 The compound of the present invention may be complexed with Zr at 0.1 μg / kg to 5 mg / kg. The beta-emitting complex of the compound of the present invention may be administered at several time points, for example, over a period of 1 to 3 weeks or longer. In animals, the indicated dosage range is, for example, 1 to 200 MBq. 90 Y or 177 In larger animals, e.g., humans, the indicated dosage range is, for example, 10 to 400 MBq. 111 In or 89 In larger animals, e.g., humans, the indicated dosage range is, for example, 10 to 5000 MBq. 90 Y or 177 0.1-100 μg / kg of the compound of the present invention complexed with Lu.

[0670] In a further aspect, the present invention relates, inter alia, to compositions and pharmaceutical compositions comprising the compounds of the present invention. The pharmaceutical composition of the present invention comprises at least one compound of the present invention and, if necessary, one or more carrier substances, excipients and / or adjuvants.The pharmaceutical composition may further comprise, for example, water, a buffer such as neutral buffered saline or phosphate buffered saline, ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, a carbohydrate such as glucose, mannose, sucrose or dextran, mannitol, a protein, an adjuvant, an amino acid such as polypeptide or glycine, an antioxidant, a chelating agent such as EDTA or glutathione, and / or a preservative.In addition, although not required, one or more other active ingredients may be contained in the pharmaceutical composition of the present invention.

[0671] The pharmaceutical composition of the present invention can be formulated for any suitable administration route, including, for example, topical administration such as transdermal or ocular, oral, buccal, nasal, vaginal, rectal or parenteral administration.The term "parenteral" as used herein includes subcutaneous, intradermal, intravascular, such as intravenous, intramuscular, intrathecal and intraperitoneal injection, and any similar injection or infusion technique.The preferred administration route is intravenous administration.

[0672] In an embodiment of the invention, the compounds of the invention containing a radionuclide are administered by any conventional route, in particular intravenously, for example in the form of an injectable solution or suspension. The compounds of the invention may also be advantageously administered by infusion, for example, over a period of 30 to 60 minutes.

[0673] According to the location of tumor, the compound of the present invention can be administered as close as possible to the tumor site, for example, by using a catheter.This administration can be carried out directly into tumor tissue, or into surrounding tissue, or into afferent blood vessel.The compound of the present invention can also be administered repeatedly in a dose, preferably in divided doses.

[0674] According to a preferred embodiment of the present invention, the pharmaceutical composition of the present invention comprises a stabilizer, e.g., a free radical scavenger, which inhibits the autoradiolysis of the compound of the present invention. Suitable stabilizers include, for example, serum albumin, ascorbic acid, retinol, gentisic acid or its derivatives, or, preferably, electrolyte- and glucose-free, e.g., non- Amino acid infusion solutions used for oral protein delivery include commercially available amino acid infusion solutions such as Proteinsteril® KE Nephro. Ascorbic acid and gentisic acid are preferred.

[0675] The pharmaceutical compositions of the present invention may contain additional additives, such as agents for adjusting the pH to 7.2-7.4, such as sodium or ammonium acetate or NaHPO. Preferably, a stabilizer is added to the non-radioactive compound of the present invention, and the introduction of the radionuclide, e.g., complexation with the radionuclide, is carried out in the presence of the stabilizer at room temperature or, preferably, at a temperature of 40-120°C. Complexation can be conveniently carried out under air-free conditions, e.g., under N or Ar. Additional stabilizers may be added to the composition after complexation.

[0676] In particular, when the effector is a radionuclide, the excretion of the compounds of the present invention occurs essentially via the kidney.Further protection of the kidney from radioactivity accumulation can be achieved by administering lysine or arginine or an amino acid solution with a high lysine and / or arginine content, such as commercially available amino acid solutions, such as Synthamin®-14 or -10, before or simultaneously with the injection of the compounds of the present invention, especially when the effector is a radionuclide.Kidney protection can also be achieved by administering a plasma expander, such as gelofuscin, instead of or in addition to amino acid infusion.Kidney protection can also be achieved by administering a diuretic, which provides a means of forced diuresis by increasing the rate of urination.Such diuretics include high-sealing loop diuretics, thiazides, carbonic anhydrase inhibitors, potassium-sparing diuretics, calcium-sparing diuretics, osmotic diuretics, and low-sealing diuretics. The pharmaceutical compositions of the present invention may contain, apart from the compounds of the present invention, at least one such further compound intended for or suitable for nephroprotection, preferably nephroprotection of the subject to whom the compounds of the present invention are administered.

[0677] It will be understood by those skilled in the art that the compounds of the present invention are disclosed herein for use in a variety of methods.It will further be understood by those skilled in the art that the compositions of the present invention and the pharmaceutical compositions of the present invention can be used equivalently in the various methods described above.It will also be understood by those skilled in the art that the compositions of the present invention and the pharmaceutical compositions of the present invention are disclosed herein for use in a variety of methods.It will also be understood by those skilled in the art that the compounds of the present invention can be used equivalently in the various methods described above.

[0678] Those skilled in the art will recognize that the compositions and pharmaceutical compositions of the present invention contain one or more additional compounds in addition to the compounds of the present invention. To the extent that such one or more additional compounds are disclosed herein as being part of the compositions and / or pharmaceutical compositions of the present invention, it will be understood that such one or more additional compounds can be administered to the subject being exposed to or to the subject of the methods of the present invention separately from the compounds of the present invention. Such administration of one or more additional compounds can be carried out before, simultaneously with, or after administration of the compounds of the present invention. It will also be recognized by those skilled in the art that one or more additional compounds may be administered to the subject in the methods of the present invention separately from the compounds of the present invention. Such administration of one or more additional compounds can be carried out before, simultaneously with, or after administration of the compounds of the present invention. To the extent that such one or more additional compounds are disclosed herein as being administered as part of the methods of the present invention, it will be understood that such one or more additional compounds are part of the compounds of the present invention and / or pharmaceutical compositions of the present invention. It is within the scope of the present invention that the compounds of the present invention and one or more additional compounds can be contained in the same or different formulations. It is also within the scope of the present invention that the compound of the present invention and the one or more additional compounds are not contained in the same formulation, but are contained in the same package that contains a first formulation comprising the compound of the present invention and a second formulation comprising the one or more additional compounds, whereby the formulation types may be the same or different.

[0679] It is within the scope of the present invention that more than one type of compound of the present invention be included in the compositions of the present invention and / or pharmaceutical compositions of the present invention, and it is also within the scope of the present invention that more than one type of compound of the present invention be used, and preferably administered, in the methods of the present invention.

