Carbonic anhydrase IX ligand

Abstract

The present invention relates to chemical compounds; peptides; carbonic anhydrase IX (CAIX) binding compounds; CAIX binding peptides; compositions comprising the compounds; compositions comprising CAIX binding compounds; compositions comprising peptides; compositions comprising CAIX peptides; compounds, CAIX binding compounds, peptides, CAIX peptides, and compositions, respectively, for use in methods for the diagnosis of disease; compounds, CAIX binding compounds, and compositions, respectively, for use in methods for the treatment of disease; compounds, CAIX binding compounds, peptides, CAIX peptides, and compositions, respectively, for use in methods for the diagnosis and treatment of disease; methods for delivering radionuclides to CAIX expressing tissues. The present invention relates to compounds, CAIX-binding compounds, peptides, CAIX peptides, and compositions, respectively, for use in methods of treating and / or preventing disease; methods for diagnosis of disease using the compounds, CAIX-binding compounds, peptides, CAIX peptides, and compositions, respectively; methods for treatment of disease using the compounds, CAIX-binding compounds, peptides, CAIX peptides, and compositions, respectively; methods for diagnosis and treatment of disease using the compounds, CAIX-binding compounds, peptides, CAIX peptides, and compositions, respectively; methods for delivery of radionuclides to CAIX-expressing tissues using the compounds, CAIX-binding compounds, peptides, CAIX peptides, and compositions, respectively.

Description

[Technical Field]

[0001] compositions comprising carbonic anhydrase IX (CAIX) binding compounds; compositions comprising peptides; compositions comprising carbonic anhydrase IX (CAIX) peptides; compounds, carbonic anhydrase IX (CAIX) binding compounds, peptides, carbonic anhydrase IX (CAIX) peptides, and compositions, respectively, for use in methods for the diagnosis of disease; compounds, carbonic anhydrase IX (CAIX) binding compounds, and compositions, respectively, for use in methods for the treatment of disease; compounds, carbonic anhydrase IX (CAIX) binding compounds, peptides, carbonic anhydrase IX (CAIX) peptides, 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"; and delivery of effectors, such as radionuclides, to carbonic anhydrase IX (CAIX)-expressing tissues. methods for the diagnosis of disease using the compounds, carbonic anhydrase IX (CAIX) binding compounds, peptides, carbonic anhydrase IX (CAIX) peptides, and compositions, respectively; methods for the treatment of disease using the compounds, carbonic anhydrase IX (CAIX) binding compounds, peptides, carbonic anhydrase IX (CAIX) peptides, and compositions, respectively; methods for the diagnosis and treatment of disease, also referred to as "therapeutic diagnosis" or "therapeutic diagnostic methods," using the compounds, carbonic anhydrase IX (CAIX) binding compounds, peptides, carbonic anhydrase IX (CAIX) peptides, and compositions, respectively; and methods for the delivery of effectors, such as radionuclides, to carbonic anhydrase IX (CAIX)-expressing tissues using the compounds, carbonic anhydrase IX (CAIX) binding compounds, peptides, carbonic anhydrase IX (CAIX) peptides, and compositions, respectively. [Background technology]

[0002] Despite the increasing availability of treatment options, cancer remains the second leading cause of death worldwide. Rapidly proliferating cells have a high demand for nutrients and oxygen. This often leads to hypoxic conditions in cancer tissues because their vasculature cannot adequately supply them (Brown et al., Nat Rev Cancer, 2004, 4, pp. 437-447). Hypoxia is a hallmark of most solid tumors, with variable incidence and severity within a given patient population (Bhandari et al., Nat Genet, 2019, 51, pp. 308-318).

[0003] A decrease in available oxygen induces increased expression of hypoxia-inducible factor 1α (HIF-1α) (Cassavaugh et al., J Cell Biochem, 2011, 112, pp. 735-744; Zhong et al., Cancer Res, 1999, 59, pp. 5830-5835). This transcription factor induces several mechanisms that confer continued growth and drug resistance (Comerford et al., Cancer Res, 2002, 62, pp. 3387-3394; Jing et al., Mol Cancer, 2019, 18, pp. 157). To produce sufficient energy, cancer cells undergo a metabolic shift induced by HIF-1α toward increased rates of glycolysis. This change leads to a constant supply of energy but also increases the production of acidic metabolites.

[0004] A side effect of the tumor's compensatory mechanisms, which allow continued growth along with a lack of oxygen supply, is reduced sensitivity to drugs and radiation therapy. These additive effects make hypoxia a prognostic predictor of poor patient outcomes (Walsh et al., Antioxid Redox Signal, 2014, 21, pp. 1516-1554; van Kuijk et al., Front Oncol, 2016, 6, pp. 69). To overcome this, specific targeting of hypoxic cancer cells and their microenvironment is a promising approach for future therapies (Paolicchi et al., Oncotarget, 2016, 7, pp. 13464-13478).

[0005] Human carbonic anhydrase IX (CAIX) was originally identified as a membrane-bound protein in HeLa cells and other human carcinomas and named "MN protein" (Zavada et al., Int J Cancer, 1993, 54, pp. 268-274). Soon after, its extracellular carbonic anhydrase domain was identified, leading to its renaming to carbonic anhydrase IX (Pastorek et al., Oncogene, 1994, 9, pp. 2877-2888). CAIX is a key effector of the HIF-1α-mediated transcriptional response to tumor hypoxia, and its critical role in tumor progression is well recognized. In recent years, CAIX has gained notoriety as a surrogate marker of widespread tumor hypoxia in solid tumors. Due to its low expression in noncancerous tissues, it has become an attractive target for both diagnostic and therapeutic molecules (Lau et al., Theranostics, 2017, 7, pp. 4322-4339). CAIX plays a major role in cellular pH homeostasis by catalyzing the interconversion between carbon dioxide and water, and the dissociated ion of carbonate.

[0006] The human CAIX protein is encoded by the CA9 gene located on chromosome 9p12-13 and consists of 11 exons encoding distinct structural domains (Opavsky et al., Genomics, 1996, 33, 480-487). The enzyme consists of four domains: an N-terminal proteoglycan-like domain, a catalytic domain containing a zinc ion, a transmembrane segment, and a cytoplasmic portion. CAIX is a 58 / 54 kDa metalloenzyme of 459 amino acids. It associates as a dimer stabilized by the formation of an intermolecular disulfide bond between identical cysteine ​​residues located in the two carbonic anhydrase catalytic domains (Whittington et al., Proc Natl Acad Sci USA, 2001, 98, 9545-9550). The active site is located in a large conical cavity extending from the surface to the center of the protein. A zinc ion is located at the bottom of this cavity (Alterio et al., Proc Natl Acad Sci USA, 2009, 106, 16233-16238). Additional post-translational modifications of the extracellular domain of CAIX include N-glycosylation with high-mannose sugar chains in the catalytic domain and O-glycosylation with heparan or chondroitin sulfate glycosaminoglycan chains in the N-terminal proteoglycan-like region.

[0007] Normal CAIX expression is restricted to rapidly proliferating normal cells of the gastric epithelium, bile duct, gallbladder duct, pancreatic duct, small intestine, and to a lesser extent the CNS where it can be found primarily in cells lining the ventricles and choroid plexus (Zamanova et al., Expert Opin Ther Pat, 2019, 29, 509-533). On the other hand, CAIX expression has been shown to be increased in breast cancer (Storci et al., J Pathol, 2008, 214, pp. 25-37), kidney cancer (Luong-Player et al., Am J Clin Pathol, 2014, 141, pp. 219-225), colon cancer (Korkeila et al., Br J Cancer, 2009, 100, pp. 874-880), ovarian cancer (Choschzick et al., Virchows Arch, 2011, 459, pp. 193-200), head and neck cancer (Kappler et al., Strahlenther Onkol, 2008, 184, pp. 393-399), pancreatic cancer (Juhasz et al., Aliment Pharmacol Ther, 2003, 18, pp. 837-846), and lung cancer (Ilie et al., Br J Cancer, 2009, 100, pp. 874-880). CAIX is upregulated in most types of solid tumors, including, but not limited to, renal cell carcinoma (Cancer, 2010, 102, 1627-1635). In clear cell renal cell carcinoma, CAIX expression is unique compared to other cancers because it is generally removed from the hypoxia-induced signaling cascade (Shuin et al., Cancer Res, 1994, 54, 2852-2855).

[0008] [Table 1]

[0009] Carbonic anhydrases are a family of zinc metalloenzymes that catalyze the reversible hydration / dehydration of carbon dioxide / bicarbonate ions. This reaction forms the basis for regulating acid-base balance in living organisms. During evolution, at least 15 carbonic anhydrase (CA) isoenzymes have emerged in humans, which are key players in many physiological processes, including renal and male reproductive tract acidification, bone resorption, respiration, gluconeogenesis, signal transduction, and gastric acid formation (Breton, JOP, 2001, 2, pp. 159-164; Sly et al., Annu Rev Biochem, 1995, 64, pp. 375-401). Of these 15 human CA isoforms, three lack catalytic activity because they do not contain zinc ions and are therefore called carbonic anhydrase-related proteins (CARPs). CA isoforms possess variable levels of catalytic activity, distinct cellular localizations, patterns of multimerization, domain organization, and membrane attachment.

[0010] [Table 2]

[0011] The carbonic anhydrase family has been divided into five classes: α (found in mammals, prokaryotes, algae, and fungi), β (found primarily in plants and some prokaryotes), γ (present only in some forms of bacteria), and two other subclasses: δ and ζ (similar to class β and found in diatoms) (Aggarwal et al., Bioorg Med Chem, 2013, 21, pp. 1526-1533). The three main classes of CAs (α, β, and γ) are structurally dissimilar and have evolved independently, likely as a result of convergent evolution. Based on cellular and subcellular location, the α carbonic anhydrase class is divided into four distinct groups: cytosolic (CAs I, II, III, VII, and XIII); mitochondrial (CAs VA and VB); secretory (CAs VI), and membrane-associated (CAs IV, IX, XII, and XIV). The α-carbonic anhydrases are very closely related, with an average primary sequence identity of >39% between them (Pinard et al., Biomed Res Int, 2015, 2015, 453543). Most of the sequence identity translates to residues located in the active site. This needs to be taken into consideration when developing drugs against specific carbonic anhydrase targets.

[0012] [Table 3]

[0013] CAII has the widest distribution in the body, being expressed in the cytosol of cells from virtually every tissue or organ. The influence of this CA isozyme in the human body is best exemplified by CAII deficiency syndrome, a human autosomal recessive disorder characterized by osteopetrosis, renal tubular acidosis, and intracerebral calcification (Shah et al., Hum Mutat, 2004, 24, 272).

[0014] CAIV is membrane-bound via a glycosylphosphatidylinositol anchor. The isozyme is expressed in the bone marrow, gastrointestinal tract, liver, and gallbladder, while low expression is observed in the pancreas, kidney, brain, adipose tissue, and soft tissue. CAIV mRNA expression in cancer is much lower than that of other CAs (e.g., CAXIV), but can be observed in glioma, renal cell carcinoma, thyroid cancer, and melanoma (Mboge et al., Metabolites, 2018, 8).

[0015] Similar to CAIX, CAXII is another membrane-bound isozyme found to be expressed in various types of cancer and can be induced under hypoxic conditions (Wykoff et al., Cancer Res., 2000, 60, 7075-7083). Like CAIX, it contains an N-terminal extracellular catalytic domain, an α-helical transmembrane region, and a small cytoplasmic C-terminal domain, but it lacks the proteoglycan domain (Whittington et al., Proc. Natl. Acad. Sci. USA, 2001, 98, 9545-9550). Similarly, together with CAIX, it forms a dimer with two active sites facing the extracellular environment. The catalytic domain contains two asparagine residues (Asn-52 and Asn-136) that can be glycosylated. CAXII is upregulated in several cancers, including breast cancer, renal cancer, colorectal cancer, non-small cell lung cancer, etc. (Waheed et al., Gene, 2017, 623, 33-40). Both CAIX and CAXII are overexpressed under hypoxic conditions. The expression patterns of CAIX and CAXII are distinct and only slightly overlap.

[0016] Carbonic anhydrase XIV is another membrane-bound isozyme of CA, possessing an extracellular catalytic domain, a single transmembrane helix, and a short intracellular polypeptide segment. It shares over 40% sequence identity with CAIX. CAXIV mRNA shows strong expression in healthy brain, muscle, seminal vesicles, and retina, and is upregulated in many cancers, most commonly melanoma, glioma, liver cancer, and uterine cancer (Mboge et al., Metabolites, 2018, 8).

[0017] In addition, there are three known human catalytically inactive isoforms of α-carbonic anhydrase (VIII, X, and XI), known as carbonic anhydrase-related proteins (CARPs). These cytosolic isoforms lack CA activity, apparently due to substitutions for one or more of the three functionally important histidine residues that interface with the zinc atom (Tashian et al., EXS, 2000, pp. 105-120). Most of these CARPs are expressed primarily in the central nervous system.

[0018] Two main classes of compounds are being explored for targeting CAIX: antibodies and small molecules. Antibodies and their derivatives are being explored for inhibiting CAIX expression or function, stimulating immune responses or delivering cytotoxic payloads. CAIX-modulating small molecules with primarily inhibitory but also activating properties have been described. To date, few peptide-based approaches have been disclosed.

[0019] Typically, prior art compounds that target CAIX suffer from at least one of the following drawbacks that make them unsuitable for use in the diagnosis and treatment of human subjects, respectively: lack of carbonic anhydrase selectivity and particularly lack of CAIX sensitivity, low tumor-to-background ratio, increased background noise, and low stability.

[0020] International Patent Application WO 2012 / 016713 disclosed CAIX targeting polypeptides comprising the amino acid sequence YNTNHVPLSPKY (SEQ ID NO: 1) or sequence variants thereof. The Example section of WO 2012 / 016713 describes a method for visualizing their tumor targeting ability by whole-body planar imaging. 125 The use of I-labeled CAIX targeting peptide is shown. 131 I-labeled versions were used to assess their organ distribution. These organ distribution experiments revealed low tumor-to-blood ratios and increased background noise, unfavorable for imaging applications (Rana et al., PLoS One, 2012, 7, e38279). Another study by the same group aimed to identify and develop additional novel peptides with affinity for regions of the extracellular domain of CAIX that share no homology with other members of the CA family. The linear dodecapeptide NMPKDVTTRMSS (SEQ ID NO: 2) was identified by phage display and shown to selectively bind to the proteoglycan domain of CAIX, but exhibited unfavorable biodistribution (Rana et al., Mol Imaging, 2013, 12), preventing its use as a diagnostic or therapeutic agent. The reason for the poor performance of these peptides may be related to, but is not limited by, their low stability.

[0021] WO 2020 / 084305 and WO 2020 / 148526 disclosed polypeptides that bind to CAIX with high affinity, in which two or more peptide loops are covalently attached to a molecular scaffold so as to span between attachment points to the scaffold. The example sections of WO 2020 / 084305 and WO 2020 / 148526 revealed very limited data regarding the in vitro activity of select peptides in CAIX competitive binding assays and CAIX enzyme inhibition assays. No data were disclosed regarding the CA isotype selectivity, stability, or in vivo performance of the described peptides. Demonstration of the ability to conjugate effectors to CAIX-targeting peptides without significant loss of binding affinity to CAIX is limited to one example, namely, the conjugation of the cytostatic agent DM-1 (mertansine) to 61-01-02-N003.

[0022] U.S. Patent Application No. 2021154334A1 disclosed a dual-target carbonic anhydrase IX complex comprising a binding peptide having the amino acid sequence NHYPLSP (SEQ ID NO: 3), or a fragment or derivative thereof; a sulfonamide derivative conjugated to the binding peptide; and a metal chelator conjugated to the binding peptide and the sulfonamide derivative. 111 In-DOTA-AAZ-CA9tp exhibited high intestinal uptake at early time points after intravenous injection that was evident over time, leading to a progressive improvement in the initially low tumor / colon uptake ratio. No data were presented regarding the selectivity of the compound for CAIX over other carbonic anhydrases.

[0023] The above summary of prior art that has attempted to provide compounds that can be used in the diagnosis and / or therapy of CAIX-expressing tumors, where such diagnosis and therapy typically utilize radiolabeled versions of such compounds, illustrates the difficulties in designing compounds of this type.

[0024] Preferred compounds for the diagnosis and / or therapy of CAIX-expressing tumors may exhibit at least one, and preferably two or more, of the following characteristics: high binding affinity, high biological stability, high target selectivity, and suitable in vivo targeting and pharmacokinetic properties. High binding affinity may promote the uptake and retention of the compound in target-expressing tissues, thereby allowing it to exert its biological effect in the tissue of interest (e.g., tumor). High biological stability is advantageous for the availability of the intact compound for a sufficient time to allow delivery to the tissue of interest. Compared to the intact compound, metabolites may lose target affinity and exhibit different in vivo distribution, potentially leading to loss of efficacy and the occurrence of unwanted side effects. High target selectivity is desirable to avoid off-target activity that may contribute to side effects. Suitable in vivo targeting and pharmacokinetic properties help ensure the compound's proper delivery to and exposure of the tissue of interest, which is a prerequisite for its diagnostic and / or therapeutic efficacy. [Prior art documents] [Patent documents]

[0025] [Patent Document 1] WO 2012 / 016713 [Patent Document 2] WO 2020 / 084305 [Patent Document 3] WO 2020 / 148526 [Patent Document 4] U.S. Patent Application No. 2021154334A1 [Patent Document 5] U.S. Patent No. 6,214,345 [Patent Document 6] U.S. Patent Application No. 2005 / 0238649 [Patent Document 7] WO 2019 / 096867 A1 [Patent Document 8] U.S. Patent No. 5,367,080 A [Patent Document 9] , U.S. Patent No. 5,364,613 A

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Non-licensed literature

[0026] [Non-licensed document 1] Brown, Nat Rev Cancer, 2004, 4, pages 437~447 [Non-licensed document 2] Bhandariら, Nat Genet, 2019, 51, pages 308~318 [Non-licensed document 3] Cassavaugh, J Cell Biochem, 2011, 112, pages 735~744

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[0027] Detailed Description of the Invention The problem underlying the present invention is the provision of compounds that are suitable as diagnostic and / or therapeutic agents, especially when conjugated to a diagnostically and / or therapeutically active radionuclide.

[0028] A further problem underlying the present invention is a compound that is suitable as a diagnostic and / or therapeutic agent, in particular when it contains a diagnostically and / or therapeutically active radionuclide, said compound having a pEC value for carbonic anhydrase IX (CAIX) of equal to or greater than 6.0. 50 and / or a pIC greater than or equal to 6.0 50 The present invention provides a compound having the formula:

[0029] A further problem underlying the present invention is the provision of compounds that are suitable as diagnostic and / or therapeutic agents in the diagnosis and / or therapy of diseases in which the diseased cells and / or tissues express carbonic anhydrase IX (CAIX), in particular when they comprise a diagnostically and / or therapeutically active radionuclide.A still further problem underlying the present invention is the provision of compounds that are suitable for delivering diagnostically and / or therapeutically active radionuclides, respectively, to diseased cells and / or tissues, more particularly to diseased cells and / or tissues expressing CAIX, preferably wherein the diseased tissues comprise cancer or tumor cells.

[0030] The problem underlying the present invention is also to provide methods for the diagnosis of diseases, methods for the treatment and / or prevention of diseases, and methods for the combined diagnosis and treatment of diseases; preferably, such diseases are diseases involving CAIX-expressing cells and / or tissues, more particularly diseased cells and / or diseased tissues that express CAIX, and preferably the diseased tissues include or contain cancer or tumor cells.

[0031] A still further problem underlying the present invention is to provide a method for identifying subjects, which are likely to respond or not to respond to treatment of a disease, a method for selecting subjects from a group of subjects, which are likely to respond or not to respond to treatment of a disease; preferably, the disease is cancer, more preferably, the disease is a solid tumor.