[0680] It will be appreciated that the compositions of the invention and pharmaceutical compositions of the invention may be prepared in a conventional manner. Radiopharmaceuticals have a radioactivity content that decreases over time as a result of radioactive decay. The physical half-life of radionuclides is often short for radiopharmaceutical diagnostics. In these cases, final preparation must be carried out immediately before administration to the patient. This is particularly the case for positron-emitting radiopharmaceuticals for tomography (PET radiopharmaceuticals). This often results in the use of semi-finished products such as radionuclide generators, radioactive precursors, and kits.

[0681] Preferably, the kits of the invention will comprise, apart from the one or more compounds of the invention, typically at least one of the following: instructions for use, a final preparation and / or quality control, one or more optional excipients, one or more optional reagents for the labelling procedure, optionally one or more radionuclides with or without a shielded container, and optionally one or more devices, wherein the device is selected from the group comprising a labelling device, a purification device, an analytical device, a handling device, a radiation protection device or an administration device.

[0682] Shielded containers, known as "pig iron" for general handling and transport of radiopharmaceutical containers, come in a variety of configurations to hold radiopharmaceutical containers such as bottles, vials, and syringes. One form often includes a removable cover that allows access to the held radiopharmaceutical solution. With the pig iron cover in place, radiation exposure is tolerable.

[0683] The labeling device is selected from the group of an open reactor, a closed reactor, a microfluidic system, a nanoreactor, a cartridge, a pressure vessel, a vial, a temperature-controllable reactor, a mixing or shaking reactor, and combinations thereof.

[0684] The purification device is preferably selected from the group of an ion exchange chromatography column or device, a size exclusion chromatography column or device, an affinity chromatography column or device, a gas or liquid chromatography column or device, a solid phase extraction column or device, a filtration device, a centrifuge vial column or device.

[0685] The analytical device is preferably selected from the group of test devices for determining the identity, radiochemical purity, radionuclide purity, radioactivity content and specific radioactivity of radiolabeled compounds.

[0686] The handling device is preferably selected from the group consisting of devices for mixing, diluting, dispensing, labeling, injecting and administering radiopharmaceuticals to a subject. Radiation protection devices are used to protect physicians and other individuals from radiation when using therapeutic or diagnostic radionuclides, and are preferably selected from the group consisting of devices having a protective barrier of radiation-absorbing material selected from the group consisting of aluminum, plastic, wood, lead, iron, lead-glass, water, rubber, plastic, and cloth, devices that ensure sufficient distance from the radiation source, devices that reduce exposure time to the radionuclide, devices that limit inhalation, ingestion, or other modes of entry of radioactive material into the body, and devices that provide a combination of these measures.

[0687] The administration device is preferably selected from the group of syringes, syringe guards, needles, pumps, and infusion devices. Syringe guards are generally hollow cylindrical structures that house the cylindrical body of the syringe and are constructed from lead or tungsten containing a lead-glass window that allows the handler to view the syringe plunger and the liquid volume within the syringe.

[0688] The invention will now be further described with reference to the following figures and examples from which further features, embodiments and advantages can be taken. [Brief explanation of the drawings]

[0689] [Figure 1] FIG. 1 shows the radiochromatogram of 177Lu-3BP-3407 in formulation buffer containing 100 mg / mL ascorbate and 5 mg / mL L-methionine, analyzed immediately after synthesis. [Figure 2] FIG. 2 shows the radiochromatogram of 177Lu-3BP-3407 in formulation buffer containing 100 mg / mL ascorbate and 5 mg / mL L-methionine, analyzed 6 days after synthesis. [Figure 3] FIG. 3 shows the radiochromatogram of 177Lu-3BP-3554 in formulation buffer containing 100 mg / mL ascorbate and 5 mg / mL L-methionine, analyzed immediately after synthesis. [Figure 4] FIG. 4 shows the radiochromatogram of 177Lu-3BP-3554 in formulation buffer containing 100 mg / mL ascorbate and 5 mg / mL L-methionine, analyzed 6 days after synthesis. [Figure 5] Figure 5 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3105 (A) and In-3BP-3168 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 6] Figure 6 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3320 (A) and In-3BP-3321 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 7]Figure 7 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3275 (A) and In-3BP-3397 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 8] Figure 8 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3398 (A) and In-3BP-3407 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 9] Figure 9 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3554 (A) and In-3BP-3652 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 10] Figure 10 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3654 (A) and In-3BP-3656 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 11] Figure 11 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3659 (A) and In-3BP-3678 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 12]Figure 12 shows the uptake of the percentage of injected dose per gram of tissue (%ID / g) in the kidney, liver, blood pool, and HEK-FAP tumor as determined by SPECT imaging of In-3BP-3692 (A) and In-3BP-3767 (B) at 1 hour, 3 hours, 6 hours, and 24 hours after injection into a mouse model. [Figure 13] FIG. 13 shows SPECT images of 111In-3BP-3554 at 1 hour, 3 hours, 6 hours, 24 hours, and 48 hours after injection into HEK-FAP tumor-bearing mice. [Figure 14] FIG. 14 shows SPECT images of 111In-3BP-3767 at 1 hour, 3 hours, 6 hours, 24 hours, and 48 hours after injection into HEK-FAP tumor-bearing mice. [Figure 15A] FIG. 15A shows tumor growth over time in HEKFAP tumor-bearing mice treated with vehicle, cold compound natLu-3BP-3554, 30 MBq (low dose) 177Lu-3BP-3554, and 60 MBq (high dose) 177Lu-3BP-3554. [Figure 15B] FIG. 15B shows the percent weight change over time in HEK-FAP tumor-bearing mice treated with vehicle, cold compound natLu-3BP-3554, 30 MBq (low dose) 177Lu-3BP-3554, and 60 MBq (high dose) 177Lu-3BP-3554. [Figure 16A] FIG. 16A shows representative SPECT / CT images of the biodistribution of 60 MBq 177Lu-3BP-3554 over time in HEK-FAP tumor-bearing mice. [Figure 16B] FIG. 16B shows representative SPECT / CT images of the biodistribution of 30 MBq 177Lu-3BP-3554 over time in HEK-FAP tumor-bearing mice. [Figure 17A] Figure 17A shows representative SPECT / CT images of four different sarcoma PDX models 3 hours after administration of 111In-3BP-3554. [Figure 17B]Figure 17B shows the %ID / g uptake of 111In-3BP-3554 in four different sarcoma PDX models at 3 hours post-injection. [Figure 18A] FIG. 18A shows tumor growth over time in mice bearing Sarc4809 PDX tumors treated with vehicle, cold compound natLu-3BP-3554, 30 MBq 177Lu-3BP-3554, or 60 MBq 177Lu-3BP-3554. [Figure 18B] FIG. 18B shows weight change over time in mice bearing sarcoma Sarc4809 PDX tumors treated with vehicle, cold compound natLu-3BP-3554, 30 MBq 177Lu-3BP-3554, or 60 MBq 177Lu-3BP-3554. [Figure 19] FIG. 19 shows the amino acid sequences of human fibroblast activation protein (FAP) (SEQ ID NO: 1), human dipeptidyl peptidase 4 (DPP4) (SEQ ID NO: 2), and human prolyl endopeptidase (PREP) (SEQ ID NO: 3).

[0690] The following examples are included to provide guidance for those skilled in the art to practice representative embodiments of the presently disclosed subject matter. In view of the present disclosure and the general level of skill in the art, those skilled in the art will recognize that the following examples are intended to be illustrative only, and that numerous changes, modifications, and variations can be employed without departing from the scope of the presently disclosed subject matter. The following synthetic descriptions and specific examples are intended for illustrative purposes only and should not be construed in any way as limiting the ability to prepare compounds of the present disclosure by other methods. [Example]

[0691] Abbreviations used in this application and particularly in the examples below are as follows: 4PL means four parameter logistic curve fitting. Å means angstrom.

[0692] ACN means acetonitrile. Ahx means 6-aminohexanoic acid. AMC means 7-amino-4-methylcoumarin.

[0693] amu means atomic mass unit. aq. means aqueous. AUC inf means the area under the curve extrapolated to infinity.

[0694] BSA means bovine serum albumin. C0 denotes the initial concentration of the compound. CAF means cancer-associated fibroblasts.

[0695] CL means clearance. CM means ChemMatrix™. CT stands for computed tomography.

[0696] Cy5 means cyanine-5. DAD stands for Diode Array Detector. DCM means dichloromethane.

[0697] Dde means N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl). DEG means diethylene glycol dimethacrylate.

[0698] DIC means N,N'-diisopropylcarbodiimide. DICOM stands for Digital Imaging and Communications in Medicine.

[0699] DIPEA means diisopropylethylamine. DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide.

[0700] DOTA means 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. DOTA(tBu)3-OH means tri-tert-butyl-1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetate.

[0701] DPP means dipeptidyl peptidase. EC means electron capture. EC 50 means half-maximal excitation concentration.

[0702] ECACC stands for European Collection of Authenticated Cell Cultures. EDC means 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0703] EMEM means Eagle's minimum essential medium. eq or eq. means equivalent. ESI means electrospray ionization.

[0704] Et2O means diethyl ether. EtOAc means ethyl acetate. FACS stands for fluorescence activated cell sorting.

[0705] FAP stands for fibroblast activation protein. Fb means background fluorescence intensity. FBS means fetal bovine serum.

[0706] FGF21 means fibroblast growth factor 21. FITC means 5(6)-fluorescein isothiocyanate. Fmoc means 9-fluorenylmethoxycarbonyl.

[0707] FRET stands for Fluorescence Resonance Energy Transfer. Ft means fluorescence intensity. Gab means gamma-aminobutyric acid.

[0708] GABA means gamma-aminobutyric acid. h means hours. HATU means O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0709] HBST means SPR running buffer. HEK-FAP means human embryonic kidney 293 cells expressing human FAP. HEPES means 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid.

[0710] HFIP means hexafluoro-2-isopanol. HOAc means acetic acid. HOAt means 1-hydroxy-7-azabenzotriazole.

[0711] HPLC means high performance liquid chromatography. HPLC / MS means high performance liquid chromatography / mass spectrometry. I C 50 means half-maximal inhibitory concentration.

[0712] ID / g means injected dose per gram. IS means nuclear isomer transition. iTLC-SG means instant thin layer chromatography-silica gel.

[0713] K2EDTA means dipotassium ethylenediaminetetraacetic acid. K D means the dissociation constant. kDa means 1000 Daltons.

[0714] K i means the inhibition constant. k off means the dissociation rate. k on means the association rate.

[0715] LC / TOF-MS stands for liquid chromatography / time of flight / mass spectrometry. LC-MS means high performance liquid chromatography with mass spectrometry. LDH means lactate dehydrogenase.

[0716] Leu means leucine. LiOH means lithium hydroxide. M means molar concentration or moles per liter.

[0717] m / z means mass divided by charge. max. means maximum. MeOH means methanol.

[0718] MeV stands for megaelectronvolt. min means minutes. MMP means matrix metalloproteinase.

[0719] MRM stands for multiple reaction monitoring. MTBE means methyl tert-butyl ether. Mtt means methyltrityl.

[0720] MTV means mean tumor volume. MW means molecular weight. nd means undecided.

[0721] Na2SO4 means sodium sulfate. NaCl means sodium chloride. NaHCO3 means sodium bicarbonate.

[0722] NCA stands for non-compartmental analysis. NHS means N-hydroxysuccinimide. NMP means 1-methyl-2-pyrrolidone.

[0723] NOS means not specified. Oic means L-octahydroindole-2-carboxylic acid. pa means for analytical purposes (quality grade).

[0724] pi means post injection. Pbf means 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl

[0725] PBS means phosphate buffered saline. PDX means patient-derived xenograft. PET stands for positron emission tomography.

[0726] pIC50 means the negative logarithm of the IC50 value when converted to a molar concentration. POP means prolyl oligopeptidase. ppm means parts per million.

[0727] PREP means prolyl endopeptidase. Prep. means to separate. PS means polystyrene.

[0728] Q-TOF stands for quadrupole time of flight. Ref means reference. RFU means relative fluorescence units.

[0729] RLB means radioligand binding assay. RMCE stands for recombinase-mediated cassette exchange. RP means reverse phase.

[0730] R t means retention time. RT means room temperature. RU means resonance unit.

[0731] SAR stands for structure-activity relationship. sat. means saturated. SCID stands for severe combined immunodeficiency disorder.

[0732] SCK stands for single cycle kinetics. sec or s means seconds. SF stands for spontaneous fission.

[0733] SPECT stands for single photon emission computed tomography. SPPS stands for solid phase peptide synthesis. t 1 / 2 means terminal half-life.

[0734] tBu means tert.butyl. TFA means trifluoroacetate or trifluoroacetic acid. TG means TentaGel.

[0735] TGI means tumor growth inhibition. THF means tetrahydrofuran. TIPS means triisopropylsilane.