[0032] The problem underlying the present invention is also to provide a pharmaceutical composition containing a compound having the characteristics outlined above, and a kit suitable for use in any of the above methods. [Means for solving the problem]

[0033] These and other problems are solved by the subject matter of the attached independent claims; preferred embodiments can be taken from the attached dependent claims.

[0034] The problem underlying the present invention is to provide a compound of formula (1a)

[0035] [ka]

[0036] The problem is also solved in a first aspect, which is also a first embodiment of the first aspect, by a compound comprising a peptide selected from the group consisting of cyclic peptides In formula (1a), the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction, Y is (i)R 0a -SO2-, R 0a -CO-, R 0a an N-terminal modifying group A selected from the group consisting of —NH—CO—, wherein R 0a is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C 10 ) aryl; or (ii) an effector E1, such as a chelator, that is covalently linked to Xaa1 when Xaa1 is present, or to Xaa2 when Xaa1 is absent and Xaa2 is present, or to Xaa3 when both Xaa1 and Xaa2 are absent; or (iii) Z1, wherein Z1 comprises a linker moiety L1 and an effector E1, such as a chelator, wherein the linker moiety L1 covalently links the effector E1 to Xaa1 when Xaa1 is present, or to Xaa2 when Xaa1 is absent and Xaa2 is present, or to Xaa3 when both Xaa1 and Xaa2 are absent; Xaa1 is present or absent and, if present, is a residue of an aliphatic or polar L-amino acid; Xaa2 is present or absent, If Xaa2 is absent, then Xaa1 is also absent; If Xaa2 is present, (i) Xaa2 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom; or (ii) Xaa2 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2, and has the formula (1b):

[0037] [ka]

[0038] A bicyclic peptide of the formula Xaa3 is a group represented by the formula (X)

[0039] [ka]

[0040] is a residue of an α-amino acid of During the ceremony, R 3a and R 3b are each and independently selected from the group consisting of H and CH3; Xaa3 is preferably a residue of an L-α-amino acid, such as Cys; Xaa4 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom; Xaa5 is a residue of an amino acid optionally linked to Z3, wherein Xaa5 is a residue of an amino acid selected from the group consisting of N-(C1-C6) alkylglycine, GIy, D-α-amino acids, and α,α-dialkylamino acids; When Xaa5 includes Z3, (i) Z3 is an effector E3 such as a chelator, and Xaa5 is preferably a residue of an amino acid selected from the group consisting of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and the effector is attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; or (ii) Z3 comprises an effector E3 such as a chelator and a linker moiety L3, wherein Xaa5 is preferably a residue of an amino acid selected from the group consisting of Nlys, D-lys, D-orn, D-dab, and D-dap, and the linker moiety L3 is attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; Xaa6 is selected from (i) polar L-α-amino acids, aromatic L-α-amino acids, aliphatic α-amino acids, S-alkylated cysteines, oxidized forms of S-alkylated cysteines, and amino acids of formula (3)

[0041] [ka]

[0042] and wherein the amino acid residue is selected from the group consisting of amino acid residues according to During the ceremony, R 6a is H and -(C5~C 10 )aryl, (C1-C8)alkyl, and (C1-C5)alkyl-(C5-C 10 ) an aryl-containing moiety; R 6b is selected from the group consisting of H and methyl; R 6c is H or (C1-C6) alkyl, w is 0 or 1, or (ii) a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG3 that forms a covalent linkage B2 with the functional group FG4 of Xaa11, wherein Xaa11 is a residue of an α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG4, and has the formula (1c):

[0043] [ka]

[0044] A bicyclic peptide of the formula Xaa7 is a residue of an amino acid selected from the group consisting of aromatic amino acids, such as heteroaromatic L-α-amino acids, and substituted aromatic amino acids, such as substituted heteroaromatic L-α-amino acids; Xaa8 is a residue of an amino acid selected from the group consisting of L-α-amino acids and cyclic α,α-dialkylamino acids; Xaa9 is a residue of an amino acid selected from the group consisting of Gly and L-α-amino acids; Xaa10 is a residue of a heteroaromatic L-α-amino acid; Xaa11 is (i) a residue of an amino acid selected from the group consisting of GIy and an L-α-amino acid, which is optionally linked to Z4, which comprises an effector E4, such as a chelator, and a linker moiety L4; or (ii) is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2; or (iii) a residue of an α-amino acid containing, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG4 that forms a covalent linkage B2 with the functional group FG3 of Xaa6; Xaa12 is a group represented by formula (XII):

[0045] [ka]

[0046] Preferably of formula (XIIa):

[0047] [ka]

[0048] is the residue of an α-aminothiol, During the ceremony, NH of each of formulas (XII) and (XIIa) is bonded to Xaa11; R 12a and R 12b are each and independently selected from the group consisting of H and CH3; R 12c is selected from the group consisting of -CO-OH, CO-NH2, -CO-Z6, and -CH2-Z6, where Z6 comprises a linker moiety L6 and an effector E6, such as a chelator; X 1 and X 2 are each and independently selected from the group consisting of CH and N.

[0049] The problem underlying the present invention is to provide a compound of formula (1a):

[0050] [ka]

[0051] and wherein the problem is solved in a second aspect, which is also a first embodiment of the second aspect, by a peptide selected from the group consisting of cyclic peptides In formula (1a), the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction, Y is (i)R 0a -SO2-, R 0a -CO-, R 0a an N-terminal modifying group A selected from the group consisting of —NH—CO—, wherein R 0a is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C10 ) aryl; or (ii) an effector E1, such as a chelator, that is covalently linked to Xaa1 when Xaa1 is present, or to Xaa2 when Xaa1 is absent and Xaa2 is present, or to Xaa3 when both Xaa1 and Xaa2 are absent; or (iii) Z1, wherein Z1 comprises a linker moiety L1 and an effector E1, such as a chelator, wherein the linker moiety L1 covalently links the effector E1 to Xaa1 when Xaa1 is present, or to Xaa2 when Xaa1 is absent and Xaa2 is present, or to Xaa3 when both Xaa1 and Xaa2 are absent; Xaa1 is present or absent and, if present, is a residue of an aliphatic or polar L-amino acid; Xaa2 is present or absent, If Xaa2 is absent, then Xaa1 is also absent; If Xaa2 is present, (i) Xaa2 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom, or (ii) Xaa2 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2, and is represented by formula (1b)

[0052] [ka]

[0053] A bicyclic peptide of the formula Xaa3 is a group represented by the formula (X):

[0054] [ka]

[0055] is a residue of an α-amino acid of During the ceremony, R 3a and R 3b are each and independently selected from the group consisting of H and CH3; Xaa3 is preferably a residue of an L-α-amino acid, such as Cys; Xaa4 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom; Xaa5 is a residue of an amino acid optionally linked to Z3, wherein Xaa5 is a residue of an amino acid selected from the group consisting of N-(C1-C6) alkylglycines, D-α-amino acids, and α,α-dialkylamino acids; When Xaa5 includes Z3, (i) Z3 is an effector E3 such as a chelator, and Xaa5 is preferably a residue of an amino acid selected from the group consisting of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and the chelator is attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; or (ii) Z3 comprises an effector E3 such as a chelator and a linker moiety L3, wherein Xaa5 is preferably a residue of an amino acid selected from the group consisting of Nlys, D-lys, D-orn, D-dab, and D-dap, and the linker moiety L3 is attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; Xaa6 is selected from (i) polar L-α-amino acids, aromatic L-α-amino acids, aliphatic α-amino acids, S-alkylated cysteines, oxidized forms of S-alkylated cysteines, and amino acids of formula (3):

[0056] [ka]

[0057] and wherein the amino acid residue is selected from the group consisting of amino acid residues according to During the ceremony, R 6a is H and -(C5~C 10 )aryl, (C1-C8)alkyl, and (C1-C5)alkyl-(C5-C 10 ) an aryl-containing moiety; R 6b is selected from the group consisting of H and methyl; R 6c is H or (C1-C6) alkyl, w is 0 or 1, or (ii) a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG3 that forms a covalent linkage B2 with the functional group FG4 of Xaa11, wherein Xaa11 is a residue of an α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG4, and has the formula (1c):

[0058] [ka]

[0059] A bicyclic peptide of the formula Xaa7 is a residue of an amino acid selected from the group consisting of aromatic amino acids, such as heteroaromatic L-α-amino acids, and substituted aromatic amino acids, such as substituted heteroaromatic L-α-amino acids; Xaa8 is a residue of an amino acid selected from the group consisting of L-α-amino acids and cyclic α,α-dialkylamino acids; Xaa9 is a residue of an amino acid selected from the group consisting of Gly and L-α-amino acids; Xaa10 is a residue of a heteroaromatic L-α-amino acid; Xaa11 is (i) a residue of an amino acid selected from the group consisting of GIy and an L-α-amino acid, the L-α-amino acid optionally being linked to Z4, which Z4 comprises an effector E4, such as a chelator, and a linker moiety L4; or (ii) is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2; or (iii) a residue of an α-amino acid containing, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG4 that forms a covalent linkage B2 with the functional group FG3 of Xaa6; Xaa12 is a group represented by formula (XII):

[0060] [ka]

[0061] Preferably, the compound of formula (XIIa)

[0062] [ka]

[0063] is the residue of an α-aminothiol, During the ceremony, NH of formula (XII) is bonded to Xaa11; R 12a and R 12b are each and independently selected from the group consisting of H and CH3; R 12c is selected from the group consisting of -CO-OH, CO-NH2, -CO-Z6, and -CH2-Z6, where Z6 comprises a linker moiety L6 and an effector E6, such as a chelator; X 1 and X 2 are each and independently selected from the group consisting of CH and N, and are both preferably CH.

[0064] According to the present invention, each and every embodiment of the compound of the first aspect is also an embodiment of the peptide of the first aspect, and vice versa.

[0065] The definitions provided for Xaa1-Xaa12 in the claims and this specification have their general meaning in the art, unless they are specifically defined herein. Insofar as the definitions of Xaa1-Xaa12 refer to expressions such as aliphatic, aromatic (e.g., heteroaromatic), polar, neutral, cyclic, α,α-dialkylamino acids, reference is made to the definitions given for these expressions provided below in the specification and examples.

[0066] Preferred embodiments in the broadest sense used in the context of Xaa1-Xaa12 are further described below. Insofar as the above preferred embodiments refer to "unnatural amino acids," reference is made to the dependent claims and the following description which specify preferred unnatural amino acids for some of Xaa1-Xaa12.

[0067] The problem underlying the present invention is to provide a compound:

[0068] DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2 (3BP-4452, also referred to as DPI-4452 in the following description) of the formula:

[0069] [ka]

[0070] The compound DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH2 (3BP-4501, also referred to as DPI-4501 in the following description) of the formula:

[0071] [ka]

[0072] The compound DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Dap}-Cys]-NH2 (3BP-4503, also referred to as DPI-4503 in the following description) of the formula:

[0073] [ka]

[0074] The problem is also solved in a third aspect, which is also a first embodiment of the third aspect, by a compound selected from the group consisting of:

[0075] The compounds of the first aspect, including any of their embodiments, the peptides of the second aspect, including any of their embodiments, and the compounds of the third aspect, including any of their embodiments, are also referred to as compounds of the invention.

[0076] The problem underlying the present invention is also solved in a fourth aspect, which is also a first embodiment of the fourth aspect, by a compound of the first aspect, a peptide of the second aspect or a compound of the third aspect, including each and every embodiment thereof, for the diagnosis of a disease.

[0077] The problem underlying the present invention is also solved in a fifth aspect, which is also a first embodiment of the fifth aspect, by a compound of the first aspect, a peptide of the second aspect, or a compound of the third aspect, including each and any embodiment thereof, for use in a method for the treatment of a disease.

[0078] The problem underlying the present invention is also solved in a sixth aspect, which is also a first embodiment of the sixth aspect, by a compound of the first aspect, a peptide of the second aspect, and a compound of the third aspect, in each and every embodiment thereof, for use in a method for identifying a subject, the subject being likely to respond or not to respond to treatment of a disease, the method for identifying a subject comprising carrying out a method of diagnosis using the compound of the first aspect, the peptide of the second aspect, or the compound of the third aspect, in each and every embodiment thereof.

[0079] The problem underlying the present invention is also solved in a seventh aspect, which is also a first embodiment of the seventh aspect, by a compound of the first aspect, a peptide of the second aspect, or a compound of the third aspect, in each and every embodiment thereof, for use in a method for the selection of a subject from a group of subjects, the subjects being likely to respond or not to treatment of a disease, the method for the selection of a subject from a group of subjects comprising the step of carrying out a method of diagnosis using the compound of the first aspect, the peptide of the second aspect, or the compound of the third aspect, in each and every embodiment thereof.

[0080] The problem underlying the present invention is also solved in an eighth aspect, which is also a first embodiment of the eighth aspect, by a compound of the first aspect, a peptide of the second aspect, or a compound of the third aspect, including each and every embodiment thereof, for use in a method for stratifying a group of subjects into those who are likely to respond to treatment of a disease and those who are likely to not respond to treatment of a disease, wherein the method for stratifying a group of subjects comprises carrying out a method of diagnosis using the compound of the first aspect, the peptide of the second aspect, or the compound of the third aspect, including any embodiment thereof.

[0081] The problem underlying the present invention is solved in a ninth aspect by a composition, preferably a pharmaceutical composition, comprising a compound of the first aspect, a peptide of the second aspect, and / or a compound of the third aspect, including any embodiment thereof, and a pharmaceutically acceptable excipient.

[0082] The problem underlying the present invention is solved in a tenth aspect by a kit comprising a compound of the first aspect, a peptide of the second aspect, and / or a compound of the third aspect, including any embodiment thereof, one or more optional excipients, and optionally one or more devices, wherein the device is selected from the group comprising a labelling device, a purification device, a manipulation device, a radiation protection device, an analytical device, or an administration device. DETAILED DESCRIPTION OF THE INVENTION

[0083] 1.Definition The term "peptide" refers to a compound comprising a consecutive sequence of at least three amino acids linked together via peptide linkages. The term "peptide linkage" in this context is intended to encompass (backbone) amide bonds as well as modified linkages that may be obtained when non-natural amino acids are introduced into a peptidic sequence. In this case, the modified linkage replaces the (backbone) amide bond formed in the consecutive peptide sequence by reacting the amino and carboxyl groups of two amino acid residues. For example, the modified linkage may be an ester, ether, thioether, thiourea, carbamate, or triazole linkage (described further below). Preferably, the amino acids forming the consecutive peptide sequence are linked together via backbone amide bonds. Peptides may be linear or branched, e.g., cyclic. Here, amino acids include both naturally occurring amino acids, as described further below, as well as non-natural (synthetic) amino acids.

[0084] The term "C-terminus" as used herein refers to the C-terminus of a peptide chain. The C-terminal amino acid residue of a peptide sequence is the last amino acid in the sequence that is attached to the peptide chain via its amino group, and its carboxy group is not involved in the attachment to the peptide chain. The carboxy group of the C-terminal amino acid residue can be a free carboxy group or a group derived from a carboxy group, such as an amide or ester group. For example, the attachment of an "X" group to the carboxy group of the C-terminal amino acid residue "Xaa" creates a structural element of ester or amide type -C(O)-X, where the carbonyl group is derived from the acid group of Xaa.

[0085] The term "N-terminus" as used herein refers to the N-terminus of a peptide chain. The N-terminal amino acid residue of a peptide sequence is the first amino acid in the sequence that is attached to the peptide chain via its carboxy group, and its amino group is not involved in the bond to the peptide chain. The amino group of the N-terminal residue may be unmodified or modified. Modification of the "N-terminal" amino acid residue means that a covalent bond is formed between the amino group in the main chain (backbone) of the amino acid residue and a binding partner (replacing one hydrogen atom), and this bond is typically selected from the group consisting of amide, urea, carbamate, thiourea, sulfonamide, and alkylamine (-CH2-N-) bond.

[0086] In one embodiment, and 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 a coordinate bond. As preferably used herein, an embodiment of a coordinate bond is a bond or group of bonds that are realized when a metal is bound by a chelating agent. Depending on the type of atoms that are linked and their atomic environment, various types of links are created. These types of links are defined by the type of atomic arrangement created by the linkage.

[0087] For example, the linkage between an amine-containing moiety and a carboxylic acid-containing moiety leads to a linkage termed an "amide" (amide linkage, -CO-N-, also referred to as -N-CO-). Those skilled in the art will recognize that this and the following examples of creating linkages are merely prototypical examples and in no way limit the scope of the present application. Those skilled in the art will recognize that the linkage between an isothiocyanate-containing moiety and an amine-containing moiety leads to a thiourea (thiourea linkage, also referred to as -N-CS-N-), and the linkage between a C-atom-containing moiety and a thiol group (-C-SH)-containing moiety leads to a thioether (thioether linkage, also referred to as -CSC-). Linkages preferably used in connection with the chelators and linkers of the present invention and their characteristic types of atomic configurations are presented in Table 4.

[0088] [Table 4]

[0089] In some embodiments of the present invention, examples of reactive groups used in forming linkages between an effector, e.g., a chelator that preferably comprises a chelated nuclide, more preferably a chelated diagnostically and / or therapeutically active radionuclide, and the remainder of the molecule, are summarized in Table 5. 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 5, nor to the reactive groups that form such linkages.

[0090] [Table 5]

[0091] The following are reactive groups and functionalities that are utilized in 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 ester such as mesylate or tosylate, Michael acceptors, strained alkenes such as trans-cyclooctene, isocyanate, isothiocyanate, azide, alkyne, and tetrazine.

[0092] 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 having pentafluorophenol, nitrophenol, benzotriazole, azabenzotriazole, thiophenol, or N-hydroxysuccinimide (NHS) as the leaving group.

[0093] As preferably used herein, the term "sulfonate ester" refers to a functional group characterized by -O-SO-R, where R is preferably (C1-C8) alkyl or aryl. Sulfonate esters, like halogens, are typical leaving groups in nucleophilic substitutions.

[0094] A "Michael acceptor" contains at least one unsaturated, non-aromatic C-C bond substituted with at least one electron-withdrawing group, preferably CO-, CN, NO2, and SO2-. These Michael acceptors are substrates for the conjugate addition of many nucleophilic partners in the well-known Michael addition reaction. Notable examples are acrylic acid, maleimide, or vinyl sulfone.

[0095] In this application, to the extent that it refers to a range indicated by a lower integer and an upper integer, such as 1 to 4, such range represents 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 said integers. In the example, the range 1 to 4 therefore means 1, 2, 3, and 4.

[0096] In one embodiment, and as preferably used herein, "(C1-C8) alkyl" refers to a saturated or unsaturated, straight-chain, cyclic, or branched hydrocarbon group having 1 to 8 carbon atoms. Representative (C1-C8) alkyl groups include 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, and the like. yl, 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-methyl-hexyl, 3-heptyl, 2-ethyl-pentyl, 3-ethyl-pentyl, 4-heptyl, 2-methyl-hex-2-yl, 2,2-dimethyl-pentyl, 3,3-dimethyl-pentyl, 4,4-dimethyl-pentyl, 3-methyl-hex-2-yl, 4-methyl-hex-2-yl, 5-methyl-hex-2-yl, 2,3-dimethyl-pentyl, 2,4-dimethyl-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, 5,2-methyl-2-ethyl-pentyl, 2-isopropyl-pentyl, 2,2-dimethyl-hex-3-yl, 2,2,4-trimethyl-pent-3-yl, and 2-ethyl-3-methyl-pentyl. The (C1-C8) alkyl 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', -COOR', -CONH2, -CONHR', -CONR'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.

[0097] "(C1-C4) alkyl", "(C1-C5) alkyl", "(C2-C5) alkyl", "(C1-C6) alkyl", and "(C1-C 10 The terms "(C1-C8)alkyl" and "(C1-C8)alkyl" are similar in meaning to the term "(C1-C8)alkyl," but differ in the indicated range of the number of C atoms. However, these alkyl groups can also be substituted with one or more groups, including but not limited to, -(C1-C8)alkyl, -O-[(C1-C8)alkyl], -aryl, -CO-R', -O-CO-R', -COOR', -CONH2, -CONHR', -CONR'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.