[0736] TLC means thin layer chromatography. TME means tumor microenvironment. t R means retention time.

[0737] UHPLC stands for ultra-high performance liquid chromatography. UV means ultraviolet. V ss means the volume of distribution at steady state.

[0738] V Z means the volume of distribution in the terminal phase. Example 1 material and method The materials and methods, as well as general procedures, are further illustrated by the following examples.

[0739] solvent: Solvents were used in the specified quality without further purification. Acetonitrile (Super Gradient, HPLC, VWR - for analytical purposes; PrepSolv, Merck - for preparative purposes; dichloromethane (synthetic, Roth); ethyl acetate (synthetic grade, Roth); N,N-dimethylformamide (peptide synthesis grade, Biosolve); 1 -methyl-2-pyrrolidone (peptide grade, IRIS BioTech); 1,4-dioxane (reinst, Roth); methanol (pa, Merck).

[0740] Water: Milli-Q Plus, Millipore, desalted. Chemicals: Chemicals were synthesized according to or similar to literature procedures or were obtained from Sigma-Aldrich-Merck (Deisenhofen, Germany), Bachem (Bubendorf, Switzerland), VWR (Darmstadt, Germany), Novabiochem (Merck Group, Darmstadt, Germany), Acros Organics (distributor Fisher Scientific GmbH, Schwerte, Germany), Iris Biotech (Marktredwitz, Germany), Amatek Chemical (Jiangsu, China), Roth (Karlsruhe, Germany), Molecular Devices (Chicago, USA), Biochrom (Berlin, Germany), Peptech (Cambridge, MA, USA), Synthetech (Albany, OR, USA), Pharmacore (High Point, NC, USA), PCAS Biomatrix Inc. (Saint-Jean-sur-Richelieu, Quebec, Canada), Alfa Aesar (Karlsruhe, Germany), Tianjin Nankai Hecheng S&T Co., Ltd. (Tianjin, China), CheMatech (Dijon, France), and Anaspec (San Jose, CA, USA), or other companies, and were used at the specified quality without further purification.

[0741] Boc4N4Ac-OH was synthesized according to literature procedures (Maecke et al. Chem. Eur. J., 2010, 16, 7, 2115).

[0742] [ka]

[0743] cell: HT29 (ECACC catalog number 91072201) and WI-38 (ECACC catalog number 90020107) were purchased from ECACC, and HEK293 cells (Q12884) expressing human FAP were produced by InSCREENeX GmbH (Braunschweig, Germany) using recombinase-mediated cassette exchange (RMCE), as described by Nehlsen et al. (2009, 9:100). HPLC / MS analysis HPLC / MS analysis was performed by injecting 5 μl of sample solution and using a two-step gradient (5 to 65% B in 12 min, followed by 65 to 90% in 0.5 min, A: 0.1% TFA in water, and B: 0.1% TFA in ACN) for all chromatograms. The RP column was from Agilent (Type Poroshell 120, 2.7 μm, EC-C18, 50 × 3.00 mm, flow rate 0.8 ml, HPLC at room temperature); mass spectrometer: Agilent 6230 LC / TOF-MS, ESI ionization. MassHunter Qualitative Analysis B.07.00 SP2 was used as the software. UV detection was performed at λ = 230 nm. Retention time (R t ) is expressed in decimal notation (e.g., 1.9 min = 1 min 54 sec) and refers to detection in a UV spectrometer. For the evaluation of the mass of the observed compounds, The "Formula" function was used. Specifically, the individual "compound neutral mass (unit: Dalton)" values ​​and the corresponding isotope distribution patterns were used to confirm the identity of the compounds. The mass spectrometer precision was approximately ±5 ppm.

[0744] Preparative HPLC: Preparative HPLC separations were performed using reverse-phase columns (Kinetex 5μ XB-C18 100Å, 150 × 30 mm, or RLRP-S 8μ, 100Å, 150 × 25 mm, manufactured by Phenomenex). The mobile phases were 0.1% TFA in water (A) and 0.1% TFA in ACN (B), mixed in a linear binary gradient. This gradient is described as "10 to 40% in 30 min," meaning a linear gradient from 10% B (and corresponding 90% A) to 40% B (and corresponding 60% A) was performed within 30 min. The flow rate was in the range of 30–50 ml / min. A typical gradient for the purification of compounds of the present invention began with 5–25% B and ended after 30 min at 30–50% B, with a difference in the percentage of B between the end and start points of at least 10%. A commonly used gradient was 15 to 40% B in 30 minutes.

[0745] General procedure for automated / semi-automated solid phase synthesis: Automated solid-phase synthesis of peptides and polyamides was performed on a Tetras Peptide Synthesizer (Advanced ChemTech) at the 50 μmol and 100 μmol scales. Manual steps were performed in fritted plastic syringes (material PE, Roland Vetter Laborbedarf OHG, Ammerbuch, Germany). The amounts of reagents in the described protocols correspond to the 100 μmol scale unless otherwise stated.

[0746] Solid-phase synthesis was performed on polystyrene (crosslinked with 1,4-divinylbenzene (PS) or di(ethylene glycol) dimethacrylate (DEG)), ChemMatrix (CM), or TentaGel (TG) resin. Resin linkers were trityl, wang, and rink amide.

[0747] Resin filling: In the case of the trityl linker, attachment of the first building block (resin loading) was performed as follows: The resin (polystyrene (PS) trityl chloride, initial loading: 1.8 mmol / g) was swollen in DCM (5 ml) for 30 min, followed by washing with DCM (3 ml, 1 min). The resin was then treated with a mixture of the corresponding building block (0.5 mmol, 5 eq.) and DIPEA (350 μl, 3.5 mmol, 35 eq.) in DCM (4 ml) for 1 h. The resin was then washed with methanol (5 ml, 5 min) and DMF (3 ml, 2 x 1 min).

[0748] In the case of the Wang linker, pre-loaded resins (polystyrene (PS) and TentaGel (TG)) were used. In the case of the Rink Amide linker, attachment of the first residue to the resin (CM, DEG) was carried out by the same procedure as for chain assembly described below.

[0749] Alloc / Allyl Deprotection: After swelling in DMF, the resin was washed with DMF and DCM. The DCM was deoxygenated by passing a stream of nitrogen through the stirred solvent. The resin was washed twice with oxygen-free solvent. 2 ml of a 2 M solution of barbituric acid in oxygen-free DCM and 1 ml of a 25 μM solution of tetrakis(triphenylphosphine)palladium(0) in oxygen-free DCM were then added to the resin. The resin was stirred for 1 hour and then washed with DCM, MeOH, DMF, 5% DIPEA in DMF, 5% dithiocarbamate in DMF, DMF, and DCM (each washing step was repeated three times for 3 ml and 1 min).