[0098] In one embodiment, and as preferably used herein, "(C3-C7)cycloalkyl" refers to a saturated, unsaturated, or branched hydrocarbon group containing a carbon ring structure having from 3 to 7 carbon atoms.

[0099] In one embodiment, and as preferably used herein, "(C3-C8)cycloalkyl" refers to a saturated, unsaturated, or branched hydrocarbon group containing a carbon ring structure having from 3 to 8 carbon atoms.

[0100] Regardless of the number of their C atoms, all groups designated as "cycloalkyl" can also be substituted with one or more groups, including but not limited to (C1-C8) alkyl, -O-[(C1-C8) alkyl], -aryl, -CO-R', -O-CO-R', -COOR', -CONH2, -CONHR', -CONR'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.

[0101] In one embodiment, and as preferably used herein, "aryl" refers to a group comprising an aromatic system, which is carbocyclic or heterocyclic, preferably consisting of 5 to 10 C- or hetero-atoms in the ring, and wherein the aryl 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-NH, -CO-NHR', -CO-NR', -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH, -NHR', -NR'2, and -CN; where each R' is independently selected from -(C1-C8)alkyl and aryl.

[0102] In one embodiment, and as preferably used herein, "heterocyclyl" refers to a heterocyclic aromatic or non-aromatic group. Examples of heterocyclic groups include, but are not limited to, furan, thiophene, pyridine, pyrimidine, benzothiophene, benzofuran, quinoline, piperidine, piperazine, morpholine, oxirane, tetrahydrofuran, and pyrrolidine.

[0103] In one embodiment, and as preferably used herein, “(C5 to C 10 ")Heterocyclyl" refers to a heterocyclic aromatic or non-aromatic group of 5 or 10 ring atoms in which at least one atom is different from carbon, including, for example, nitrogen, sulfur, or oxygen. Heteroaromatic 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', -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH, -NHR', -NR'2, and -CN; where each R' is independently selected from -(C1-C8)alkyl and aryl.

[0104] In one embodiment, 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.

[0105] In one embodiment, and as preferably used herein, “(C5 to C 10")Heteroaryl" refers to a heteroaromatic group of 5 or 10 ring atoms in which at least one atom is different from carbon, including, for example, nitrogen, sulfur, or oxygen. Heteroaromatic 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', -NH-CO-R', -SO2-R', -SO-R', -OH, -halogen, -N3, -NH, -NHR', -NR'2, and -CN; where each R' is independently selected from -(C1-C8)alkyl and aryl.

[0106] In one embodiment, and as preferably used herein, “(C1-C5) alkyl-(C5-C 10 )aryl" means -(C5-C 10 ) refers to a (C1-C5) alkyl group covalently bonded to an aryl group.

[0107] In one embodiment, and as preferably used herein, “(C3-C7)cycloalkyl-(C5-C 10 )Aryl" means (C5-C 10 ) a cycloalkyl group consisting of 3, 4, 5, 6, or 7 C atoms attached to an aryl group.

[0108] The compounds of the present invention typically contain the amino acid sequences provided herein. As used herein, the term "amino acid" refers to a compound containing or derived from at least one amino group and at least one acidic group, preferably a carboxy group. The distance between the amino group and the acidic group is not particularly limited. Unless otherwise specified, α-, β-, γ-, δ-, and ε-amino acids are suitable, however, in many cases, α-amino acids and especially α-aminocarboxylic acids are particularly preferred. The term "amino acid" encompasses both naturally occurring amino acids, such as naturally occurring proteinogenic amino acids, and synthetic amino acids not found in nature ("unnatural amino acids"). The term "residue" or "residue of an amino acid" is used to characterize an amino acid attached to a neighboring amino acid or moiety that differs from the amino acid from which it is derived only in the structural elements involved in the attachment to the neighboring amino acid or moiety.

[0109] Conventional amino acids, also referred to as "natural amino acids," are identified according to their standard three-letter codes and one-letter abbreviations as set forth in Table 6.

[0110] [Table 6]

[0111] An unconventional amino acid, also referred to as an "unnatural amino acid," is any type of non-oligomeric compound that contains an amino group and a carboxylic acid group and is not a conventional amino acid. The size of an unnatural amino acid is not particularly limited, but can correspond to a molecular weight of up to 500 g / mol, such as up to 400 g / mol.

[0112] Examples of unnatural amino acids and other building blocks used in constructing the compounds of the invention are identified according to their abbreviations and names found in Table 7. The structures of some building blocks are depicted along with exemplary reagents for introducing the building block into a peptide (e.g., like carboxylic acids), 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 residues of amino acids, as that is how they are presented after implementation in a peptide sequence. Some larger chemical moieties consisting of more than one moiety are also shown.

[0113] [Table 7A]

[0114] [Table 7B]

[0115] [Table 7C]

[0116] [Table 7D]

[0117] [Table 7E]

[0118] [Table 7F]

[0119] [Table 7G]

[0120]

Table 7H

[0121]

Table 7I

[0122]

Table 7J

[0123] Table 7K

[0124] Table 7L

[0125] Table 7M

[0126] Table 7N

[0127] The amino acid sequences of the peptides provided herein are depicted in a typical peptide sequence format, as would be understood by one of ordinary skill in the art. For example, the three-letter code for a natural amino acid, or the code for an unnatural amino acid, or the abbreviation for an additional building block, indicates the presence of the amino acid or building block at the designated location within the peptide sequence. The code for each amino acid or building block is connected to the code for the next and / or previous amino acid or building block in the sequence by a hyphen (typically representing an amide linkage). When a hyphen precedes an amino acid abbreviation, it usually symbolizes that the amino group of the amino acid is covalently modified, and when a hyphen follows an amino acid abbreviation, it usually symbolizes that the previous carboxyl group is covalently modified. The remaining characteristic parts of an amino acid after one or more covalent modifications are referred to as amino acid residues. Depending on the context, reference to an amino acid or building block abbreviation may symbolize either the entire amino acid or building block, or a residue thereof. In conjunction with the use of a hyphen following the abbreviation, it is clearly specified that an amino acid or building block residue is addressed.

[0128] Depending on the spacing between the amino and carboxy groups in amino acids, they are classified as α-, β-, γ-, δ-, and ε-(etc.)-amino acids, which means that these groups are typically spaced apart by 1, 2, 3, 4, and 5 atoms (typically carbons), respectively.

[0129] For amino acids, the first letter in their abbreviations indicates the stereochemistry of the C-α-atom, if applicable. For example, 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. If the abbreviation begins with a number, the first letter in the abbreviation will be characteristic of the stereochemistry, if applicable. However, for increased clarity, it is an option to more clearly specify the stereochemistry of any amino acid abbreviation, for example, by adding a "D-" prefix to any abbreviation. For example, "lys", "D-Lys", or "D-lys" describes all D-configured Lys.

[0130] It is clear to those skilled in the art that many amino acids can be N-methylated at their amino group. These N-methyl amino acid traits can exist in combination with some other attributes, such as L-α- or D-α-N-methyl amino acids, which are N-methylated L-α- or D-α-amino acids.

[0131] The term "α,α-dialkylamino acid" refers to an amino acid containing two alkyl groups independently at the α-carbon atom, which in some cases can form a ring structure with each other to form a cyclic α,α-dialkylamino acid. A typical example of an α,α-dialkylamino acid is 2-aminoisobutyric acid (Aib).

[0132] The term "cyclic α,α-dialkylamino acid" refers to an achiral, D-, or L-α,α-dialkylamino acid in which two alkyl residues substituting the α-amino group combine to form a cyclic structure. The resulting cyclic structure may contain, for example, 4 to 7 C atoms, as in 1-amino-1-cyclopentanecarboxylic acid. One or more of the carbon atoms of the cyclic structure may be replaced by a heteroatom, such as O, S, or N.

[0133] The term "aromatic amino acid" refers to an amino acid containing an aromatic structure, including heteroaromatic structures, while the term "non-aromatic amino acid" refers to an amino acid lacking any aromatic structure. Preferably, the term "aromatic amino acid" refers to an amino acid selected from the group consisting of Phe, Trp, Tyr, His, Mamb, Pamb, and derivatives thereof, such as substituted Phe.

[0134] The term "heteroaromatic amino acid" refers to an amino acid containing any type of heteroaromatic structure.

[0135] An "aliphatic amino acid" is a non-aromatic amino acid consisting of only C and H atoms apart from the amino and carboxy groups. Preferably, the term "aliphatic amino acid" refers to an amino acid selected from the group consisting of Gly, Ala, Val, Leu, Ile, Pro, Npg, Cha, Egz, and derivatives thereof, more preferably Gly, Ala, Val, Leu, Ile, and Pro.

[0136] A "polar amino acid" is any type of amino acid that contains, apart from the amino and carboxy groups, at least one functional group or atom selected from the group consisting of O, S, P, OH, and N, but which does not introduce an additional charge due to this functional group or atom (at a pH ranging from about 4 to about 8). Preferably, the term "polar amino acid" refers to an amino acid selected from the group consisting of Asn, Gln, Ser, Thr, Cys, and Tyr, more preferably Asn, Gln, Ser, and Thr.

[0137] A "charged amino acid" is any type of amino acid that contains at least one functional group, apart from amino and carboxy groups, that leads to a net charge at a pH ranging from about 4 to about 8, such as COOH, phosphate, phosphonate, sulfonate, sulfate, imidazole, pyridine, guanidinium, ammonium, and amino nitrogen. Preferably, the term "charged amino acid" refers to an amino acid selected from the group consisting of Asp, Glu, Lys, Arg, Orn, Dab, Dap, APac, and His, more preferably Asp, Glu, Lys, and Arg.

[0138] A "neutral amino" acid is any type of amino acid that has no net charge at a pH ranging from about 4 to about 8. Preferably, the term "neutral amino acid" refers to an amino acid selected from the group of aliphatic, aromatic, or polar amino acids.

[0139] The expression "hydrophobic amino acid" or related terms such as "hydrophobic moiety provided by an amino acid residue" refers to neutral amino acids that, apart from their amino and carboxy groups, comprise to a large extent primarily hydrophobic moieties. Preferably, the ratio of the sum of aliphatic, aromatic carbon, and halogen atoms to heteroatoms such as O, N, and S is at least 4:1. In some embodiments, the term "hydrophobic amino acid" refers to Gly, Ala, Val, Leu, Aic, Ile, Pro, Tyr, Phe, Eaa, naphthylalanine, and Trp, preferably Ala, Val, Leu, Ile, Pro, Tyr, Phe, and Trp.

[0140] "N-(C1-C6) alkylglycine" refers to an N-alkylated glycine in which the alkyl rest is (C1-C6) alkyl optionally substituted with one substituent, preferably selected from the group consisting of OH, NH2, NH, COOH, CONH2, and S.

[0141] An "S-alkylated cysteine" is a cysteine ​​that has been alkylated and then contains a sulfur atom that is part of a thioether functionality. Typical alkylating agents may be of benzylic nature. The alkylation is preferably carried out using (C1-C5) alkyl-(C5-C 10 ) leading to substitution by aryl or (C1-C6) alkyl residues.

[0142] An "aza-analogue" of an aromatic amino acid is an analogue in which one or more carbon atoms of each aromatic part of the amino acid are replaced by a nitrogen atom, preferably only one carbon atom is replaced by a nitrogen atom; for example, 7-aza-tryptophan [7Nw] is an exemplary aza-analogue of tryptophan.

[0143] When an amino acid contains more than one amino and / or carboxy group, all orientations of this amino acid are in principle possible for forming a covalent bond, but for α-amino acids, use of the α-amino and α-carboxy groups is preferred for attachment to neighboring moieties; if other orientations are preferred, they are explicitly specified.

[0144] Those skilled in the art will recognize whether stereocenters exist in the compounds disclosed herein, whether such centers are part of an amino acid moiety or any other part or moiety of the compounds of the invention. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0145] Unless indicated to the contrary, amino acid sequences are presented herein in an N- to C-terminal direction.

[0146] Those skilled in the art will recognize that Iva, Ac, 3OHPr, and 4OHPhp are carboxylic acid-containing building blocks. They are typically incorporated into the compounds of the present invention by forming an amide bond with an amino group of the peptide. In a preferred embodiment, they modify the N-terminus of the compounds of the present invention.

[0147] For example, one skilled in the art will understand that "Ac" as an abbreviation for acetic acid after forming an amide bond to its neighbor changes to "Ac-" to represent acetyl (bonded to any partner).

[0148] Linear peptides A typical linear peptide is typically written from N to C terminal as shown below: NT-Xaa1-Xaa2-Xaa3-Xaa4-....Xaan-CT;

[0149] among them, 1. Xaax is an abbreviation, descriptor, or symbol for the amino acid or building block at specific sequence position x as shown in Table 5; 2. NT is the structural formula of the N-terminal group, e.g., "H" (hydrogen for the free N-terminal amino group), or an abbreviation for a specific terminal carboxylic acid or other chemical group, such as "Ac" for acetic acid, or a chemical group linked via a hyphen to the N-terminal amino acid code (Xaa1); 3. CT is an abbreviation for the C-terminal group, typically "OH" or "NH2" (as a terminal carboxylic acid or amide), or a specific terminal amine linked via a hyphen to the C-terminal amino acid code (Xaan).

[0150] Branched peptides with side chains modified by specific building blocks or peptides A typical linear or branched peptide is written from N to C terminus as shown below: NT-Xaa1-Xaa2-Xaa3(NT-Xab1-Xab2-........Xabn)-........Xaan-CT

[0151] In this regard, statements 1. to 3. regarding the description of linear peptides apply to the specification of Xaax, NT, and CT in the backbone of branched peptides.

[0152] The point of branching is designated by parentheses after the Xaax abbreviation. Branching typically occurs at a lysine (Lys) residue (or similar), meaning that the branch is attached to the lysine side chain ε-amino function via an amide bond.

[0153] The contents of the parentheses describe the sequence / structure of the peptide branch "NT-Xab1-Xab2-.......Xabn". 1. Xabx is an abbreviation, descriptor, or symbol for the amino acid or building block at specific sequence position x of the branch as shown in Table 3; 2. NT is the structural formula of the N-terminal group, an abbreviation for a specific terminal carboxylic acid or other chemical group, such as "Ac" for acetic acid, or a chemical group linked via a hyphen to the N-terminal amino acid code (Xab1), 3. The final building block of the branch, Xabn, which connects the branch to the main chain by forming an amide bond with its own carboxyl function together with the side chain amino function of this lysine (or similar residue).

[0154] Cyclic peptides - Type I - with direct side chain to side chain cyclization - connection An exemplary generic Type I cyclic peptide, written from N to C-terminus, is shown below: NT-Xaa1-[Xaa2-Xaa3-Xaa4-.......Xaan]-CT;

[0155] In this context, statements 1. to 3. above regarding the description of linear peptides apply with regard to the specification of Xaax, NT, and CT in the backbone of cyclic peptides. The characteristics of the peptide ring are designated by square brackets.

[0156] 1. The left square bracket indicates the unit (ring-initiating residue) whose side chain initiates the ring, 2. The right bracket indicates a unit whose side chain terminates the ring (the ring-terminating residue).

[0157] In the exemplary generic cyclic peptide shown above, the side chain of Xaa2 is linked directly to the side chain of Xaan.

[0158] The chemical nature of the connection between these two residues is 1. Among those shown residues, if one residue 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), then an amide bond, or 2. Disulfide bonds if the indicated residues / amino acids contain sulfhydryl moieties (e.g., Cys) is.

[0159] Cyclic peptides - type II - have a bridging element that connects two side chains intramolecularly by forming a macrocycle An exemplary generic Type II cyclic peptide with a bridging element, written N to C-terminal, is shown below: NT-Xaa1-[Xaa2(3MeBn)-Xaa3-Xaa4-.......Xaan]-CT; 1. In that respect, statements 1. to 3. above regarding the description of linear peptides apply to the specification of Xaax, NT, and CT in the backbone of cyclic peptides. 2. Regarding the characteristics of the peptide ring, statements 1 and 2 for the description of cyclic peptides (Type I - with direct side chain to side chain cyclization - connection) apply. In Type II rings, both the ring-initial and ring-terminating residues are cysteines. Consequently, in the above generic formula, Xaa2 is Cys and Xaan is Cys. 3. Additionally, the "3MeBn" descriptor in parentheses immediately to the right of the ring-initiating residue Xaa2 indicates that a m-xylene (3-methylbenzylidene) unit is inserted into the peptide ring as a bridging element. Both cysteine ​​ring residue side chains (Xaa2 and Xaan) are connected to the respective methyl groups of the bridging m-xylene unit by thioether linkages.

[0160] In the exemplary generic cyclic peptide with the bridging element shown above, the side chain of Xaa2 is linked to the side chain of Xaan via a 3-methylbenzylidene unit. It will be apparent to those skilled in the art that the locations of the ring-initiation and ring-terminating residues can be at variable positions in the peptide sequence, as shown in each specific sequence of the compounds of the invention.

[0161] As a non-limiting example, the structure of DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Ser-Cys]-NH2 is depicted below.

[0162] [ka]

[0163] among them, 1. DOTA and APAc correspond to NT in the general formula. 2. Val, Tyr, Cys, Glu, pro, Asp, Trp, Leu, Thr, Trp, Ser, and Cys correspond to Xaa1 to Xaa12 in the general formula. 3. NH2 corresponds to CT in the general formula. 4. A left square bracket ("[") adjacent to the N-terminal cysteine ​​in a sequence indicates that a ring begins at this residue (ring-start residue). 5. A right square bracket ("]") adjacent to the N-terminal cysteine ​​in the sequence indicates that the ring terminates at this residue (ring-terminating residue). 6. The 3MeBn in parentheses adjacent to the Cys shown as the initiating residue designates the cyclization extension element, which is further bound to the Cys shown as the cyclization termination residue, to which the extension element is connected via a thioether linkage.

[0164] Bridged Cyclic Peptides - Type III - Possess both direct side chain to side chain cyclization-connection and cyclization with a bridging element that connects two side chains intramolecularly by forming an additional bridged macrocycle An exemplary general extended type III cyclic peptide, written from N to C-terminus, is shown below: NT-Xaa1-[Xaa2(3MeBn)-{Xaa3-Xaa4-Xaa5}.......Xaan]-CT; 1. Regarding the specification of Xaax, NT, and CT in the backbone of a cyclic peptide, statements 1. to 3. for the description of linear peptides apply. 2. Statements 2 and 3 for the description of cyclic peptides (type II - with a bridging element that connects two side chains intramolecularly by forming a macrocycle) apply. A ring with a bridging element is indicated by a left square bracket ("[") adjacent to the ring-initial residue on the left and a "3MeBn" descriptor in parentheses immediately to the right of the ring-initial residue, and a right square bracket ("]") adjacent to the ring-terminating residue on the right. 3.Furthermore, a. A left curly bracket ("{") instead of a left square bracket indicates the ring-initiation residue; b. A right curly brace ("}") instead of a right square bracket indicates a ring-terminating residue The statements made for the description of cyclic peptides (type I) apply, except that:

[0165] In the exemplary generic bridged cyclic peptide shown above, the side chain of Xaa2 is linked to the side chain of Xaan via a 3-methylbenzylidene unit, and the side chain of Xaa3 is linked in tandem to the side chain of Xaa5. It will be apparent to those skilled in the art that the locations of both ring-initiation and both ring-terminating residues can be at variable positions in the peptide sequence, as shown in each specific sequence of the compounds of the invention.

[0166] As a non-limiting example, the structure of DOTA-APAc-Val-{Asp-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Dap}-Cys]-NH2 is depicted below.

[0167] [ka]

[0168] among them, 1. DOTA and APAc correspond to NT in the general formula. 2. Val, Asp, Cys, Glu, Pro, Asp, Trp, Leu, Thr, Trp, Dap, and Cys correspond to Xaa1 to Xaa12 in the general formula. 3. NH2 corresponds to CT in the general formula. 4. A left square bracket ("[") immediately to the left of the N-terminal cysteine ​​(Cys) in the sequence indicates that a ring begins at this residue (ring-start residue). 5. A right square bracket ("]") immediately to the right of the N-terminal cysteine ​​(Cys) in the sequence indicates that the ring terminates at this residue (ring-terminating residue). 6. The 3MeBn in parentheses adjacent to the Cys shown as the initiating residue designates the cyclization bridge element, which is further attached to the Cys shown as the cyclization-terminating residue. The bridge element is connected to said residue via a thioether linkage. 7. The immediate left curly brace ("{") to the left of the N-terminal aspartic acid (Asp) in the sequence indicates that a direct side chain to side chain ring begins at this residue (ring-initiator residue). 8. The immediate right curly brace ("}") to the right of diaminopropionic acid (Dap) in the sequence indicates that a direct side chain to side chain ring terminates at this residue (a ring-terminating residue). 9. The side chains of Asp and Dap are connected to each other so that the direct peptide ring is a macrolactam.

[0169] In this disclosure, when a compound of the present invention is referred to by a specific code name 3BP-XYZ, such as 3BP-4452 or 3BP-4501, this code name may be used interchangeably with the code name DPI-XYZ (the two names 3BP-XYZ and DPI-XYZ therefore define the same compound). Thus, for example, a compound referred to as 3BP-4452 may also be referred to as DPI-4452, and vice versa.

[0170] The term "effector" characterizes a chemical moiety and / or element (e.g., a naturally occurring or synthetic substance) attached to a peptide for the purpose of diagnostic and / or therapeutic intervention with respect to CAIX receptor-related diseases and / or cancer cells. In some embodiments, the term "effector" should be understood as a moiety (e.g., a chromophore, a fluorophore, a radiolabeled moiety, a chelator containing a chelated diagnostically active nuclide) that allows and / or facilitates detection and / or visualization of the complementary moiety to which it is attached. For example, the moiety can be detected and / or visualized by molecular imaging techniques known in the art, such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), etc. In some embodiments, the term "effector" should be understood as a pharmacologically active substance (e.g., a chelator containing a chelated therapeutically active nuclide, a cytotoxic drug) that can inhibit or prevent the function of a cell and / or kill a cell. In some embodiments, the term "effector" should be understood to be synonymous with other terms commonly used in the art, such as "cytotoxic agent," "toxin," or "drug" as used in the field of cancer therapy.

[0171] The term "chromophore" refers to an organic or metallo-organic compound capable of absorbing electromagnetic radiation in the range of 350 nm to 1100 nm, or any subrange thereof, such as 350 to 500 nm or 500 to 850 nm, or 350 to 850 nm.

[0172] The term "phosphorophore" refers to a compound that, when excited by exposure to light of a particular wavelength, emits light at a different wavelength and at a lower intensity for an extended period of time, for example, up to several hours.

[0173] The term "fluorophore" refers to a chemical compound that, when excited by exposure to light of a particular wavelength, emits light at a different (higher) wavelength. Fluorophores are usually described in terms of their emission profile or "color." For example, green fluorophores such as Cy3 or FITC generally emit at wavelengths in the range of 515-540 nm, while red fluorophores such as Cy5 or tetramethylrhodamine generally emit at wavelengths in the range of 590-690 nm. The term "fluorophore" should be understood to encompass, among other things, organic fluorescent dyes such as fluorescein, rhodamine, AMCA, Alexa Fluor dyes (e.g., Alexa Fluor 647), and biological fluorophores.

[0174] The term "chelator" or "chelating agent" refers to a molecule containing a single central metal ion and two or more electron donor atoms that can form coordinate bonds with, for example, a radionuclide. Typically, chelators coordinate to the metal ion through oxygen, nitrogen, or sulfur donor atoms, or a combination thereof. After the first coordinate bond is formed, each successive donor atom that binds creates a ring containing the metal ion. A chelator can be bidentate, tridentate, tetradentate, etc., depending on whether it contains two, three, four, or more donor atoms that can bind to the metal ion. However, the chelation mechanism is not fully understood and depends on the chelator and / or the radionuclide. For example, DOTA can coordinate to a radionuclide through its carboxylate and amino groups (donor groups), thus forming a complex with high stability (Dai et al., Nature Com. 2018, 9, 857). The term "chelating agent" should be understood to include chelators and their salts. Chelators having carboxylic acid groups, such as DOTA, TRITA, HETA, HEXA, EDTA, DTPA, etc., can be derivatized to convert one or more carboxylic acid groups to amide groups, for example, for attachment to a compound, i.e., to a reactive moiety or linker; alternatively, for example, the compound can be derivatized to allow attachment to a compound via one of the CH2 groups in the chelate ring.

[0175] The term "radionuclide," as used herein, refers to an atom having an unstable nucleus, a nucleus characterized by excess energy released by various types of radioactive decay. Radionuclides can be naturally occurring or artificially produced. In one embodiment, references to "nuclide" made in the specification and claims should preferably be understood as references to "radionuclide."

[0176] As used herein, the phrase or term "drug-derived moiety" refers to a moiety corresponding to a natural drug that differs from the natural drug only by the structural modification required for attachment to a proximal moiety, such as a reactive moiety, linker, or branching group contained in the compounds of the invention. This may involve a covalent bond formed by an existing functional group (available in the natural drug) or a covalent bond and proximal functional group newly introduced for this purpose. Consequently, the drug may be used in its unmodified form (except for, for example, replacement of a hydrogen atom by a covalent bond), or it may be chemically modified to incorporate a functional group that allows for covalent attachment to a reactive moiety, linker, or branching group contained in the compounds of the invention. As used herein, the phrase or term "drug-derived moiety" is intended to encompass both meanings.

[0177] In a similar manner, the term "derivative" is used to characterize moieties attached to proximal moieties that differ from the molecule from which they are derived only by the structural elements involved in the attachment to the proximal moiety. This may involve a covalent bond formed by an existing functional group, or a covalent bond and proximal functional group newly introduced for this purpose.

[0178] As preferably used, "linker" refers to an element, moiety, or structure that separates or spaces two parts of a molecule.

[0179] A "pharmaceutically acceptable salt" of a compound of the present invention is preferably an acidic or basic salt generally considered in the art to be suitable for use in contact with human or animal tissues without excessive toxicity or carcinogenicity, and more preferably without irritation, allergic response, or other problems or complications. Such salts include inorganic 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 also form internal salts that are pharmaceutically acceptable.

[0180] Suitable pharmaceutically acceptable salts include those of hydrochloric acid, phosphoric acid, hydrobromic 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 These salts include, but are not limited to, salts of acids such as -COOH, where 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 base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, the use of nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred.

[0181] 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 the 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 excessive toxicity or carcinogenicity, more preferably without irritation, allergic response, or other problems or complications. Such solvents include organic solvents such as alcohols, ethers, esters, and amines.

[0182] "Hydrates" of the compounds of the present invention are formed by the association of one or more water molecules with one or more molecules of the compounds of the present invention. Such hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and tetrahydrates. Regardless of hydrate composition, all hydrates are generally considered to be pharmaceutically acceptable.

[0183] Hereinafter, in this description and claims of the present invention, use of the terms "comprising" and "including" should be understood so that, in addition to the listed elements, additional unlisted elements may be present. However, these terms should also be understood to disclose, as a more limited embodiment, the term "consisting of," insofar as this makes technical sense, such that no additional unlisted elements may be present.

[0184] Unless otherwise specified or the context dictates otherwise, references to "substituted" or "optionally substituted" groups include, but are not limited to, F, Cl, Br, I, CN, NO, NH, NH-(C-C)alkyl, N[(C-C)alkyl], -X-(C-C)alkyl, -X-(C-C)alkenyl, -X-(C-C)alkynyl, -X-(C-C 14 )aryl, -X-(5- to 14-membered heteroalkyl having 1 to 3 heteroatoms selected from N, O, S), where X represents a single bond, -(CH2)-, -O-, -S-, -S(O)-, -S(O)2-, -NH-, -CO-, or any combination thereof, including, for example, -C(O)-NH-, -NH-C(O)-. The number of substituents is not particularly limited and can range from 1 to the maximum valency that can be saturated with substituents. This is typically 1, 2, or 3, usually 1 or 2, and most typically 1. Furthermore, for example with respect to Xaa7, the term "substituted" refers to the substituent NH-R as defined in the context of formulas (4a) and (4b), respectively. 7a and NH-R 7d It also extends to.

[0185] Unless otherwise specified, all valencies of individual atoms of compounds or moieties described herein are saturated. In particular, they are saturated by the indicated binding partners. When no binding partners or too few binding partners are indicated, the remaining valencies of each atom are saturated by the corresponding number of hydrogen atoms.

[0186] Unless otherwise specified, chiral compounds and moieties can exist in the form of pure stereoisomers or in the form of mixtures of stereoisomers, including 50:50 racemates. In the context of this invention, reference to a specific stereoisomer should be understood as a reference to a compound or moiety in which the specified stereoisomer is present in at least 90% enantiomeric excess (ee), more preferably at least 95% ee, and most preferably 100% ee, where % ee is defined as (|RS|) / (R+S)*100%, where R and S represent the molar amount of each enantiomer.

[0187] Unless the context dictates otherwise and / or an alternative meaning is expressly provided herein, all terms are intended to have their generally accepted meaning in the art as reflected by the IUPAC Gold Book (status as of December 1, 2021) or the Dictionary of Chemistry, Oxford, 8th Edition.

[0188] 2.Chemical compounds, peptides, CAIX-binding compounds, CAIX-binding peptides The present invention relates to chemical compounds, peptides, carbonic anhydrase IX (CAIX) binding compounds, and carbonic anhydrase IX (CAIX) binding peptides.

[0189] The present inventors have surprisingly found that the compounds of the present invention exhibit high affinity for carbonic anhydrase IX. Furthermore, the present inventors have surprisingly found that the compounds of the present invention exhibit other characteristics that make them particularly suitable for use in the diagnosis and therapy of diseases involving carbonic anhydrase IX. Such other characteristics include high stability in plasma and selectivity for carbonic anhydrase IX over other isoforms of carbonic anhydrase, and in particular carbonic anhydrase XII.

[0190] Without wishing to be bound by any theory, it is believed that the cyclic peptide structure formed by the amino acids Xaa3-Xaa12 defined herein, which includes an aromatic group as the hydrophobic moiety in the bridge between the amino acid residue Xaa3 and the aminothiol residue Xaa12, leads to high affinity for carbonic anhydrase IX.

[0191] The inventors have also found that preferred compounds of the present invention contain certain core structures or motifs.

[0192] In one embodiment (A), such a core structure is formed by the hydrophobic portion provided by amino acid residues Xaa7, Xaa8, and Xaa10 and the aromatic group in the bridge between amino acid residue Xaa3 and aminothiol residue Xaa12, with Xaa1 being absent.

[0193] Without wishing to be bound by any theory, it is believed that the core structure formed by Xaa7, Xaa8, and Xaa10 confers high affinity for CAIX, while other amino acids and their residues in the cyclic peptide may further enhance affinity and / or provide appropriate and stable spacing and orientation of the listed fragments or groups.

[0194] In a preferred embodiment of embodiment (A), Xaa7 is a residue of an optionally substituted aromatic L-α-amino acid, preferably an optionally substituted Phe residue or an optionally substituted Trp residue, more preferably an optionally substituted Phe residue, most preferably a substituted Phe residue of formula (4a) or (4b) as specified herein (the term "herein" means in the present specification and / or claims); and / or Xaa8 is a residue of a cyclic α,α-dialkyl amino acid, such as Egz, Ega, Aic, Thp, or a residue of an aliphatic L-α-amino acid, such as Leu, Npg, Nle, or Cha, more preferably a residue of a natural aliphatic L-α-amino acid, such as Leu; and / or Xaa10 is Trp or a derivative of Trp such as Trp substituted with a substituent selected from the group consisting of methyl, halogen, or OH, or an aza-analogue of Trp optionally substituted with methyl, halogen, or OH, preferably Trp.

[0195] In a further preferred aspect of embodiment (A), the above meanings of Xaa7, Xaa8, and Xaa10 are combined with at least one, e.g. one, two, three, four, or five, preferably all, of the following preferred meanings of the remaining residues: Xaa2 is preferably a residue of an amino acid selected from the group consisting of polar L-α-amino acids and charged L-α-amino acids, more preferably a residue of a naturally occurring polar L-α-amino acid such as Gln or a naturally occurring charged amino acid such as Glu; and / or Xaa3 is preferably a residue of an α-amino acid of formula (X) as specified herein, having the (R) configuration at the α-C-atom, more preferably L-Cys; and / or Xaa4 is preferably a residue of an amino acid selected from the group consisting of polar and charged L-α-amino acids, more preferably a naturally occurring polar L-α-amino acid such as Gln or a naturally occurring charged amino acid such as Glu; and / or Xaa5 is preferably a residue of a D-α-amino acid, Gly, Nmg, more preferably a hydrophobic D-α-amino acid, most preferably a hydrophobic D-α-amino acid such as D-pro and D-pip; and / or Xaa6 is preferably an amino acid selected from the group consisting of polar and charged L-α-amino acids, more preferably a residue of a naturally occurring polar or charged (e.g. acidic) L-α-amino acid such as Asn or Asp; and / or Xaa9 is preferably an L-α-amino acid, more preferably a polar L-α-amino acid, most preferably a residue of a polar natural L-α-amino acid such as Thr; and / or Xaa11 is preferably an L-α-amino acid, more preferably a polar L-α-amino acid, most preferably a residue of a polar natural L-α-amino acid such as Ser; and / or Xaa12 is preferably the residue of an aminothiol of formula (XII) as specified herein, more preferably Xaa12 is the residue of an aminothiol of formula (XIIa).

[0196] In a preferred embodiment of embodiment (A), Y comprises an effector E1, such as a chelator optionally comprising a chelated (radio)nuclide, which effector E1 is covalently linked to Xaa2 (if Xaa1 is absent); or Z1, which comprises a linker moiety L1 and an effector E1, such as a chelator optionally comprising a chelated (radio)nuclide, which linker moiety L1 covalently links effector E1 to Xaa2 (if Xaa1 is absent). Preferred embodiments of the effector, chelator, and optional linker L1 are described herein and in the claims.

[0197] In a more preferred aspect of embodiment (A), Xaa7 is an amino acid of formula (4a) or (4b) as specified herein, preferably R 7e or R 7g are OH, SO2NH2, and SO2NH-R, respectively. 7f, CO(NHOH), COOH, CONH2, and NH, more preferably -SO2NH2 or -COOH.

[0198] Further suitable embodiments of the above meanings for Y and Xaa2 to Xaa12 disclosed in connection with embodiment (A) are described in the present specification and claims.

[0199] In accordance with embodiment (Ab), the compounds of embodiment (A) are modified, for example, to accommodate the bicyclic peptide structure (1b).

[0200] The compounds of embodiment (Ab) have the same preferred meanings for Y, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, and Xaa12 as specified above. With regard to Xaa2 and Xaa11, the following applies: Xaa2 is a residue of an L-α-amino acid containing, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is a residue of an L-α-amino acid containing, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2. The functional groups FG1 and FG2 can be selected from the preferred embodiments described herein. FG1 is a carboxy group, e.g., as in Glu, and FG2 is an amino group, e.g., as in (S)-2,3-diaminopropionic acid [dap].

[0201] Alternatively, a second ring can be formed in embodiment (Ab) and bicyclic peptide structure (1b) where Xaa2 is Asp and Xaa11 is Dap, Xaa2 is Dap and Xaa11 is Asp, or Xaa2 is Dap and Xaa11 is Glu.

[0202] Further suitable embodiments of the above meanings for Y and Xaa2 to Xaa12 disclosed in connection with embodiment (Ab) are described in the present specification and claims.

[0203] In one embodiment (B) of the compounds of the present invention, such a core structure is formed by the hydrophobic portion provided by amino acid residues Xaa7, Xaa8, and Xaa10 and the aromatic group in the bridge between amino acid residue Xaa3 and aminothiol residue Xaa12, and the compounds of embodiment (B) further comprise amino acid residue Xaa1 when compared to the compounds of embodiment (A).

[0204] In a preferred embodiment of embodiment (B), Xaa7 is a residue of an optionally substituted aromatic L-α-amino acid, preferably an optionally substituted Phe residue or an optionally substituted Trp residue, more preferably a substituted Phe residue, most preferably a substituted Phe residue of formula (4a) or (4b) as specified herein (the term "herein" means in the present specification and / or claims); and / or Xaa8 is a residue of a cyclic α,α-dialkyl amino acid, such as Egz, Ega, Aic, Thp, or a residue of an aliphatic L-α-amino acid, such as Leu, Npg, Nle, or Cha, more preferably a residue of a natural aliphatic L-α-amino acid, such as Leu; and / or Xaa10 is Trp or a derivative of Trp such as Trp substituted with a substituent selected from the group consisting of methyl, halogen, or OH, or an aza-analogue of Trp optionally substituted with methyl, halogen, or OH, preferably Trp.

[0205] In a further preferred aspect of embodiment (B), the above meanings of Xaa7, Xaa8, and Xaa10 are combined with at least one, e.g. one, two, three, four, or five, preferably all, of the following preferred meanings of the remaining residues: Xaa1 is selected from the group consisting of Val, Ile, Tle, Thr, and Ser, preferably selected from the group consisting of Val, Ile, and Ser; and / or Xaa2 is preferably a residue of an amino acid selected from the group consisting of polar, aromatic and charged L-α-amino acids, preferably a naturally occurring polar L-α-amino acid such as Gln or Ser, a naturally occurring aromatic L-α-amino acid such as Tyr or Phe, or a naturally occurring charged amino acid such as Glu or Arg; and / or Xaa3 is preferably a residue of an α-amino acid of formula (X) as specified herein, having the (R) configuration at the α-C-atom, more preferably L-Cys; and / or Xaa4 is preferably a residue of an amino acid selected from the group consisting of polar and charged L-α-amino acids, preferably a naturally occurring polar L-α-amino acid such as Gln, or a naturally occurring charged amino acid such as Glu; and / or Xaa5 is preferably a residue of a D-α-amino acid, Gly, Nmg, preferably a hydrophobic D-α-amino acid, more preferably a hydrophobic D-α-amino acid such as D-pro and D-pip; and / or Xaa6 is preferably an amino acid selected from the group consisting of polar and charged L-α-amino acids, more preferably a residue of a naturally occurring polar or charged (e.g. acidic) L-α-amino acid such as Asn or Asp; and / or Xaa9 is preferably an L-α-amino acid, more preferably a polar L-α-amino acid, most preferably a residue of a polar natural L-α-amino acid such as Thr; and / or Xaa11 is preferably an L-α-amino acid, more preferably a polar L-α-amino acid, most preferably a residue of a polar natural L-α-amino acid such as Ser; and / or Xaa12 is preferably the residue of an aminothiol of formula (XII) as specified herein, more preferably Xaa12 is the residue of an aminothiol of formula (XIIa).

[0206] In a preferred embodiment of embodiment (B), Y comprises an effector E1, such as a chelator optionally comprising a chelated (radio)nuclide, which effector E1 is covalently linked to Xaa2 (if Xaa1 is absent); or Z1, which comprises a linker moiety L1 and an effector E1, such as a chelator optionally comprising a chelated (radio)nuclide, which linker moiety L1 covalently links effector E1 to Xaa2 (if Xaa1 is absent). Preferred embodiments of the effector, chelator, and optional linker L1 are described herein and in the claims.

[0207] In a more preferred aspect of embodiment (B), Xaa7 is an amino acid of formula (4a) or (4b) as specified herein, preferably R 7e or R 7g are OH, SO2NH2, and SO2NH-R, respectively. 7f , CO(NHOH), COOH, CONH2, and NH, more preferably -SO2NH2 or -COOH.