[0750] Fmoc deprotection: After swelling in DMF, the resin was washed with DMF and then with piperidine / DMF (1:4, 3 ml, 2 and 20 min), followed by washing with DMF (3 ml, 5 times × 1 min).

[0751] Dde deprotection: After swelling in DMF, the resin was washed with DMF and then treated with hydrazine hydrate / DMF (2 / 98, 3 ml, 2 times 10 min) followed by washing with DMF (3 ml, 5 times 1 min).

[0752] Mtt deprotection: After swelling in DCM, the resin was washed with DCM and then treated with HFIP / DCM (7 / 3, 4–6 ml, 4 h), followed by washing with DCM (3 ml, 3 times × 1 min), DMF (3 ml, 3 times × 1 ml), and DIPEA (0.9 M in DMF, 3 ml, 1 min).

[0753] Reagent solutions: Building blocks (0.3M in DMF or NMP), DIPEA (0.9M in DMF), HATU (0.4M in DMF), acetic anhydride (0.75M in DMF) Coupling: Coupling of building blocks / amino acids (chain construction): Unless otherwise stated, coupling of building blocks was carried out as follows: After subsequent addition of a solution of the corresponding building block (1.7 mL, 5 eq.), a DIPEA solution (1.15 ml, 10 eq.), and a HATU solution (1.25 ml, 5 eq.), the resin was shaken for 45 min. If necessary, the resin was washed with DMF (3 ml, 1 min) and the coupling step was repeated.

[0754] Terminal acetylation: After addition of DIPEA solution (1.75 ml, 16 eq.) and acetic anhydride solution (1.75 ml, 13 eq.), the resin was shaken for 10 min, after which it was washed with DMF (3 ml, 6 times 1 min).

[0755] Cleavage Method A: Cleavage of Protected Fragments from Highly Acid-Labile Resins: After completion of the sequence assembly, the resin was finally washed with DCM (3 ml, 4 times 1 min) and then dried in vacuo. The resin was then treated with HFIP / DCM (7 / 1, 4 ml, 4 h), and the collected solution was evaporated to dryness. The residue was either purified by preparative HPLC or used without further purification.

[0756] Cleavage Method B: Cleavage of the Unprotected Fragment (Full Resin Cleavage): After completion of the sequence assembly, the resin was finally washed with DCM (3 ml, 4 times 1 min), dried in vacuo overnight, and (unless otherwise stated) treated with TFA, EDT, water, and TIPS (94 / 2.5 / 2.5 / 1) for 2 h. The cleavage solution was then poured into a cold mixture of MTBE and cyclohexane (1 / 1, 10-fold excess relative to the volume of the cleavage solution), centrifuged for 5 min at 4 °C, and the precipitate was collected and dried in vacuo. The residue was lyophilized from water / acetonitrile prior to purification or further modification.

[0757] Cleavage Method C: Cleavage of Peptide Protecting Groups in Solution The protected / partially protected compounds were dissolved in THF, water, and TIPS (95 / 2.5 / 2...

Claims

1. Formula (I) 【Chemistry 1】 Cyclic peptides and an N-terminal modifying group A attached to Xaa1, the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction; Xaa1 is Cys, the N-terminal modification group A is covalently bonded to the nitrogen atom of Xaa1; the carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2; the sulfur atom of Xaa1 is covalently bonded to Yc as a thioether; Xaa2 is Pro, Aib, Gly, ala, Oic, Ala, or Nmg; Xaa3 is Pro, Oic or Hyp; Xaa4 is Thr, Xaa5 is Glu or Gln, Xaa6 is Phe, Thi, Ala, or Mpa; Xaa7 is a group represented by formula (IX) 【Chemistry 2】 is an aminothiol or amino acid residue of R ７ａ -CO-XXX, -COOH, -CONH ２ , -CH ２ -OH, -(CO)-NH-R ７ｂ , -(CO)-(NR ７ｃ )-R ７ｂ , or H, and R ７ｂ and R ７ｃ are each independently (C １ ~C ４ ) alkyl, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom; t is 1, Yc is tMeBn, 3MeBn, 2Lut or 3Lut, which may contain a chelator; Yc is a group represented by the formula (X) 【Transformation 3】 and connecting the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages, thereby forming a compound of formula (XXI) 【Chemistry 4】 forming a ring structure of the substitution pattern of the aromatic group of formula (X) is ortho, meta, or para; R 1b is H; n=0, t=1, Y １ is C—H or N, Y ２ is N or C-R ｃ１ and R ｃ１ is H or CH ２ -R ｃ２ and R ｃ２ is of formula (XI), (XII), or (XXII) 【Transformation 5】 The structure is R ｃ３ and R ｃ４ are each independently H and (C １ ~C ４ ) alkyl; R c5 is H or a Z group, where the Z group is a chelator that may include a linker; u=1, x and y are both 1, X=S, In formulas (XI) and (XXII), one of the nitrogen atoms is R ｃ１ No-CH ２ -, and in formula (XII), -X- is R ｃ１ No-CH ２ - is bonded to the N-terminal modification group A is a blocking group Ab1 or an amino acid Aaa; or a pharmaceutically acceptable salt, solvate or hydrate thereof, formula 【Transformation 6】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, excluding compounds represented by the formula: (i) Xaa2 and Xaa3 are Pro; (ii) Xaa2 is Pro and Xaa6 is Phe; or (iii) The compound of claim 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Xaa3 is Pro and Xaa6 is Phe.