[0208] Further suitable embodiments of the above meanings for Y and Xaa1 to Xaa12 disclosed in connection with embodiment (B) are described in the present specification and claims.

[0209] In accordance with embodiment (Bb), the compound of embodiment (B) is modified, for example, to accommodate the bicyclic peptide structure (1b).

[0210] The compounds of embodiment (Bb) have the same preferred meanings for Y, Xaa1, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, and Xaa12 as specified above. With regard to Xaa2 and Xaa11, the following applies: Xaa2 is a residue of an L-α-amino acid containing, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is a residue of an L-α-amino acid containing, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2. The functional groups FG1 and FG2 can be selected from the preferred embodiments described herein. FG1 is a carboxy group, e.g., as in Glu, and FG2 is an amino group, e.g., as in (S)-2,3-diaminopropionic acid [dap].

[0211] Alternatively, a second ring can be formed in embodiment (Bb) and bicyclic peptide structure (1b) where Xaa2 is Asp and Xaa11 is Dap, Xaa2 is Dap and Xaa11 is Asp, Xaa2 is Dap and Xaa11 is Glu, Xaa2 is Glu and Xaa11 is Dap, or Xaa2 is Cys and Xaa11 is Cys.

[0212] Further suitable embodiments of the above meanings for Y and Xaa1 to Xaa12 disclosed in connection with embodiment (Bb) are described in the present specification and claims.

[0213] Further embodiments of the compounds (peptides) of the invention, as well as the broadest meanings used in connection with Y and Xaa1 to Xaa12, are explained in more detail below.

[0214] The present invention relates to a compound of the following formula (1a):

[0215] [ka]

[0216] The present invention relates to a compound comprising or to a peptide represented by

[0217] In formula (1a), Y is (i)R 0a -SO2-, R0a -CO-, R 0a an N-terminal modifying group A selected from the group consisting of —NH—CO—, wherein R 0a is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C 10 ) an N-terminal modifying group A selected from the group consisting of aryl; (ii) a moiety comprising (or consisting of) effector E1, wherein effector E1 is covalently linked to Xaa1 if Xaa1 is present, or to Xaa2 if Xaa1 is absent and Xaa2 is present, or to Xaa3 if both Xaa1 and Xaa2 are absent; and (iii) a Z1 group, Z1 comprising a linker moiety L1 and an effector E1, wherein the linker moiety L1 covalently links the effector E1 to Xaa1, if Xaa1 is present, or to Xaa2, if Xaa1 is absent and Xaa2 is present, or to Xaa3, if both Xaa1 and Xaa2 are absent; is a moiety selected from

[0218] In some embodiments, Y is (i) an N-terminal modifying group A selected from the group consisting of 3-methylbutanoyl [Iva], acetyl [Ac], hexanoyl [Hex], benzoyl [Bz], phenylacetyl [Pha], and propionyl [Prp]. Preferably, Y is Ac.

[0219] In some embodiments, Y is (ii) a moiety that comprises (or consists of) an effector E1, wherein the effector is (α) (α1) a phosphorophore, and (α2) a moiety derived from a chromophore, preferably selected from a fluorophore such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug is selected from the group consisting of:

[0220] In some embodiments, Y is (iii) a Z group, where Z comprises a linker moiety L and an effector E, and the linker moiety L provides (a) a carboxy group that forms an amide bond with the α-amino group provided by Xaa, if Xaa, is present, or with the α-amino group provided by Xaa2, if Xaa is absent and Xaa2 is present, or with the α-amino group provided by Xaa3, if both Xaa and Xaa2 are absent, and (b) an amino group that forms a covalent bond to the effector.

[0221] In one embodiment, the linker moiety L1 (however, the following description also applies to linker moieties L3, L4, and L6) is an optionally cleavable group comprising 1 to 10 amino acids, and / or the effector is as defined above. In particular, the linker can be an amino acid or a peptide of up to 10 amino acids, which are independently selected from the group comprising natural amino acids, unnatural amino acids, α-amino acids, and amino acids in which the amino and carboxylic acid groups are further spaced apart, such as β-amino acids, γ-amino acids, δ-amino acids, ε-amino acids, and ω-amino acids.

[0222] The linker may also allow for release of an effector, e.g., a conjugated drug. Preferably, the effector (e.g., a drug) is released while the compound of the invention is bound to a tumor cell or is within or in close proximity to a tumor, e.g., in the tumor environment.

[0223] The effector (e.g., drug) may be released enzymatically, proteolytically (preferably by tumor-specific proteases), by other enzymes (preferably tumor-specific proteases), due to the half-life of the conjugation (chemical or biological instability), by pH shifts in the tumor environment, tumor metabolites, proteins, carbohydrates, lipids, or nucleic acids present in the tumor, co-administered agents, external or endoscopic treatment, electromagnetic radiation (gamma, x-ray, ultraviolet, visible, infrared, microwave radio), ultrasound, magnetic fields, temperature (heating and / or cooling), or physical treatment.

[0224] In one embodiment, the linker is cleavable under intracellular conditions, such that cleavage of the linker liberates the effector (e.g., drug) from the compound of the invention in the intracellular environment. In some embodiments, the linker is cleaved by a cleaving agent present in the intracellular environment (e.g., within a lysosome, endosome, or caveolae). The linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids in length or at least three amino acids in length. Cleavage agents can include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives, resulting in the release of the effector (e.g., active drug) inside target cells (see, e.g., Dubowchik and Walker, Pharm. Therapeutics, 1999, 83, pp. 67-123). In specific embodiments, the peptidyl linker cleavable by an intracellular protease is a Val-Cit (valine-citrulline) linker or a Phe-Lys (phenylalanine-lysine) linker (see, e.g., U.S. Pat. No. 6,214,345, which describes the synthesis of doxorubicin with various examples of Val-Cit and Phe-Lys linkers). Exemplary Val-Cit and Phe-Lys linker structures include, but are not limited to, MC-vc-PAB, MC-vc-GABA, MC-Phe-Lys-PAB, or MC-Phe-Lys-GABA, where MC is an abbreviation for maleimidocaproyl, vc is an abbreviation for Val-Cit, PAB is an abbreviation for p-aminobenzylcarbamate, and GABA is an abbreviation for γ-aminobutyric acid.

[0225] The advantage of using intracellular proteolytic release of a therapeutic agent is that the agent is typically weakened when conjugated, and the serum stability of the conjugate is typically high. In yet another embodiment, the linker unit is non-cleavable, and the drug is released by degradation of the NTR1 tracer unit (see U.S. Patent Application Publication No. 2005 / 0238649). Typically, such a linker is substantially insensitive to the extracellular environment. As used herein, "substantially insensitive to the extracellular environment" in the context of a linker means that when the NTR1 tracer drug conjugate compound is present in an extracellular environment (e.g., plasma), no more than 20%, typically no more than about 15%, more typically no more than about 10%, and even more typically no more than about 5%, no more than about 3%, or no more than about 1% of the linkers in a sample of the NTR1 tracer drug conjugate compound are cleaved. Whether a linker is substantially insensitive to the extracellular environment can be determined, for example, by incubating the NTR1 tracer drug conjugate compound with plasma for a predetermined period of time (e.g., 2, 4, 8, 16, or 24 hours) and then quantifying the amount of free drug present in the plasma.

[0226] The enzymatically cleavable sequence is shown below: a) Dipeptides: -Phe-Lys-, -Ala-Lys-, -Val-Lys-, -Val-Cit-, -Phe-Cit-, -Ile-Cit-, -Leu-Cit-, -Trp-Cit-, -Phe-Ala-, and -Phe-Arg-; and b) tripeptides: -Phe-Phe-Lys-, -Val-Phe-Lys-, and -Gly-Phe-Lys-; and c) Tetrapeptides: -Gly-Phe-Leu-Gly and -Ala-Leu-Ala-Leu-.

[0227] The linker moiety can be optimized for its sensitivity and selectivity for enzymatic cleavage by a particular enzyme, such as a tumor-associated protease, hi one embodiment, the linker is cleaved by cathepsin B, C, or D, or by plasmin protease.

[0228] In one embodiment, the linker is a dipeptide, tripeptide, or tetrapeptide. In a further embodiment, a preferred linker moiety comprises a Gly residue at the C-terminus. In another embodiment, the linker comprises a Gly-Gly dipeptide at the C-terminus. In yet another embodiment, the linker comprises a C-terminal dipeptide unit that can act as a highly specific substrate for the exopeptidase activity of Cat B (exo-Cat B). Examples of exo-Cat B cleavable linker systems are described in WO 2019 / 096867 A1. In particular, the linker may comprise a C-terminal dipeptide unit ("Axx-Ayy" or "Ayy-Axx") as defined in claim 1, 2, or 3 of WO 2019 / 096867 A1.

[0229] In this context, "self-immolative" linkers are another valuable tool. The main function of these types of linkers is to release the effector unit, preferably in its unmodified or at least effective form, after selective triggered activation via spontaneous chemical degradation. A commonly used concept that utilizes the protease cleavage described above as the initial trigger combines this with a para-amino-benzyl type (PAB) self-immolative linker that is attached to the drug as a carbamate or carbonate. A representative example of this type of combination is -Val-Cit-PAB-OC-tubulysin / cryptophycin / paclitaxene / SN-38.

[0230] In one embodiment, the linker moiety L1 is selected from the group consisting of X11 and X11-X12, where X11 and X12 are each and individually residues of an amino acid, and when the linker moiety L1 is X11, the carboxy group is provided by X11; when the linker moiety L1 is X11-X12, the carboxy group is provided by X12, and the carboxy group of L1 forms an amide bond with the α-amino group provided by Xaa1, if Xaa1 is present, or with the α-amino group provided by Xaa2, if Xaa1 is absent and Xaa2 is present, or with the α-amino group provided by Xaa3, if both Xaa1 and Xaa2 are absent; and X11 provides the amino group that forms the covalent bond to the effector.

[0231] Preferably, X11 and X12 are each and individually selected from 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and an amino acid according to any one of the following formulae (32) to (34):

[0232] [ka]

[0233] and its ortho- and para-substituted isomers, and

[0234] [ka]

[0235] is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formulas (32) and (33) are optionally substituted.

[0236] The amino acids of formulas (32) and (33) have R at the α-carbon atom covalently bonded to the COOH group in formulas (32) and (33). X11 -CO-NH-, wherein R X11 is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C 10 ) aryl. Preferably, R X11 is methyl.

[0237] More preferably, X11 and X12 are each and individually selected from 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and a compound of formula (35):

[0238] [ka]

[0239] The residue is an amino acid selected from the group consisting of the ε-amino acids

[0240] Xaa1 is present or absent, and if present, is the residue of an aliphatic or polar L-amino acid. When Xaa1 represents an aliphatic L-amino acid, it is preferably an aliphatic L-α-amino acid that may be selected from natural or non-natural aliphatic L-α-amino acids.

[0241] When Xaa1 represents a polar L-amino acid, the polar L-amino acid is preferably a polar L-α-amino acid which may be selected from natural polar L-α-amino acids or non-natural polar L-α-amino acids.

[0242] In preferred embodiments, Xaa1 is selected from the group consisting of Val, Ile, (2S)-2-amino-3,3-dimethylbutanoic acid [Tle], Ser, and Thr. In other preferred embodiments, Xaa1 is absent.

[0243] Xaa2 is present or absent, and when Xaa2 is absent, Xaa1 is also absent; when Xaa2 is present, (i) Xaa2 is the residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom, or (ii) Xaa2 is the residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is the residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2, and has the formula (1b):

[0244] [ka]

[0245] A bicyclic peptide of the formula:

[0246] (i) When Xaa2 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom, it may be selected from natural or unnatural α-amino acids. According to this embodiment, Xaa2 is preferably a residue of an L-α-amino acid that is optionally N-methylated and selected from the group consisting of aromatic amino acids, polar amino acids, and charged amino acids. (i) It is further preferred that Xaa2 represents a polar, optionally N-methylated L-α-amino acid, which may be selected from natural polar L-α-amino acids (e.g., Gln or Glu) or unnatural polar L-α-amino acids.

[0247] In preferred embodiments, (i) Xaa2 is a residue of an L-α-amino acid selected from the group consisting of Tyr, (S)-N-methyl-tyrosine [Nmy], Phe, Gln, Arg, (S)-dimethylornithine [Dmo], Ser, Thr, Asp, Glu, and Glu(AGLU). In more preferred embodiments, (i) Xaa2 is a residue of an L-α-amino acid selected from the group consisting of Tyr, (S)-N-methyl-tyrosine [Nmy], Gln, Arg, (S)-dimethylornithine [Dmo], and Ser. Most preferably, (i) Xaa2 is Gln. According to these embodiments, Xaa1 is preferably absent.

[0248] (ii) When Xaa2 is a residue of an L-α-amino acid containing, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, the covalent linkage B1 is preferably selected from the group consisting of an amide linkage, a disulfide linkage, a thioether linkage, a thiourea linkage, a triazole linkage, a carbamate linkage, an amine linkage, a sulfonamide linkage, an ester linkage, a thioester linkage, an ether linkage, a urea linkage, and a hydrocarbon linkage. More preferably, the covalent linkage B1 is selected from the group consisting of an amide linkage or a disulfide linkage. Most preferably, the covalent linkage B1 is an amide linkage.

[0249] In some embodiments, the functional group FG1 of Xaa2 that forms the covalent linkage B1 with the functional group FG2 of Xaa11 is selected from the group consisting of NH2, NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonic acid ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne.

[0250] In a preferred embodiment, (ii) Xaa2 is a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, and Glu. More preferably, (ii) Xaa2 is a residue of Glu.

[0251] Furthermore, the functional group FG2 of Xaa11, which forms the covalent linkage B1 with the functional group FG1 of Xaa2, is preferably selected from the group consisting of NH2, NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne. In a preferred embodiment, Xaa11 (forming the covalent linkage B1 with Xaa2) is a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, and Glu. Most preferably, Xaa11 is a residue of (S)-2,3-diaminopropionic acid [Dap]. According to these embodiments, Xaa1 is preferably absent and Xaa2 is Glu.

[0252] Xaa3 is an α-amino acid, preferably an L-α-amino acid of formula (X):

[0253] [ka]

[0254] It is a residue.

[0255] In formula (X), R 3a and R 3b are each and independently selected from the group consisting of H and CH. In a preferred embodiment, R 3a and R 3b are both H. Most preferably, Xaa3 is a residue of (L)-Cys.

[0256] Xaa4 is an L-α-amino acid residue that is optionally N-methylated at the α-nitrogen atom. In a preferred embodiment, Xaa4 is an L-α-amino acid residue selected from the group consisting of aliphatic amino acids, polar amino acids, and charged amino acids. In a more preferred embodiment, Xaa4 is an L-α-amino acid residue selected from the group consisting of Ala, Ser, (S)-homoserine [Hse], (S)-N-methyl-serine [Nms], Gln, Asn, Glu, Asp, Dmo, and Glu(AGLU). In an even more preferred embodiment, Xaa4 is an L-α-amino acid residue selected from the group consisting of Ala, Ser, Glu, Gln, and (S)-homoserine [Hse]. Most preferably, Xaa4 is a Glu residue.

[0257] Xaa5 is a residue of an amino acid optionally linked to the moiety Z3, wherein Xaa5 is a residue of an amino acid selected from the group consisting of N-(C1-C6) alkylglycine, Gly, D-α-amino acids, and α,α-dialkylamino acids. It is particularly preferred that Z3 is absent from (not linked to) Xaa5.

[0258] When Xaa5 comprises a moiety Z3, Z3 is (i) an effector E3, or (ii) a moiety comprising an effector E3 and a linker moiety L3, wherein the effector E3 is preferably (α) (α1) a phosphorophore, and (α2) a moiety derived from a chromophore, preferably selected from a fluorophore such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug is selected from the group consisting of:

[0259] In some embodiments, Xaa5 is a residue of an amino acid from which Z3 is absent. In this case, Xaa5 is preferably a residue of an amino acid selected from the group consisting of Gly, N-methyl-glycine [Nmg], D-ala, D-pro, (R)-piperidine-2-carboxylic acid [D-pip], (R)-azetidine-2-carboxylic acid [D-aze], (R)-N-methyl-alanine [Nma], and 2-amino-isobutyric acid [Aib], more preferably a residue of D-pro.

[0260] In some embodiments, Xaa5 is the residue of an amino acid linked to moiety Z3, where Z3 is (i) an effector E3, or (ii) a moiety comprising an effector E3 and a linker moiety L3, in which case Xaa5 is preferably the residue of an amino acid selected from the group consisting of N-(C1-C4) alkylglycine, non-aromatic D-α-amino acid, non-aromatic N-methyl-D-α-amino acid, cyclic D-α-amino acid, and α,α-dialkylamino acid, which comprises at least one functional group that forms a covalent linkage with effector E3 or linker moiety L3. More preferably, Xaa5 is a residue of an amino acid selected from the group consisting of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and the effector E3 or linker moiety L3 is covalently attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap.

[0261] In a preferred embodiment, the bond connecting the effector E3 or the linker moiety L3 to the N atom other than the α-nitrogen atom is an amide bond. The linker moiety L3 may provide (a) a carboxy group that forms an amide bond with the N atom other than the α-nitrogen atom of any one of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and (b) an amino group that forms a covalent bond to the effector E3.

[0262] When present, the linker moiety L3 can be selected from the group consisting of X31 and X31-X32, where X31 and X32 are each and individually amino acid residues, and when the linker moiety L3 is X31, the carboxy group is provided by X31; when the linker moiety L3 is X31-X32, the carboxy group is provided by X32, and the carboxy group of L3 forms an amide bond with an N atom other than the α-nitrogen atom of any one of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and X3 provides the amino group that forms a covalent bond to the effector E3. Preferably, X31 and X32 are each and individually selected from 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and an amino acid according to any one of formulas (32) to (34):

[0263] [ka]

[0264] and its ortho- and para-substituted isomers, and

[0265] [ka]

[0266] is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formulas (32) and (33) are optionally substituted.

[0267] In some embodiments, the amino acids of formulas (32) and (33) have R at the α-carbon atom that is covalently bonded to the COOH group in formulas (32) and (33). X11 -CO-NH-, wherein R X11 is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C 10 ) aryl. Preferably, R X11 is methyl.

[0268] In a preferred embodiment, X31 and X32 are each and individually selected from 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and a compound of formula (35):

[0269] [ka]

[0270] The α-amino acids are residues of amino acids selected from the group consisting of:

[0271] Xaa6 can be selected from polar L-α-amino acids, aromatic L-α-amino acids, aliphatic L-α-amino acids, S-alkylated cysteines, oxidized forms of S-alkylated cysteines, and the amino acids represented by formula (3)

[0272] [ka]

[0273] and the residue of an amino acid selected from the group consisting of residues of amino acids according to During the ceremony, R 6a is H and -(C5~C 10 )aryl, (C1-C8)alkyl, and (C1-C5)alkyl-(C5-C 10 ) an aryl-containing moiety; R 6b is selected from the group consisting of H or methyl; R 6c is H or (C1-C6) alkyl, w is 0 or 1.

[0274] In some embodiments, Xaa6 is a residue of a polar N-methylated L-α-amino acid.

[0275] In some embodiments, Xaa6 is a residue of an aliphatic L-α-amino acid, which is preferably Ala.

[0276] In some embodiments, Xaa6 is a residue of an S-alkylated cysteine.

[0277] In some embodiments, Xaa6 is a residue of an oxidized form of an S-alkylated cysteine, preferably a sulfoxide or sulfone of an S-alkylated cysteine ​​(meaning that the S atom present in the side chain of the S-alkylated cysteine ​​is oxidized to form a sulfoxide or sulfone group).

[0278] In some embodiments, Xaa6 is a residue of an amino acid according to formula (3), and R 6a is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, (C1-C5)alkyl-(C5-C 10 )aryl, and (C3-C7)cycloalkyl-(C5-C 10 ) aryl. Preferably, R 6c is (C1-C4) alkyl.