3. Formula (I) 【Transformation 7】 Cyclic peptides and an N-terminal modifying group A attached to Xaa1, the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction; Xaa1 is Cys, the N-terminal modification group A is covalently bonded to the nitrogen atom of Xaa1; the carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2; the sulfur atom of Xaa1 is covalently bonded to Yc as a thioether; Xaa2 is Pro, Aib, Gly, ala, Oic, Ala, or Nmg; Xaa3 is Pro, Oic or Hyp; Xaa4 is Thr, Xaa5 is Glu or Gln, Xaa6 is Phe, Thi, Ala, or Mpa; Xaa7 is a group represented by formula (IX) 【Transformation 8】 is an aminothiol or amino acid residue of R ７ａ -CO-XXX, -COOH, -CONH ２ , -CH ２ -OH, -(CO)-NH-R ７ｂ , -(CO)-(NR ７ｃ )-R ７ｂ or H, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom; R ７ｂ and R ７ｃ are each independently (C １ ~C ４ ) alkyl, the amino acid or peptide may be substituted with a Z group, wherein the Z group is a chelator which may include a linker; t is 1, Yc is tMeBn, 3MeBn, 2Lut or 3Lut, which may contain a chelator; Yc is a group represented by the formula (X) 【Chemistry 9】 and connecting the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages, thereby forming a compound of formula (XXI) 【Chemistry 10】 forming a ring structure of the substitution pattern of the aromatic group of formula (X) is ortho, meta, or para; R 1b is H; n=0, t=1, Y １ is C—H or N, Y ２ is N or C-R ｃ１ and R ｃ１ is H or CH ２ -R ｃ２ and R ｃ２ is of formula (XI), (XII), or (XXII) 【Chemistry 11】 The structure is R ｃ３ and R ｃ４ are each independently H and (C １ ~C ４ ) alkyl; R ｃ５ is H or a Z group, where the Z group is a chelator which may include a linker; u=1, x and y are both 1, X=S, In formulas (XI) and (XXII), one of the nitrogen atoms is R ｃ１ No-CH ２ -, and in formula (XII), -X- is R ｃ１ No-CH ２ - is bonded to the N-terminal modification group A is a blocking group Ab1 or an amino acid Aaa, and the amino acid Aaa is optionally substituted with a Z group, wherein the Z group is a chelator that may include a linker; or a pharmaceutically acceptable salt, solvate or hydrate thereof, formula 【Chemistry 12】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, excluding compounds represented by the formula: (i) Xaa2 and Xaa3 are Pro; (ii) Xaa2 is Pro and Xaa6 is Phe; or (iii) The compound of claim 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Xaa3 is Pro and Xaa6 is Phe.

5. R ｃ５ is a Z group, where the Z group is a chelator which may include a linker; R ７ａ -CO-XXX, -COOH, -CONH ２ , -CH ２ -OH, -(CO)-NH-R ７ｂ , -(CO)-(NR ７ｃ )-R ７ｂ , or H, and R ７ｂ and R ７ｃ are each independently (C １ ~C ４ ) alkyl, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, and the amino acid or peptide is not substituted with a Z group, wherein the Z group is a chelator that may include a linker; When the N-terminal modification group A is an amino acid Aaa, the amino acid Aaa is not substituted with a Z group, wherein the Z group is a chelator that may include a linker.

5. A compound according to claim 3 or 4, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

6. R ７ａ is different from —CO-XXX, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom; When the N-terminal modification group A is an amino acid Aaa, the amino acid Aaa is not substituted with a Z group, wherein the Z group is a chelator that may include a linker.

6. A compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

7. R ７ａ is —CO-XXX, wherein XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, and wherein the amino acid or peptide is substituted with a Z group, wherein the Z group is a chelator that may include a linker; R ｃ１ or R ｃ５ is H, When the N-terminal modification group A is an amino acid Aaa, the amino acid Aaa is not substituted with a Z group, wherein the Z group is a chelator that may include a linker.

5. A compound according to claim 3 or 4, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

8. the N-terminal modification group A is an amino acid Aaa substituted with a Z group, wherein the Z group is a chelator which may include a linker; R ｃ１ or R ｃ５ is H, R ７ａ -CO-XXX, -COOH, -CONH ２ , -CH ２ -OH, -(CO)-NH-R ７ｂ , -(CO)-(NR ７ｃ )-R ７ｂ , or H, and R ７ｂ and R ７ｃ are each independently (C １ ~C ４ ) alkyl, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, and the amino acid or peptide is not substituted by a Z group, wherein the Z group is a chelator that may include a linker; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

9. R ７ａ is different from -CO-XXX, and XXX is an amino acid or peptide that forms an amide bond with the carbonyl carbon atom, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

10. The amino acid Aaa each has the structure (XIV): 【Chemistry 13】 is a D-amino acid residue or an L-amino acid residue of R ａ２ But (C １ ~C ６ ) alkyl, modified (C １ ~C ６ ) alkyl, (C １ ~C ３ ) alkyl, modified (C １ ~C ３ ), (C ３ ~C ８ ) carbocycle, aryl, heteroaryl, and (C ３ ~C ８ ) heterocycles; Modified (C １ ~C ６ ) alkyl with one —CH ２ -group is replaced by -S- or -O-, and modified (C １ ~C ３ ) alkyl in which one of H is replaced by OH, F, or COOH, or two of H are replaced by F, and R ａ３ is a Z group, where the Z group is a chelator which may include a linker; 9. A compound according to any one of claims 3, 4 and 8, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

11. The blocking group Abl is R ａ１ -C(O)-, R ａ１ -S(O ２ ) -, R ａ１ —NH—C(O)—, and R ａ１ —O—C(O)—; R ａ１ are each independently OH, F, COOH, (C ３ ~C ８ ) cycloalkyl, aryl, heteroaryl, and (C ３ ~C ８ ) heterocycles, optionally substituted with up to two substituents selected from the group consisting of １ ~C ８ ) alkyl, and (C １ ~C ８ ) In alkyl, -CH ２ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein one of the - groups is optionally replaced by -S- or -O-.

12. 12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said blocking group Ab1 is hexanoyl or pentylsulfonyl.

13. 13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said blocking group Ab1 is hexanoyl.

14. The amino acid Aaa each has the structure (XIV): 【Chemistry 14】 is a D-amino acid residue or an L-amino acid residue of R ａ２ But (C １ ~C ６ ) alkyl, modified (C １ ~C ６ ) alkyl, (C １ ~C ３ ) alkyl, modified (C １ ~C ３ ), (C ３ ~C ８ ) carbocycle, aryl, heteroaryl, and (C ３ ~C ８ ) heterocycles; Modified (C １ ~C ６ ) alkyl with one —CH ２ -group is replaced by -S- or -O-, and modified (C １ ~C ３ ) alkyl in which one of H is replaced by OH, F, or COOH, or two of H are replaced by F, and R ａ３ is H or acetyl; 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

15. 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the amino acid Aaa is selected from the group consisting of amino acid residues of Nle ((S)-norleucine), nle ((R)-norleucine), Met, and met, and derivatives thereof.

16. Formula (LI), (LII), (LIII), or (LIV) 【Chemistry 15】 16. The compound of any one of claims 1 to 15, comprising the structure: or a pharmaceutically acceptable salt, solvate or hydrate thereof.

17. Yc is a group represented by formula (XIII) 【Chemistry 16】 The structure is 17. A compound according to any one of claims 1, 2 and 11 to 16, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

18. Yc comprises an NH group, said NH group allowing for conjugation of Yc to a moiety; 18. The compound of claim 17, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

19. 19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the NH group is a reactive NH group.

20. The NH group has structure R ｃ１ Provided by R ｃ１ is CH ２ -R ｃ２ and R ｃ２ but Formulas (XXIb), (XIc), and (XIIb) 【Chemistry 17】 and R ｃ４ is H or methyl, 20. The compound of any one of claims 17 to 19, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein u=1.

21. 21. The compound of any one of claims 1 and 11 to 20, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound comprises a Z group, the Z group being covalently linked to Yc, wherein the Z group is a chelator which may include a linker.

22. the Z group is covalently bonded to the structure of formula (X); The Z group is R ｃ２ and covalently bonded to the formulae (XXIIc), (XId), and (XIId) [Chemistry 18] and forming any one of the structures R ｃ４ is H or methyl, 22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein u=1.

23. 23. The compound of any one of claims 1, 2 and 11 to 22, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the N-terminal modification group A is amino acid Aaa, and the compound comprises a Z group covalently attached to the amino acid Aaa, wherein the Z group is a chelator which may include a linker, and if present, the linker covalently links the chelator to the amino acid Aaa.

24. 24. The compound of claim 23, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the linker, if present, covalently links the chelator to the alpha nitrogen of the amino acid Aaa.

25. 25. The compound of claim 24, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the covalent linkage between the linker and the alpha nitrogen of amino acid Aaa is an amide.

26. The linker may be selected from the group consisting of Ttds (1,13-diamino-4,7,10-trioxatridecane-succinic acid), O2Oc (3,6-dioxaoctanoic acid), Apac (2-(4-(amino)piperidin-1-yl)acetic acid), Gly, Bal (β-alanine), Gab (γ-aminobutyric acid), Mamb (3-aminomethyl-benzoic acid), Pamb (4-aminomethyl-benzoic acid), Ppac (4-carboxymethylpiperazine), 4Amc (4-trans-amino 26. The compound of any one of claims 3 to 25, or a pharmaceutically acceptable salt, solvate or hydrate thereof, selected from the group consisting of PEG-amino acids, Np (isonipecotic acid), Sni ((S)-nipecotic acid), Rni ((R)-nipecotic acid), Nmg (N-methyl-glycine), Cmp (4-carboxymethyl-piperidine), PEG6, PEG12, and other PEG-amino acids.

27. 27. The compound of claim 26, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the linker is selected from the group comprising Ttds, O2Oc, Apac, 4Amc, PEG6, and PEG12.

28. 28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the linker is selected from the group consisting of Ttds, O2Oc, and PEG6.

29. an amino acid or peptide is attached to Xaa7, said amino acid being selected from the group consisting of Asp, asp, Bal (β-alanine), Gly, Gab (γ-aminobutyric acid), Ser, Nmg (N-methyl-glycine), Bhf ((S)-β-homophenylalanine), and Bhk ((S)-β-homolysine); wherein the majority of the amino acids of the peptide are charged or polar; the peptide has a net charge of −2, −1, 0, +1, or +2; 29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

30. The peptide has the formula (XXXa-f) Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16 (XXXa) Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15 (XXXb) Xaa10-Xaa11-Xaa12-Xaa13-Xaa14 (XXXc) Xaa10-Xaa11-Xaa12-Xaa13 (XXXd) Xaa10-Xaa11-Xaa12 (XXXe) Xaa10-Xaa11 (XXXf) and Xaa10 is Asp, asp, Bal, Gly, Gab, Ser, Nmg, Bhf, Lys, Ttds (1,13-diamino-4,7,10-trioxatridecane-succinic acid), or Bhk; Xaa11 is His, his, Lys, Ttds, Arg, Ape (1,5-diaminopentane), or Ala; Xaa12 is Phe, Nmf ((S)-N-methyl-phenylalanine), Tic ((S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), Aic (2-aminoindan-2-carboxylic acid), Ppa ((S)-4-pyridyl-alanine), Mpa (3-pyridyl-alanine), Amf ((S)-α-methyl-phenylalanine), phe, Lys, Ape, and Ttds; Xaa13 is Arg, Lys, Ape, Ttds, or arg; Xaa14 is Asp, Ala, asp, Lys, Ape, or Ttds; Xaa15 is Ttds, Ape, or Lys; Xaa16 is Lys or Ape, Xaa11 and Xaa12 may together form a single amino acid selected from the group consisting of Gab, Pamb (4-aminomethyl-benzoic acid), Cmp (4-carboxymethyl-piperidine), Mamb (3-aminomethyl-benzoic acid); Xaa10, Xaa11, and Xaa12 may together form a single amino acid selected from the group consisting of Gab, Pamb, Cmp, and Mamb; 30. The compound of claim 29, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein in the peptides of formula (XXXa-f), Ape, if present, is the C-terminal building block.

31. 31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the Z group is covalently attached to the peptide, and wherein the Z group is a chelator which may include a linker.

32. 32. The compound of claim 31, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein a chelator is covalently attached to the amino acid bound to Xaa7, or a chelator is covalently attached to the C-terminal amino acid of the peptide. Claim 33: Formula (LI), (LII), (LIII), or (LIV) 【Chemistry 19】 The structure of 33. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the chelator is covalently attached to the C-terminal amino acid of a peptide of any one of formulas (LI), (LII), (LIII), and (LIV).

34. 34. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein a chelator is covalently attached to the amino acid attached to Xaa7, or a chelator is covalently attached to the C-terminal amino acid of a peptide of any one of formulas (LI), (LII), (LIII), and (LIV).

35. 24. The compound of any one of claims 3, 4, 15 to 23, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the Z group is covalently attached to an amino acid, and wherein the Z group is a chelator which may include a linker.

36. 36. The compound of claim 35, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the amino acid is the amino acid attached to Xaa7 or the amino acid Aaa of the N-terminal modification group A.

37. The chelator may be DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcofagin, FSC, NETA, H4octapa, Pycup, N ｘ S ４－ｘ (N4, N2S2, N3S), Hynic, ９９ｍ Tc(CO) ３ - chelators, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

38. 38. The compound of claim 37, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the chelator is selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N4.

39. 39. The compound of claim 38, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the chelator is selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, and N4.

40. 40. The compound of claim 39, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the chelator is N4Ac.