[0279] In a preferred embodiment, Xaa6 is a residue of an amino acid selected from the group consisting of Ala, Asp, Asn, (S)-homoserine [Hse], Gln, Glu, Lys, (S)-ornithine [Orn], (S)-2,4-diaminobutyric acid [Dab], N-methyl-Asp, (S)-benzylcysteine ​​[C(Bzl)], (S)-2-amino-3-(quinolin-2-ylmethylsulfanyl)-propionic acid [C(2Quyl)], (S)-benzyl-cysteine ​​sulfone [Eem], (S)-4-benzyloxy-L-phenylalanine [Tyr(Bzl)], and (S)-2-amino-4-[(naphthalen-1-ylmethyl)-carbamoyl]-butyric acid [E(NHMe2Nph)]. More preferably, Xaa6 is a residue of Asp.

[0280] Xaa6 can be the residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG3 that forms a covalent linkage B2 with the functional group FG4 of Xaa11, and Xaa11 is the residue of an α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG4, and has the formula (1c):

[0281] [ka]

[0282] A bicyclic peptide of the formula:

[0283] The covalent linkage B2 is preferably selected from the group consisting of an amide linkage, a disulfide linkage, a thioether linkage, a thiourea linkage, a triazole linkage, a carbamate linkage, an amine linkage, a sulfonamide linkage, an ester linkage, a thioester linkage, an ether linkage, a urea linkage, and a hydrocarbon linkage, more preferably from the group consisting of an amide linkage or a disulfide linkage.

[0284] In some embodiments, the functional group FG3 of Xaa6, which forms the covalent linkage B2 with the functional group FG4 of Xaa11, may be selected from the group consisting of NH2, NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne. Xaa6 is preferably a residue of an α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, and Glu.

[0285] In some embodiments, the functional group FG4 of Xaa11 that forms the covalent linkage B2 with the functional group FG3 of Xaa6 is selected from the group consisting of NH2, NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne. Xaa11 is preferably a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, D-asp, D-glu, and Glu.

[0286] Xaa7 is a residue of an amino acid selected from the group consisting of aromatic amino acids, such as heteroaromatic L-α-amino acids, and substituted aromatic amino acids, such as substituted heteroaromatic L-α-amino acids. Preferably, Xaa7 is a residue of an aromatic amino acid optionally substituted on the aromatic ring system with at least one substituent. In some embodiments, the aromatic amino acid is selected from the group consisting of (S)-3-benzothienylalanine [Bta], Trp, and Phe.

[0287] In some embodiments, Xaa7 is selected from the group consisting of substituted (S)-3-benzothienylalanine [Bta], substituted Trp, substituted Phe, modified 3-aminophenylalanine [Af3(R 7c )]:

[0288] [ka]

[0289] and modified 4-aminophenylalanine [Aph(R 7d )]:

[0290] [ka]

[0291] is a residue of an amino acid selected from the group consisting of: During the ceremony, the substituted Bta and substituted Trp are each and individually substituted on the aromatic ring with a substituent selected from the group consisting of halogen, methyl, and OH; provided that in the substituted Bta and substituted Trp, one or two of the aromatic carbon atoms may be replaced by a N atom; A substituted Phe is substituted on the aromatic ring with one, two, or three substituents, each and any of which is individually and independently selected from halogen, methyl, OH, NH, OR, 7a wherein: R 7a is (C1-C6) alkyl, In formula (4a), R 7c HA-CO-R 7e and During the ceremony, R 7e is (C1-C5) alkyl, (C5-C 10 ) aryl, and (C5-C 10 ) heterocyclyl; (C1-C5) alkyl is OH, SO2NH2, SO2NH-R 7f , CO(NHOH), COOH, CONH2, and NH2; one alkyl carbon atom of the (C1-C5)alkyl is optionally replaced by an atom or moiety selected from the group consisting of ether oxygen and sulfone (SO2) moieties; (C5~C 10 ) Aryl is halogen, OH, SO2NH2, SO2NH-R 7f , CO(NHOH), COOH, CONH2, and NH2; (C5~C 10 )Heterocyclyl is halogen, OH, SO2NH2, SO2NH-R 7f, NH—SO—NH, CO(NHOH), COOH, CONH, and NH; During the ceremony, R 7f is (C1-C4) alkyl, In formula (4b), R 7d HA-CO-R 7g and During the ceremony, R 7g is (C2-C5) alkyl, (C5-C 10 ) aryl, and (C5-C 10 ) heterocyclyl, (C1-C5) alkyl is OH, SO2NH2, SO2NH-R 7h , CO(NHOH), COOH, CONH2, and NH2; one alkyl carbon atom of the (C2-C5)alkyl is optionally replaced by an atom or moiety selected from the group consisting of ether oxygen and sulfone (SO2) moieties; (C5~C 10 ) Aryl is halogen, OH, SO2NH2, SO2NH-R 7h , CO(NHOH), COOH, CONH2, and NH2; (C5~C 10 )Heterocyclyl is halogen, OH, SO2NH2, SO2NH-R 7h , NH—SO—NH, CO(NHOH), COOH, CONH, and NH; During the ceremony, R 7h is (C1-C4) alkyl.

[0292] In a preferred embodiment, Xaa7 is a residue of the amino acid Modified 3-aminophenylalanine [Af3(R 7c )]:

[0293] [ka]

[0294] Modified 4-aminophenylalanine [Aph(R 7d )]:

[0295] [ka]

[0296] and Xaa7 is selected from the group consisting of substituted Trp, substituted (S)-3-benzothienylalanine [Bta], (S)-3-(1-naphthyl)alanine [1Ni], (S)-4-benzyloxy-L-phenylalanine [Tyr(Bzl)], Tyr, substituted Phe, and (S)-benzylcysteine ​​[Cys(Bzl)], and preferably Xaa7 is selected from the group consisting of modified 3-aminophenylalanine [Af3(R 7c )] or modified 4-aminophenylalanine [Aph(R 7d )].

[0297] In a preferred embodiment, Xaa7 is selected from the group consisting of D / L-1-methyltryptophan [1MW], D / L-7-methyltryptophan [7MW], 5-chloro-tryptophan [5Clw], DL-5-methyl-tryptophan [Egc], substituted [Bta], (S)-4-benzyloxy-L-phenylalanine [Tyr(Bzl)], (S)-3-(1-naphthyl)alanine [1Ni], (2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid [Mtf], (2S)- 2-amino-3-[4-(trifluoromethyl)phenyl]propanoic acid [Ptf], (S)-3,4-dichlorophenylalanine [Eaa], 4-(tert-butyl)-phenylalanine [Eap], (2S)-2-amino-3-(4-iodophenyl)propanoic acid [Pif], (S)-biphenylalanine [Bip], (S)-3,3-diphenylalanine [Dip], (S)-benzylcysteine ​​[Cys(Bzl)], modified 3-aminophenylalanine of formula (4a) [Af3(R 7c)], and modified 4-aminophenylalanine [Aph(R 7d ), wherein R 7c teeth,

[0298] [ka]

[0299] and preferably R 7c teeth,

[0300] [ka]

[0301] wherein R 7d teeth,

[0302] [ka]

[0303] is selected from the group consisting of: 7d teeth,

[0304] [ka]

[0305] is selected from the group consisting of:

[0306] In a more preferred embodiment, Xaa7 is a modified 3-aminophenylalanine [Af3(R 7c )] and modified 4-aminophenylalanine [Aph(R 7d ), wherein: R 7c teeth,

[0307] [ka]

[0308] wherein R 7d teeth,

[0309] [ka]

[0310] is selected from the group consisting of:

[0311] Most preferably, Xaa7 is a modified 3-aminophenylalanine of formula (4a) [Af3(R 7c )], where R 7c teeth,

[0312] [ka]

[0313] Preferably,

[0314] [ka]

[0315] is; or Xaa7 is a modified 4-aminophenylalanine [Aph(R 7d )], where R 7d teeth,

[0316] [ka]

[0317] Preferably,

[0318] [ka]

[0319] is.

[0320] According to the most preferred embodiment of Xaa7, it is further preferred that Xaa1 is absent.

[0321] Xaa8 is a residue of an amino acid selected from the group consisting of an L-α-amino acid and a cyclic α,α-dialkylamino acid. In some embodiments, Xaa8 is an aliphatic L-α-amino acid of formula (IX) or an amino acid of formula (XI):

[0322] [ka]

[0323] is a residue of During the ceremony, R 8a is selected from the group consisting of (C1-C4) alkyl, (C3-C7) cycloalkyl, and H; t=0, 1, 2, 3, or 4 s=0, 1, 2, or 3 In the amino acid of formula (XI), one aryl ring is optionally annulated to a ring bond that does not include the α-C-atom, In the carbocyclic part of the amino acid of formula (XI), the CH2 group that is spaced at least one carbon atom from the α-carbon atom is optionally replaced by an O atom or an NH group.

[0324] In a preferred embodiment, Xaa8 is a residue of an amino acid selected from the group consisting of Leu, Nle, Npg, Cha, Aic, Thp, Eca, and Egz, more preferably Leu.

[0325] Xaa9 is a residue of an amino acid selected from the group consisting of GIy and L-α-amino acids. In some embodiments, Xaa9 is a residue of an amino acid selected from the group consisting of GIy and formula (XIII):

[0326] [ka]

[0327] and wherein the residue of an amino acid is selected from the group consisting of the L-α-amino acids During the ceremony, R 9a are H, OH, COOH, CONH2, N(R 9b )2, CONH-R 9c , X 9 , and -NH-CO-X 9 is selected from the group consisting of During the ceremony, X 9 is (C1-C6) alkyl, (C5-C 10 ) aryl, and (C3-C 10 ) heteroaryl; and X 9 are each and individually substituted with one or two substituents selected from the group consisting of methyl, CONH, halogen, NH, and OH; u=1, 2, 3, or 4, optionally one or two hydrogens of the β-CH group and / or the γ-CH group are each and individually replaced by methyl, and / or one of the hydrogens of the β-CH group is optionally replaced by OH; R 9b are each and independently selected from the group consisting of (C1-C4) alkyl and H; R 9c is selected from the group consisting of (C1-C8) alkyl and (C1-C8) cycloalkyl optionally substituted with 1, 2, 3, 4, 5, or 6 OH groups, provided that each carbon atom is not bound to an O or N atom or is bound to one O or N atom.

[0328] In a preferred embodiment, Xaa9 is a residue of an amino acid selected from the group consisting of Gly, Ala, His, Thr, (S)-dimethylornithine [Dmo], and Glu (AGLU), more preferably Thr.

[0329] Xaa10 is a residue of a heteroaromatic L-α-amino acid. In some embodiments, Xaa10 is selected from the group consisting of Trp optionally substituted with a substituent selected from the group consisting of methyl, halogen, or OH, and an aza-analogue of Trp optionally substituted with methyl, halogen, or OH. Preferably, Xaa10 is a residue of an amino acid selected from the group consisting of Trp and (S)-7-aza-tryptophan [7Nw].

[0330] In some embodiments, Xaa11 may be a residue of an amino acid selected from the group consisting of GIy and an L-α-amino acid, which is optionally linked to a moiety Z4, which is a moiety comprising an effector E4 and a linker moiety L4, which effector E4 is preferably (α) (α1) a phosphorophore, and (α2) a moiety derived from a chromophore, preferably selected from a fluorophore such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug is selected from the group consisting of:

[0331] Preferably, Xaa11 is a residue of an amino acid selected from the group consisting of Gly and L-α-amino acids and Z4 is absent, more preferably Xaa11 is a residue of Ser (Z4 is absent).

[0332] In some embodiments, Xaa11 can be the residue of an L-α-amino acid that contains, in addition to an amino group and a carboxy group attached to its α-C atom, a functional group FG2 that forms a covalent linkage B1 with functional group FG1 of Xaa2, thereby forming a bicyclic peptide of formula (1b). In other embodiments, Xaa11 can be the residue of an L-α-amino acid that contains, in addition to an amino group and a carboxy group attached to its α-C atom, a functional group FG4 that forms a covalent linkage B2 with functional group FG3 of Xaa6, thereby forming a bicyclic peptide of formula (1c).

[0333] In some embodiments, Xaa11 is a residue of an amino acid selected from the group consisting of GIy and an L-α-amino acid, wherein the L-α-amino acid is linked to a moiety Z4, which is a moiety comprising an effector E4 and a linker moiety L4 that covalently links the effector E4 to the L-α-amino acid of Xaa11. Preferably, Xaa11 is selected from the group consisting of Glu, Gln, and a group of formula (XI):

[0334] [ka]

[0335] and wherein the residue of an L-α-amino acid is selected from the group consisting of: During the ceremony, v=1, 2, 3, or 4, R 11a are H, OH, COOH, CONH2, NH-(C=NH)-NH2, N(R 11b )2, CONH-R 11c , -CO(Z4), X 13 and -NH-CO-X 13 , NH—CO(Z4), O—CO(Z4), Z4, and NH—CS—Z4, wherein X 13 is selected from the group consisting of (C1-C6) alkyl, (C5-C6) aryl, and (C3-C5) heteroaryl; and X 13 are each and individually optionally substituted with one or two substituents selected from the group consisting of methyl, CONH, halogen, NH, and OH; R 11b are each and independently selected from the group consisting of (C1-C4) alkyl and H; optionally, one or two hydrogens of the β-CH2 group and / or the γ-CH2 group in formula (XI) are each and individually replaced by methyl; One of the hydrogens of the β-CH 2 group in formula (XI) is optionally replaced by OH.

[0336] In a preferred embodiment, Xaa11 is attached to Z4 and is a residue of an amino acid selected from the group consisting of Ala, Ser, Gly, Arg, Lys, (S)-dimethylornithine [Dmo], and Glu (AGLU). In this context, it is understood that the amino acid from which Xaa11 is derived contains a functional group that allows covalent attachment of Z4 thereto. More preferably, Xaa11 is a residue of Ser (Z4 is attached to Xaa11).

[0337] In some embodiments, Xaa11 comprises a functional group FG5 different from a carboxyl group and an amino group attached to the α-C atom of Xaa11, and a linker moiety L4 covalently links the effector E4 to the functional group FG5 of the L-α-amino acid of Xaa11. Preferably, Xaa11 is a residue of an L-α-amino acid of formula (XI), and the functional group FG5 is R 11a In particular, the linker moiety L4 may provide (a) a first amino group that forms a covalent bond with the functional group FG5 of the L-α-amino acid of Xaa11, and (b) a second amino group that forms a covalent bond to the effector E4.

[0338] In some embodiments, the linker moiety L4 is either X41 or a residue selected from the group consisting of X41-X42 and X42-X41; X41 is a residue of a diamine that provides the first and second amino groups; X42 is an amino acid residue that provides an amino group and a carboxy group, X41-X42 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the first amino group of X41, the second amino group is the amino group of X42, The second amino group of X41 forms an amide bond with the carboxy group of X42, X42-X41 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the amino group of X42, the second amino group is the second amino group of X41, The carboxy group of X42 forms an amide bond with the first amino group of X41.

[0339] In some embodiments, X41 is a residue of a linear or cyclic diamine. In particular, Xaa11 can be a residue of an L-α-amino acid of formula (XI), where R 11a is selected from the group consisting of -CO(Z4), -NH-CO(Z4), -O-CO(Z4), -Z4, and -NH-CS-Z4. Preferably, L4 is connected to R by an amide bond. 11a is covalently attached to a carbonyl or thiocarbonyl carbon atom contained in

[0340] In a preferred embodiment, X41 is represented by the formulae (35) to (37):

[0341] [ka]

[0342] and a residue of a diamine selected from the group consisting of any one of the diamines During the ceremony, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; f is 0, 1, 2, 3, 4, 5, or 6; g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The diamine of any one of formulas (35) and (36) is optionally substituted with -CONH2; J is selected from the group consisting of CH and N.

[0343] In the diamine of either one of formulas (35) and (36), the carbon atom substituted with a nitrogen atom may be further substituted with -CONH2.

[0344] In a more preferred embodiment, X41 is a residue of a diamine selected from the group consisting of 1,3-diaminopropane [Apr], 1,5-diaminopentane [Ape], diaminobutane, and ethylenediamine.

[0345] In a more preferred embodiment, X42 is selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and any one of amino acids of formulae (32), (33), and (34):

[0346] [ka]

[0347] and its ortho- and para-substituted isomers, and

[0348] [ka]

[0349] is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formulas (32) and (33) are optionally substituted.

[0350] The amino acids of formula (32) and (33) have R at the α-carbon atom covalently bonded to the COOH group in formula (32) and (33), respectively. X11-CO-NH-, wherein R X11 is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C 10 ) aryl. Preferably, R X11 is methyl.

[0351] Most preferably, X42 is selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and the compounds of formula (35):

[0352] [ka]

[0353] The amino acid residue is selected from the group consisting of:

[0354] Xaa12 is a group represented by formula (XII):

[0355] [ka]

[0356] Preferably of formula (XIIa):

[0357] [ka]

[0358] is a residue of an aminothiol, During the ceremony, NH of formula (XII) is bonded to Xaa11; R 12a and R 12b are each and independently selected from the group consisting of H and CH3, preferably H; R 12c is selected from the group consisting of -COOH, CONH2, -CO-Z6, and -CH2-Z6, where Z6 comprises a linker moiety L6 and an effector E6.

[0359] Effector E6 is preferably (α) (α1) a phosphorophore, and (α2) a moiety derived from a chromophore, preferably selected from a fluorophore such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug is selected from the group consisting of:

[0360] Most preferably, R 12a and R 12b are both H and Xaa12 is in the (R)-configuration.

[0361] In some embodiments, R 12c is selected from the group consisting of -COOH and -CONH2.

[0362] In some embodiments, R 12c is selected from the group consisting of -CO-Z6 and -CH2-Z6, Z6 being an effector E6, and R 12c Preferably, R 12c is -CO-Z6, and the linker moiety L6 is (a) R 12c and (b) a second amino group that forms a covalent bond to the effector.

[0363] In some embodiments, the linker moiety L6 is either X61 or a residue selected from the group consisting of X61-X62 and X62-X61; X61 is a residue of a diamine providing a first amino group and a second amino group; X62 is an amino acid residue that provides an amino group and a carboxy group, X61-X62 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the first amino group of X61, the second amino group is the amino group of X62, The second amino group of X61 forms an amide bond with the carboxy group of X62, X62-X61 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the amino group of X62, the second amino group is the second amino group of X61, The carboxy group of X62 forms an amide bond with the first amino group of X61.

[0364] Preferably, X61 is represented by the formula (35 to 37):

[0365] [ka]

[0366] and a residue of a diamine selected from the group consisting of any one of the diamines During the ceremony, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; f is 0, 1, 2, 3, 4, 5, or 6; g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The diamine of either one of formulas (35) and (36) is optionally substituted with -CONH2, and J is selected from the group consisting of CH and N.

[0367] In the diamine of either one of formulas (35) and (36), the carbon atom substituted with a nitrogen atom may be further substituted with -CONH2.

[0368] More preferably, X61 is 1,3-diaminopropane [Apr], 1,5-diaminopentane [Ape], diaminobutane, ethylenediamine, diamines of formula (39), and diamines of formula (40).

[0369] [ka]

[0370] is the residue of a diamine selected from the group consisting of:

[0371] In some embodiments, X62 is selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and an amino acid according to any one of formulas (32)-(33):

[0372] [ka]

[0373] and its ortho- and para-substituted isomers, and

[0374] [ka]

[0375] is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formula (32) and formula (33) are each optionally substituted.

[0376] The amino acids of formula (32) and formula (33) have R at the α-carbon atom covalently bonded to the COOH group in formula (32) and formula (33). X11 -CO-NH-, each of which may be substituted with -CO-NH-, X11 is (C1~C 10 ) Alkyl, (C5-C 10 )aryl, and (C1-C5)alkyl-(C5-C 10 ) aryl. Preferably, R X11 is methyl.