41. The compound is a compound of the formula 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 【Chemical Formula 77】 【Transformation 78】 【Transformation 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Transformation 87】 【Chemical 88】 【Chemistry 89】 【Chemistry 90】 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 【Chemical 95】 【Chemistry 96】 【Chemistry 97】 【Chem.98】 【Chem.99】 【Chemistry 100】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemical 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemical 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 【Chemistry 121】 【Chemistry 122】 【Chemical 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 【Chemistry 132】 【Chemistry 133】 【Chemistry 134】 【Chemistry 135】 【Transformation 136】 【Chemistry 137】 【Chemistry 138】 【Chemistry 139】 [Chemical 140] 【Chemistry 141】 【Chemistry 142】 【Chemistry 143】 【Chemistry 144】 【Chemistry 145】 【Chemistry 146】 【Chemistry 147】 【Chemistry 148】 【Chemistry 149】 [Chemical 150] 【Chemistry 151】 【Chemistry 152】 【Chemistry 153】 【Chemistry 154】 【Chemistry 155】 【Chemistry 156】 【Chemistry 157】 【Chemistry 158】 【Chemistry 159】 and [Chemical 160] or a pharmaceutically acceptable salt, solvate or hydrate thereof, selected from the group consisting of:

42. 42. A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising a therapeutically active nuclide.

43. 43. The compound of claim 42, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the therapeutically active nuclide is a particle-emitting isotope for therapeutic use and has a decay energy of 0.039 to 10 MeV.

44. 44. The compound of claim 43, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the particle-emitting isotope for therapeutic use has a decay energy of 0.4 to 6.5 MeV.

45. 45. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising a diagnostically active nuclide.

46. 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the diagnostically active nuclide is a gamma-emitting isotope for diagnostic use and has a decay energy of 0.004 to 10 MeV, or wherein the diagnostically active nuclide is a positron-emitting isotope for diagnostic use and has a decay energy of 0.6 to 13.2 MeV.

47. 47. The compound of claim 46, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said gamma-emitting isotope for diagnostic use has a decay energy of 0.05 to 4 MeV, or said positron-emitting isotope for diagnostic use has a decay energy of 1 to 6 MeV.

48. 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound comprises a diagnostically active radionuclide or a therapeutically active radionuclide.

49. said diagnostically active radionuclide ４３ Sc, ４４ Sc, ５１ Mn, ５２ Mn, ６４ Cu, ６７ Ga, ６８ Ga, ８６ Y. ８９ Zr, ９４ｍ Tc, ９９ｍ Tc, １１１ In, １５２ Tb, １５５ Tb, ２０１ Tl, ２０３ Pb, １８ F. ７６ Br, ７７ Br, １２３ I, １２４ I, and １２５ I, or said therapeutically active radionuclide is selected from the group consisting of ４７ Sc, ６７ Cu, ８９ Sr, ９０ Y. １５３ Sm, １４９ Tb, １６１ Tb, １７７ Lu, １８６ Re, １８８ Re, ２１２ Pb, ２１３ Bi, ２２３ Ra, ２２５ Ac, ２２６ Th, ２２７ Th, １３１ I, ２１１ 49. The compound of claim 48, or a pharmaceutically acceptable salt, solvate or hydrate thereof, selected from the group consisting of:

50. said diagnostically active radionuclide being ４３ Sc, ４４ Sc, ６４ Cu, ６７ Ga, ６８ Ga, ８６ Y. ８９ Zr, ９９ｍ Tc, １１１ In, １５２ Tb, １５５ Tb, ２０３ Pb, １８ F. ７６ Br, ７７ Br, １２３ I, １２４ I, and １２５ I, or said therapeutically active radionuclide ４７ Sc, ６７ Cu, ９０ Y. １７７ Lu, １８８ Re, ２１２ Pb, ２１３ Bi, ２２５ Ac, ２２７ Th, １３１ I, and ２１１ 50. The compound of claim 49, or a pharmaceutically acceptable salt, solvate or hydrate thereof, selected from the group consisting of:

51. said diagnostically active radionuclide being ６４ Cu, ６８ Ga, ８９ Zr, ９９ｍ Tc, １１１ In, １８ F. １２３ I, and １２４ I, or said therapeutically active radionuclide ９０ Y. １７７ Lu, ２２５ Ac, ２２７ Th, １３１ I, and ２１１ 51. The compound of claim 50, or a pharmaceutically acceptable salt, solvate or hydrate thereof, selected from the group consisting of:

52. 52. A composition comprising a compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

53. 53. The composition of claim 52, wherein the composition is a pharmaceutical composition.

54. 54. The composition of claim 52 or 53, which is a pharmaceutical composition, comprising a stabilizer that inhibits autoradiolysis of the compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

55. 55. The composition of claim 54, wherein the stabilizer is a free radical scavenger.

56. The composition of any one of claims 52 to 55, for use in: Use in a method for the diagnosis of a disease, Use in a method for the treatment of a disease, 52. Use in a method for identifying a subject, wherein said subject is likely to respond or not likely to respond to treatment of a disease, and said method for identifying a subject comprises the step of performing a method of diagnosis using a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate or hydrate thereof. or 52. Use in a method for selecting a subject from a group of subjects, wherein the subject is likely to respond or not to respond to treatment of a disease, and wherein the method for selecting a subject from a group of subjects comprises a step of performing a method of diagnosis using a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate or hydrate thereof. or 52. Use in a method for stratifying a group of subjects into those likely to respond to a treatment of a disease and those not likely to respond to a treatment of a disease, wherein said method for stratifying a group of subjects comprises the step of performing a method of diagnosis using a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate or hydrate thereof. The composition for

57. 57. The composition of claim 56, wherein the disease involves cells that exhibit upregulated expression of fibroblast activation protein (FAP).

58. 58. The composition of claim 57, wherein the disease involves affected tissues containing cells that exhibit upregulated expression of fibroblast activation protein (FAP).

59. 59. The composition of claim 58, wherein the disease is a disease involving tumor-associated fibroblasts.

60. 60. The composition of any one of claims 56 to 59, wherein the disease is a neoplasm.

61. 61. The composition of claim 60, wherein the neoplasm is a cancer or tumor.

62. 62. The composition of claim 61, wherein the cancer or tumor is selected from the group comprising solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cholangiocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and carcinomas, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, and thyroid cancer.

63. 52. A kit comprising the compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the kit may comprise one or more excipients or one or more devices, said devices being selected from the group comprising a labeling device, a purification device, a handling device, a radiation protection device, an analytical device, or an administration device.

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