[0377] In a preferred embodiment, X62 is selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and the compounds of formula (35):

[0378] [ka]

[0379] The amino acid residue is selected from the group consisting of:

[0380] Most preferably, X62 is a residue of an amino acid selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb].

[0381] In formula (1a), X 1 and X 2 are each independently selected from the group consisting of CH and N. Preferably, X 1 and X 2 At least one of X is CH and N. Most preferably, X 1 and X 2 Both of these are CH.

[0382] However, in a more preferred embodiment, the compound of the invention contains only one effector selected from E1, E3, E4, and E6, and the effector may be attached to the compound via a linker moiety L1, L3, L4, or L6.

[0383] According to the present invention, the compound of the present invention may contain one or more effectors (i.e., E1, E3, E4, and E6) attached to the compound of the present invention directly or via a linker. However, the compound of the present invention contains at most two effectors, more preferably only one effector. Most preferably, such one effector is contained by the N-terminal group Y.

[0384] In a preferred embodiment, the compound of the present invention is Y-Xaa1-Xaa2-[Cys(3MeBn)-Xaa4-Xaa5-Xaa6-Trp-Leu-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xaa4-Xaa5-Xaa6-Trp-Leu-Xaa9-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Trp-Nle-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Trp-Nle-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Trp-Npg-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Trp-Npg-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Trp-Cha-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xaa6-Trp-Cha-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Trp-Aic-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Trp-Aic-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Trp-Thp-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Trp-Thp-Ca9-7Nw-Ca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Trp-Eca-Ca-Ca9-Trp-Ca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Trp-Eca-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xa5-Xaa6-Trp-Egz-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Trp-Egz-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Af3(Cpsu)-Leu-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Cpsu)-Leu-Caca9-7Nw-Caca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Cpsu)-Nle-Cata9-Trp-Ca11-Cys]-NH2 Y-Case1-Case2-[Cys(3MeBn)-Ca4-Ca5-Cae6-Af3(Cpsu)-Nle-Case9-7Nw-Case11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Af3(Cpsu)-Npg-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Cpsu)-Npg-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Af3(Cpsu)-Cha-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Cpsu)-Cha-Ca-Ca9-7Nw-Ca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Cpsu)-Aic-Caa9-Trp-Ca11-Cys]-NH2 Y-Cae1-Cae2-[Cys(3MeBn)-Ca4-Ca5-Cae6-Af3(Cpsu)-Aic-Cae9-7Nw-Cae11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Af3(Cpsu)-Thp-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Cana6-Af3(Cpsu)-Thp-Cana9-7Nw-Cana11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Cpsu)-Eca-Ca-Ca9-Trp-Ca11-Cys]-NH2 Y-Case1-Case2-[Cys(3MeBn)-Ca4-Ca5-Cae6-Af3(Cpsu)-Eca-Case9-7Nw-Case11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Af3(Cpsu)-Egz-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Cana6-Af3(Cpsu)-Egz-Cana9-7Nw-Caca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Af3(Sapr)-Leu-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Sapr)-Leu-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Af3(Sapr)-Nle-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Sapr)-Nle-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Af3(Sapr)-Npg-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Sapr)-Npg-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Af3(Sapr)-Cha-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Af3(Sapr)-Cha-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Af3(Sapr)-Aic-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Sapr)-Aic-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Af3(Sapr)-Thp-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Sapr)-Thp-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Af3(Sapr)-Eca-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Af3(Sapr)-Eca-Ca-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Af3(Sapr)-Egz-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Af3(Sapr)-Egz-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(Cpsu)-Leu-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Leu-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(Cpsu)-Nle-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Nle-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(Cpsu)-Npg-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Npg-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(Cpsu)-Cha-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(Cpsu)-Cha-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Aic-Caa9-Trp-Ca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Aic-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(Cpsu)-Thp-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Thp-Ca9-7Nw-Ca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Eca-Ca-Ca9-Trp-Ca11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(Cpsu)-Eca-Ca-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(Cpsu)-Egz-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca56-Aph(Cpsu)-Egz-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(SaPr)-Leu-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(SaPr)-Leu-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xaa4-Xa5-Xaa6-Aph(SaPr)-Nle-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(SaPr)-Nle-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Aph(SaPr)-Npg-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xa6-Aph(SaPr)-Npg-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(SaPr)-Cha-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(SaPr)-Cha-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xaa4-Xaa5-Xa6-Aph(SaPr)-Aic-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(SaPr)-Aic-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xa4-Xaa5-Xaa6-Aph(SaPr)-Thp-Xa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(SaPr)-Thp-Xa9-7Nw-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(SaPr)-Eca-Xa9-Trp-Xaa11-Cys]-NH2 Y-Ca1-Ca2-[Cys(3MeBn)-Ca4-Ca5-Ca6-Aph(SaPr)-Eca-Ca-Ca9-7Nw-Ca11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Xaa4-Xa5-Xaa6-Aph(SaPr)-Egz-Xaa9-Trp-Xaa11-Cys]-NH2 Y-Xa1-Xa2-[Cys(3MeBn)-Xa4-Xa5-Xa6-Aph(SaPr)-Egz-Xa9-7Nw-Xaa11-Cys]-NH2 The slide shows up in the background. wherein Y, Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 are as defined above, and preferably at least one, e.g., two, three, four, or more than four, of Y, Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 are defined as follows: (a) Y is a group selected from (a1) Ac, (a2) a moiety comprising an effector E1, and (a3) ​​Z1; (b) Xaa1 is absent or represents an L-α-amino acid residue selected from the group consisting of Val, Ile, Tle, Ser, and Thr; (c) Xaa2 is (c1) a residue of an L-α-amino acid selected from the group consisting of Tyr, Nmy, Phe, Gln, Arg, Dmo, Ser, Thr, Asp, Glu, and Glu(AGLU), or (c2) a residue of an L-α-amino acid containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (d) Xaa4 is an L-α-amino acid residue selected from the group consisting of Ala, Ser, Hse, Nms, Gln, Asn, Glu, Asp, Dmo, and Glu(AGLU); (e) Xaa5 is an amino acid residue selected from the group consisting of Gly, Nmg, D-ala, D-pro, D-pip, D-aze, Nma, and Aib, and Z3 is absent; (f) Xaa6 is (f1) a residue of an L-α-amino acid selected from the group consisting of Ala, Asp, Asn, Hse, Gln, Glu, Lys, Orn, Dab, N-methyl-Asp, C(Bzl), C(2Quuyl), Eem, Tyr(Bzl), and E(NHMe2Nph), or (f2) a residue of an L-α-amino acid containing a functional group FG3 that forms a covalent linkage B2 with the functional group of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (g) Xaa9 is an amino acid residue selected from the group consisting of Gly, Ala, His, Thr, Dmo, and Glu (AGLU); (h) Xaa11 is selected from (h1) a residue of Ser, (h2) an L-α-amino acid residue containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; and (h3) an L-α-amino acid residue containing a functional group FG4 that forms a covalent linkage B2 with the functional group FG3 of Xaa6, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu.

[0385] In a further preferred embodiment, in the above formula, at least one, such as two, three, four, or more than four, of Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 is defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent or represents a Val residue; (c) Xaa2 is (c1) an L-α-amino acid residue selected from the group consisting of Tyr, Nmy, Gln, Arg, Dmo, and Ser, or (c2) an L-α-amino acid residue containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (d) Xaa4 is an L-α-amino acid residue selected from the group consisting of Ala, Ser, Glu, Gln, and Hse; (e) Xaa5 is an amino acid residue selected from the group consisting of Gly, Nmg, D-ala, D-pro, D-pip, D-aze, Nma, and Aib, and Z3 is absent; (f) Xaa6 is (f1) a residue of an L-α-amino acid selected from the group consisting of Ala, Asp, Asn, Hse, Gln, Glu, Lys, Orn, Dab, N-methyl-Asp, C(Bzl), C(2Quuyl), Eem, Tyr(Bzl), and E(NHMe2Nph); (g) Xaa9 is an amino acid residue selected from the group consisting of Gly, Ala, His, Thr, Dmo, and Glu (AGLU); (h) Xaa11 is (h1) a residue of Ser, or (h2) a residue of an L-α-amino acid containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu.

[0386] In a further preferred embodiment, in the above formula, at least one, such as two, three, four, or more than four, of Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 is defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent; (c) Xaa2 is (c1) a residue of Gln or (c2) a residue of an L-α-amino acid containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa2 is Glu; (d) Xaa4 is a Glu residue; (e) Xaa5 is a D-pro residue; (f) Xaa6 is an Asp residue; (g) Xaa9 is a Thr residue; (h) Xaa1 is (h1) a residue of Ser, or (h2) a residue of an L-α-amino acid containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, and Xaa11 is Dap.

[0387] In a further preferred embodiment, in the above formula, Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 are all defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent or represents an L-α-amino acid residue selected from the group consisting of Val, Ile, Tle, Ser, and Thr; (c) Xaa2 is (c1) a residue of an L-α-amino acid selected from the group consisting of Tyr, Nmy, Phe, Gln, Arg, Dmo, Ser, Thr, Asp, Glu, and Glu(AGLU), or (c2) a residue of an L-α-amino acid containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (d) Xaa4 is an L-α-amino acid residue selected from the group consisting of Ala, Ser, Hse, Nms, Gln, Asn, Glu, Asp, Dmo, and Glu(AGLU); (e) Xaa5 is an amino acid residue selected from the group consisting of Gly, Nmg, D-ala, D-pro, D-pip, D-aze, Nma, and Aib, and Z3 is absent; (f) Xaa6 is (f1) a residue of an L-α-amino acid selected from the group consisting of Ala, Asp, Asn, Hse, Gln, Glu, Lys, Orn, Dab, N-methyl-Asp, C(Bzl), C(2Quuyl), Eem, Tyr(Bzl), and E(NHMe2Nph), or (f2) a residue of an L-α-amino acid containing a functional group FG3 that forms a covalent linkage B2 with the functional group of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (g) Xaa9 is an amino acid residue selected from the group consisting of Gly, Ala, His, Thr, Dmo, and Glu (AGLU); (h) Xaa11 is selected from (h1) a residue of Ser, (h2) an L-α-amino acid residue containing a functional group FG2 selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu, which forms a covalent linkage B1 with the functional group FG1 of Xaa2, and (h3) an L-α-amino acid residue containing a functional group FG4 selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu, which forms a covalent linkage B2 with the functional group FG3 of Xaa6.

[0388] In a further preferred embodiment, in the above formula, Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 are all defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent or represents a Val residue; (c) Xaa2 is (c1) an L-α-amino acid residue selected from the group consisting of Tyr, Nmy, Gln, Arg, Dmo, and Ser, or (c2) an L-α-amino acid residue containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (d) Xaa4 is an L-α-amino acid residue selected from the group consisting of Ala, Ser, Glu, Gln, and Hse; (e) Xaa5 is an amino acid residue selected from the group consisting of Gly, Nmg, D-ala, D-pro, D-pip, D-aze, Nma, and Aib, and Z3 is absent; (f) Xaa6 is (f1) a residue of an L-α-amino acid selected from the group consisting of Ala, Asp, Asn, Hse, Gln, Glu, Lys, Orn, Dab, N-methyl-Asp, C(Bzl), C(2Quuyl), Eem, Tyr(Bzl), and E(NHMe2Nph); (g) Xaa9 is an amino acid residue selected from the group consisting of Gly, Ala, His, Thr, Dmo, and Glu (AGLU); (h) Xaa11 is (h1) a residue of Ser, or (h2) a residue of an L-α-amino acid containing a functional group FG2 selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu, which forms a covalent linkage B1 with the functional group FG1 of Xaa2.

[0389] In a further preferred embodiment, in the above formula, Xaa1, Xaa2, Xaa4, Xaa5, Xaa6, Xaa9, and Xaa11 are all defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent; (c) Xaa2 is (c1) a residue of Gln or (c2) a residue of an L-α-amino acid containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa2 is Glu; (d) Xaa4 is a Glu residue; (e) Xaa5 is a D-pro residue; (f) Xaa6 is an Asp residue; (g) Xaa9 is a Thr residue; (h) Xaa1 is (h1) a residue of Ser, or (h2) a residue of an L-α-amino acid containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, and Xaa11 is Dap.

[0390] In a preferred embodiment, the compound of the present invention is Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Nle-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Nle-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Npg-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Npg-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Cha-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Cha-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Aic-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Aic-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Thp-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Thp-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Eca-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Eca-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Egz-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Trp-Egz-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Nle-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Nle-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Npg-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Npg-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Cha-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Cha-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Aic-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Aic-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Thp-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Thp-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Eca-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Eca-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Egz-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Egz-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Leu-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Leu-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Nle-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Nle-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Npg-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Npg-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Cha-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Cha-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Aic-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Aic-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Thp-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Thp-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Eca-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Eca-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Egz-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Af3(Sapr)-Egz-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Leu-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Leu-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Nle-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Nle-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Npg-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Npg-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Cha-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Cha-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Aic-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Aic-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Thp-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Thp-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Eca-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Eca-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Egz-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(Cpsu)-Egz-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Nle-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Nle-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Npg-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Npg-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Cha-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Cha-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Aic-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Aic-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Thp-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Thp-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Eca-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Eca-Thr-7Nw-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Egz-Thr-Trp-Xaa11-Cys]-NH2 Y-Xaa1-Xaa2-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Egz-Thr-7Nw-Xaa11-Cys]-NH2 is selected from the group consisting of wherein Y, Xaa1, Xaa2, and Xaa11 are as defined above, and preferably at least one, for example two, three, or four, of Y, Xaa1, Xaa2, and Xaa11 are defined as follows: (a) Y is a group selected from (a1) Ac, (a2) a moiety comprising an effector E1, and (a3) ​​Z1; (b) Xaa1 is absent or represents an L-α-amino acid residue selected from the group consisting of Val, Ile, Tle, Ser, and Thr; (c) Xaa2 is (c1) a residue of an L-α-amino acid selected from the group consisting of Tyr, Nmy, Phe, Gln, Arg, Dmo, Ser, Thr, Asp, Glu, and Glu(AGLU), or (c2) a residue of an L-α-amino acid containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (h) Xaa11 is selected from (h1) a residue of Ser, (h2) an L-α-amino acid residue containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; and (h3) an L-α-amino acid residue containing a functional group FG4 that forms a covalent linkage B2 with the functional group FG3 of Xaa6, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu.

[0391] In a further preferred embodiment, in the above formula, at least one, for example two or three, of Xaa1, Xaa2, and Xaa11 are defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent or represents a Val residue; (c) Xaa2 is (c1) an L-α-amino acid residue selected from the group consisting of Tyr, Nmy, Gln, Arg, Dmo, and Ser, or (c2) an L-α-amino acid residue containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu; (h) Xaa11 is (h1) a residue of Ser, or (h2) a residue of an L-α-amino acid containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, selected from the group consisting of Dap, Dab, Orn, Lys, Cys, Hcy, Pen, Asp, and Glu.

[0392] In a further preferred embodiment, in the above formula, at least one, for example two or three, of Xaa1, Xaa2, and Xaa11 are defined as follows, while Y is preferably as defined above under item (a): (b) Xaa1 is absent; (c) Xaa2 is (c1) a residue of Gln or (c2) a residue of an L-α-amino acid containing a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa2 is Glu; (h) Xaa1 is (h1) a residue of Ser, or (h2) a residue of an L-α-amino acid containing a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, and Xaa11 is Dap.

[0393] In a more preferred embodiment, the compound of the present invention is Ac-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Glu(NH-Apr-DOTA)-Cys]-NH2(3BP-3478) DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-3583) Ac-Lys(DOTA)-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-3840) DOTA-APAc-Val-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Dap}-Cys]-NH2(3BP-4175) DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(HO-Succinyl)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4237) DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4369) DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4400) DOTA-PPAc-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4448) DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4452) DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4453) DOTA-Rni-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4455) DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4501) DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Dap}-Cys]-NH2(3BP-4503) DOTA-PPAc-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Dap}-Cys]-NH2(3BP-4504) DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Dap}-Cys]-NH2(3BP-4505) is selected from the group consisting of:

[0394] Even more preferably, the compound of the present invention is DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4452) DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4501) DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Dap}-Cys]-NH2(3BP-4503) is selected from the group consisting of:

[0395] Most preferably, the compounds of the present invention are DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH2(3BP-4452) is.

[0396] In one embodiment, the compound of the present invention is a compound whose amino acid sequence has at least 72.7% identity, in terms of amino acid residues, to the amino acid sequence of a compound of the present invention consisting of amino acid residues Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, Xaa11, and Xaa12 (hereinafter in "Reference Compound of the Present Invention"), wherein Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, Xaa11, and Xaa12 have the preferred meanings according to either of embodiments (A) and (Ab) described above. Preferably, the amino acid sequence of the reference compound of the invention is selected from the group consisting of Gln-Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys, Gln-Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys, and Glu-Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Dap-Cys. Preferably, the identity is at least 81.8%, more preferably, the identity is at least 90.9%. It will be understood by those skilled in the art that 72.7% identity means that the compound of the present invention differs from the reference compound of the present invention by three amino acid residues, 81.8% identity means that the compound of the present invention differs from the reference compound of the present invention by two amino acid residues, and 90.9% identity means that the compound of the present invention differs from the reference compound of the present invention by one amino acid residue.

[0397] In one embodiment, the compound of the present invention is a compound whose amino acid sequence has at least 75% identity, in terms of amino acid residues, to the amino acid sequence of a compound of the present invention consisting of amino acid residues Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, Xaa11, and Xaa12 (hereinafter in "Reference Compound of the Present Invention"), wherein amino acid residues Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, Xaa11, and Xaa12 have the preferred meanings of either of embodiments (B) and (Bb) described above. Preferably, the amino acid sequences of the reference compounds of the present invention are Val-Tyr-Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Glu-Cys, Ser-Tyr-Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Glu-Cys, Ile-Tyr-Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Glu-Cys, Thr-Tyr-Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Glu

[0039] Preferably, the identity is at least 83.3%, and more preferably, the identity is at least 92.7%. It will be understood by those skilled in the art that 75% identity means that the compound of the invention differs from the reference compound of the invention by three amino acid residues, 83.3% identity means that the compound of the invention differs from the reference compound of the invention by two amino acid residues, and 92.7% identity means that the compound of the invention differs from the reference compound of the invention by one amino acid residue.

[0398] The identity between two amino acid sequences can be determined as known to those skilled in the art. More specifically, a sequence comparison algorithm can be used to calculate the percent sequence identity (or homology) for a test sequence relative to a reference sequence based on designated program parameters. The test sequence is preferably an amino acid sequence that is said to be identical, or to be tested to see whether it is identical, and if so, to what extent, with a different amino acid sequence, such as the amino acid sequence of the reference compound of the present invention. Optimal alignment of amino acid sequences can be achieved, for example, by the Smith & Waterman local homology algorithm (Smith & Waterman (1981), Adv. Appl. Math. 2: 482), by the Needleman & Wunsch homology alignment algorithm (Needleman & Wunsch (1970) A general method applicable to the search for similarities in the amino acid sequences of two proteins. J. Mol. Biol. 48(3): 443-53), by the Pearson & Lipman similarity search method (Pearson & Lipman (1988) Improved tools for biological sequence comparison. Proc. Nat'l. Acad. Sci. USA 85: 2444), or by computer implementations of these algorithms (Wisconsin Genetics software package, Genetics Computer Group, Inc., 575 Science Dr., Madison, This may be done by a standardized testing program (GAP, BESTFIT, FASTA, and TFASTA in Wis.) or by visual inspection.

[0399] One example of an algorithm that is suitable for determining percent sequence identity is the algorithm used in the basic local alignment search tool (hereinafter "BLAST"), see, e.g., Altschul et al. (Altschul SF, Gish W. et al. (1990) Basic local alignment search tool. J Mol Biol. 215(3):403-10; Altschul SF, Madden TL et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25(17):3389-402). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (hereinafter "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 S., Madden TL et al. (2004) BLAST: at the core of a powerful and diverse set of sequence analysis tools. Nucleic Acids Res. 32 (Web Server Edition): W20-5).

[0400] 3. Effector In certain embodiments, the compounds of the present invention comprise one or more "effectors." By effector, we understand a chemical group and / or chemical element attached to a compound or peptide for the purpose of diagnostic and / or therapeutic intervention in CAIX receptor-related diseases / cancer cells. The effectors that can be used are not particularly limited, and any effector, such as a label and / or a pharmaceutically active molecule, can be employed.

[0401] In a preferred embodiment, each effector E1, E3, E4, and E6 independently: (α) a moiety derived from a chromophore, the chromophore preferably being selected from (α1) a phosphorophore, and (α2) a fluorophore, such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug is selected from the group consisting of:

[0402] When the compound of formula (1a) contains more than one kind of effector, for example, two, three or four kinds of effectors, the effectors can be different from each other or identical.Preferably, the effectors are identical to each other.However, it is particularly preferred that the compound of the present invention contains only one kind of effector.It is even more preferred that the effector is contained by N-terminal group Y.

[0403] In one embodiment, the effector is a moiety derived from a chromophore, preferably selected from phosphorophores and fluorophores. Fluorophores can be used, for example, in resection surgery, i.e., surgery to remove cancerous tissue, to make tumors visible by the fluorescence emitted upon appropriate irradiation ("luminescence effect"). According to this embodiment, the compounds of the present invention preferably do not contain a chelating agent in addition to the fluorophore. In these embodiments, the fluorophore can be covalently linked to the cyclic peptide structure by a linker moiety such as L1, L3, L4, or L6 (described above).

[0404] In one embodiment, the effector is a chelator comprising a chelated nuclide. The chelator can be covalently linked to the cyclic peptide structure by a linker moiety such as L1, L3, L4, or L6 (described above). 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 it is attached. The linker group can, in principle, comprise any chemical group capable of forming an amide bond with both the chelator group and the part of the compound of the present invention at the specified position.

[0405] In one embodiment, the effector is a chelator that does not contain a chelated nuclide, ie, the chelator is a chelator without a chelated nuclide.

[0406] The use of a linker is usually purpose-driven. In some situations, it is necessary to space a larger moiety 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 achievable to combine a chelating agent with a bioactive compound without the need for such a linker.

[0407] As preferably used herein, when there is no linker interspersed between the amino acid and the chelator, the amino acid is directly linked to the chelator.

[0408] Preferably, the chelator is part of the compound of the invention, whereby the chelator is attached to the compound of the invention directly or indirectly, such as by a linker. The chelator forms a metal chelate, preferably comprising at least one radiometal. The at least one radiometal is preferably useful or suitable for diagnostic and / or therapeutic and / or therapeutic diagnostic uses, more preferably useful or suitable for imaging and / or radiotherapy.

[0409] It will be appreciated by those skilled in the art that the radionuclide that is or may be attached to the compounds of the present invention will be selected taking into account the particularities of the disease to be treated and / or the disease to be diagnosed, respectively, and / or the patient and patient group to be treated and diagnosed, respectively.

[0410] In one embodiment of the present invention, a radioactive nuclide is also referred to as a radionuclide. Radioactive decay is the process by which the nucleus of an unstable atom loses energy by emitting ionizing particles (ionizing radiation). There are various types of radioactive decay. The decay or loss of energy occurs when an atom with one type of nucleus, called a parent radionuclide, changes into an atom with a nucleus in a different state, or into a different nucleus containing a different number of protons and neutrons. Both of these products are named 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 a new element). For example, radioactive decay can be alpha decay, beta decay, and gamma decay. Alpha decay occurs when a nucleus ejects an alpha particle (helium nucleus). This is the most common process of emitting a nucleon, but in rarer types of decay, the nucleus can eject a proton, or specific nuclei of other elements (in a process called cluster decay). Beta decay occurs when a nucleus releases an electron (β - -decay) or positron (β + -decay) and releases one type of neutrino. In contrast, there are radioactive decay processes that do not result in transmutation. The energy of an excited nucleus can be emitted as gamma rays in gamma decay, or can be used to eject an orbital electron by interaction with the 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 to a neutron, causing the emission of an electron neutrino in a process called electron capture (EC), or can be released without changing the number of protons and neutrons in a process called isomerization (IT). Another form of radioactive decay, spontaneous fission (SF), is found only in very heavy chemical elements, resulting in the spontaneous breakdown of the nucleus into smaller nuclei and a few isolated nuclear particles.

[0411] In a preferred embodiment of the present invention, radionuclides may be used to label the compounds of the present invention.

[0412] In one embodiment of the present invention, the radionuclide is suitable for complexing with a chelating agent, leading to a radionuclide chelate complex.

[0413] In further embodiments, one or more atoms of the compounds of the invention are of unnatural isotopic composition, preferably these atoms are radionuclides; more preferably, these atoms are radionuclides of carbon, oxygen, nitrogen, sulfur, phosphorus, and the halogens. These radioactive atoms are typically part of amino acids, in some cases halogen containing amino acids, and / or building blocks, and in some cases halogenated building blocks of the compounds of the invention, respectively.

[0414] 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.

[0415] In a preferred embodiment of the present invention, the radionuclide has a decay energy that allows for diagnostic and / or therapeutic medical use. Specifically, for gamma-emitting isotopes, the decay energy is 0.004 to 10 MeV, preferably 0.05 to 4 MeV, for diagnostic use. For positron-emitting isotopes, the decay energy is 0.6 to 13 MeV, preferably 1 to 6 MeV, for diagnostic use. For particle-emitting isotopes, the decay energy is 0.04 to 10 MeV, preferably 0.4 to 7 MeV, for therapeutic use.

[0416] In a preferred embodiment of the present invention, the radionuclide is produced industrially for medical use, particularly the radionuclide is available in GMP quality.

[0417] In a preferred embodiment of the present invention, the daughter nuclide after radioactive decay of the radionuclide is compatible with diagnostic and / or therapeutic medical use. Furthermore, the daughter nuclide is stable or decays further in a manner that does not interfere with or even support diagnostic and / or therapeutic medical use. Representative radionuclides that can be used in the context of the present invention are well known to those skilled in the art and include, but are not limited to: 11 C. 13 N, 18 F, 24 Na, 28 Mg, 31 Si, 32 P, 33 P, 38 S, 34m Cl, 38 Cl, 39 Cl, 37 Ar, 41 Ar, 44 Ar, 42 K. 43 K. 44 K. 45 K. 47 Ca, 43 Sc, 44 Sc, 44m Sc, 47 Sc, 48 Sc, 49 Sc, 45 Ti, 47 V, 48 V, 48 Cr, 49 Cr, 51 Cr, 51 Mn, 52 Mn, 52m Mn, 56 Mn, 52 Fe, 59 Fe, 55 Co, 61 Co, 62m Co, 56 Ni, 57 Ni, 65 Ni, 66 Ni, 60 Cu, 61 Cu, 64 Cu, 67 Cu, 62 Zn, 63 Zn, 69 Zn,69m Zn、 71m Zn、 72 Zn、 65 Ga、 66 Ga、 67 Ga、 68 Ga、 70 Ga、 72 Ga、 73 Ga、 66 Ge、 67 Ge、 69 Ge、 71 Ge、 75 Ge、 77 Ge、 78 Ge、 69 As、 70 As、 71 As、 72 As、 74 As、 76 As、 77 As、 78 As、 70 Se、 72 Se、 73 Se、 73m Se、 81 Se、 81m Se、 83 Se、 74 Br、 74m Br、 75 Br、 76 Br、 77 Br、 80 Br、 80m Br、 82 Br、 83 Br、 84 Br、 74 Kr、 76 Kr、 77 Kr、 79 Kr、 85 Kr、 87 Kr、 88 Kr、 78 Rb、 79 Rb、 81 Rb、 82 Rb、 84 Rb、 84m Rb、 86 Rb、 88 Rb、 89 Rb、 80 Sr. 81 Sr. 82 Sr. 83 Sr. 85mMr, 87 Mr, 91 Mr, 92 Mr, 84 AND, 85 AND, 85m AND, 86 AND, 86m AND, 87 AND, 87m AND, 90 AND, 90m AND, 91m AND, 92 AND, 93 AND, 94 AND, 95 AND, 86 Zr、 87 Zr、 89 Zr、 97 Zr、 88 Nb、 89 Nb、 89m Nb、 90 Nb、 92 Nb、 95 Nb、 95m Nb、 96 Nb、 97 Nb、 98m Nb、 101 Mo、 102 Mo、 90 Mo、 91 Mo、 93m Mo、 99 Mo、 101 Tc、 104 Tc、 93 Tc、 93m Tc、 94 Tc、 94m Tc、 95 Tc、 96 Tc、 99m Tc、 103 Ru、 105 Ru、 94 Ru、 95 Ru、 97 Ru、 100 Rh, 101m Rh, 105 Rh, 106m Rh, 107 Rh, 97 Rh, 97m Rh, 99 Rh, 99m Rh, 100 P.S, 101 P.S, 103 P.S,109 Pd、 111 Pd、 111m Pd、 112 Pd、 98 Pd、 99 Pd、 101 Ag、 103 Ag、 104 Ag、 104m Ag、 105 Ag、 106 Ag、 106m Ag、 111 Ag、 112 Ag、 113 Ag、 115 Ag、 104 CD, 105 CD, 107 CD, 111 CD, 115 CD, 115m CD, 117 CD, 117m CD, 118 CD, 107 In, 108m In, 109 In, 110 In, 110m In, 111 In, 112 In, 113 In, 114m In, 115m In, 116m In, 117 In, 117m In, 119m In, 108 Sn、 109 Sn、 110 Sn、 111 Sn、 117 Sn、 121 Sn、 123m Sn、 125 Sn、 127 Sn、 128 Sn、 115 Sb、 116 Sb、 116m Sb、 117 Sb、 118m Sb、 119 Sb、 120 Sb、 120m Sb、 122 Sb、 126 Sb、 126m Sb、 127 Sb、 128Sb、 128m Sb、 129 Sb、 129m Sb、 130 Sb、 131 Sb、 114 Tea, 116 Tea, 117 Tea, 118 Tea, 119 Tea, 119m Tea, 121 Tea, 127 Tea, 129 Tea, 129m Tea, 131 Tea, 131m Tea, 132 Tea, 133 Tea, 133m Tea, 134 Tea, 118 THE, 119 THE, 120 THE, 120m THE, 121 THE, 123 THE, 124 THE, 126 THE, 128 THE, 130 THE, 131 THE, 132 THE, 132m THE, 133 THE, 134 THE, 135 THE, 120 Xe、 121 Xe、 122 Xe、 123 Xe、 125 Xe、 127 Xe、 133 Xe、 133m Xe、 135 Xe、 135m Xe、 138 Xe、 125 Cs、 127 Cs、 129 Cs、 130 Cs、 131 Cs、 132 Cs、 134 Cs、 135 Cs、 136 Cs、 138 Cs、 124 Ba、 126 Ba、 127 Ba、 128 Ba、 129 Ba、129m Well, 131 Well, 131m Well, 133 Well, 135 Well, 139 Well, 140 Well, 141 Well, 142 Well, 129 At, 131 At, 132 At, 133 At, 135 At, 140 At, 141 At, 142 At, 143 At, 130 What, 132 What, 133 What, 133m What, 134 What, 135 What, 137 What, 137m What, 141 What, 143 What, 146 What, 134 Mr. 134m Mr. 136 Mr. 137 Mr. 138m Mr. 139 Mr. 142 Mr. 143 Mr. 144 Mr. 145 Mr. 146 Mr. 147 Mr. 135 Yes, 136 Yes, 137 Yes, 138 Yes, 139 Yes, 139m Yes, 140 Yes, 141 Yes, 147 Yes, 149 Yes, 151 Yes, 152 Yes, 141 P.m, 148 P.m, 148m P.m, 149 P.m, 150 P.m, 151 P.m, 140 Sm、 141 Sm、 141m Sm、 142Sm、 153 Sm、 155 Sm、 156 Sm、 145 I, 146 I, 147 I, 150 I, 152m I, 154 I, 156 I, 157 I, 158 I, 159 I, 145 God, 146 God, 147 God, 149 God, 159 God, 147 Tb、 148 Tb、 149 Tb、 150 Tb、 151 Tb、 152 Tb、 153 Tb、 154 Tb、 154m Tb、 155 Tb、 156 Tb、 156m Tb、 161 Tb、 163 Tb、 151 Live, 152 Live, 153 Live, 155 Live, 157 Live, 165 Live, 166 Live, 154 Hey, 155 Hey, 156 Hey, 157 Hey, 158m Hey, 159 Hey, 161 Hey, 162 Hey, 162m Hey, 164 Hey, 164m Hey, 166 Hey, 167 Hey, 156 Is, 157 Is, 158 Is, 159 Is, 160 Is, 161 Is, 163 Is, 165 Is, 169 Is, 171 Is,172 Er、 161 Tm、 162 Tm、 163 Tm、 165 Tm、 166 Tm、 167 Tm、 172 Tm、 173 Tm、 175 Tm、 162 Yb、 163 Yb、 164 Yb、 166 Yb、 167 Yb、 169 Yb、 175 Yb、 177 Yb、 178 Yb、 167 Lu、 169 Lu、 170 Lu、 171 Lu、 172 Lu、 176m Lu、 177 Lu、 178 Lu、 178m Lu、 179 Lu、 168 Hf、 170 Hf、 173 Hf、 177m Hf、 179m Hf、 180m Hf、 181 Hf、 182m Hf、 183 Hf、 184 Hf、 172 Breed, 173 Breed, 174 Breed, 175 Breed, 176 Breed, 177 Breed, 178 Breed, 180 Breed, 182m Breed, 183 Breed, 184 Breed, 185 Breed, 186 Breed, 174 W、 175 W、 177 W、 178 W、 179 W、 187 W、 190 W、 177 King、 178 King、 179 King、 181 King、182 Re, 182m Re, 184 Re, 186 Re, 188 Re, 188m Re, 189 Re, 190m Re, 180 You, 181 You, 182 You, 183 You, 183m You, 191 You, 193 You, 196 You, 182 Go, 183 Go, 184 Go, 185 Go, 186 Go, 186m Go, 187 Go, 188 Go, 189 Go, 190 Go, 194 Go, 195 Go, 195m Go, 196m Go, 184 PT, 186 PT, 187 PT, 188 PT, 189 PT, 191 PT, 195 PT, 197 PT, 197m PT, 199 PT, 200 PT, 202 PT, 186 Au、 190 Au、 191 Au、 192 Au、 193 Au、 194 Au、 196 Au、 196m Au、 198 Au、 198m Au、 199 Au、 200 Au、 200m Au、 190 Hg、 191 Hg、 192 Hg、 193 Hg、 195 Hg、 195m Hg、 197 Hg、 197mHg、 199 Hg、 203 Hg、 194 Tl 194m Tl 195 Tl 196 Tl 196m Tl 197 Tl 198 Tl 198m Tl 199 Tl 200 Tl 201 Tl 202 Tl 194 Pb、 195 Pb、 196 Pb、 197m Pb、 198 Pb、 199 Pb、 199m Pb、 200 Pb、 201 Pb、 202m Pb、 203 Pb、 204 Pb、 209 Pb、 211 Pb、 212 Pb、 214 Pb、 200 Hello 200m Hello 201 Hello 202 Hello 203 Hello 204 Hello 205 Hello 206 Hello 210 Hello 212 Hello 212m Hello 213 Hello 214 Hello 200 Night, 201 Night, 202 Night, 203 Night, 204 Night, 205 Night, 206 Night, 207 Night, 205 And 206 And 207 And 208 And 209 And 210 And 211 And 208 Rn 209 Rn 210 Rn211 Rn、 212 Rn、 221 Rn、 222 Rn、 223 Rn、 212 Fr、 222 Fr、 223 Fr、 223 Ra、 224 Ra、 225 Ra、 227 Ra、 230 Ra、 224 Ac、 225 Ac、 226 Ac、 228 Ac、 229 Ac、 226 Th、 227 Th、 231 Th、 233 Th、 234 Th、 236 Th、 227 Pa、 228 Pa、 229 Pa、 230 Pa、 232 Pa、 233 Pa、 234 Pa、 235 Pa、 229 U、 230 U、 231 U、 237 U、 239 U、 240 U、 242 U、 231 Np、 232 Np、 233 Np、 234 Np、 236m Np、 238 Np、 239 Np、 240 Np、 241 Np、 232 Pu、 235 Pu、 237 Pu、 243 Pu、 245 Pu、 246 Pu、 235 Am、 237 Am、 238 Am、 239 Am、 240 Am、 242 Am、 244 Am、 244m Am、 245 Am、246 Am, 246m Am, 247 Am, 239 Cm, 240 Cm, 241 Cm, 251 Cm, 245 Bk, 246 Bk, 248 Bk, 250 Bk, 251 Bk, 244 Cf, 245 Cf, 246 Cf, 247 Cf, 253 Cf, 255 Cf, 249 Es, 250 Es, 250m Es, 251 Es, 253 Es, 254m Es, 255 Es, 256m Es, 250 Fm, 251 Fm, 252 Fm, 254 Fm, 255 Fm, 255 Md, 256 Md, 257 Md, 259 No. Their properties are described in more detail, for example, in Nuclear Data Sheets (Elsevier, Amsterdam, NL).

[0418] In one embodiment of the present invention, the radionuclide is used for diagnostic purposes. Preferably, the radioisotope 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, 177 Lu, 201 Tl, 203 Pb, 18 F, 76Br, 77 Br, 149Tb, 123 I, 124 I, and 125 More preferably, the radionuclide is selected from the group including, but not limited to, 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 111 In, 152 Tb, 155 Tb, and 203 Even more preferably, the radionuclide is selected from the group including Pb. 64 Cu, 68 Ga, 111 In, and 203 Pb. However, it will also be appreciated by those skilled in the art that the use of said radionuclides is not limited to diagnostic purposes, but also encompasses their use in therapy and therapeutic diagnostic methods when conjugated to the compounds of the present invention.

[0419] In one embodiment of the present invention, the 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, and 211 More preferably, the radioisotope is selected from the group including At. 47 Sc, 67 Cu, 90 Y, 177 Lu, 212 Pb, 213 Bi,225 Ac, and 227 Even more preferably, the radionuclide is selected from the group including: 90 Y, 177 Lu, 212 Pb, 225 Ac, and 227 However, it will be appreciated by those skilled in the art that the use of said radionuclides is not limited to therapeutic purposes, but also encompasses their use in diagnostic and therapeutic methods when conjugated to the compounds of the present invention.

[0420] Chelators that are in principle useful and / or suitable in the practice of the present invention, including the diagnosis and / or therapy of disease, are known to those skilled in the art. A wide variety of individual chelators are available and are reviewed, for example, by 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. No. 5,367,080 A, U.S. Pat. No. 5,364,613 A, U.S. Pat. No. 5,021,556 A, U.S. Pat. No. 5,075,099 A, and U.S. Pat. No. 5,886,142 A.

[0421] Representative chelating agents and their derivatives include AAZTA, BAT, CDTA, DTA, DTPA, CY-DTA, DTCBP, CTA, cyclam, cyclen, TETA, sarcophagazine, CPTA, TEAMA, 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-mono-acid, 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, HOPO, 2,3-HOPO, 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-a Mido-DOTA, BCN-DOTA, Butyne-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2A(trans-H2do2a), H2DO2A, H2ODO2A, DO3A, DO3A-thiol, DO3AM-acetic acid, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA -NHS-ester, maleimide-DOTA-GA, maleimide-mono-amide-DOTA, maleimide-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, hybrid thiosemicarbazone-benzothiazole, thiosemicarbazone-styrylpyridine tetradentate ligand H2L, 2-4HBED, HBED-CC, dmHBED, dmEHPG, HBED-nn, SHBED, Br-Me 2HBED, BPCA, HEHA, BF-HEHA, HYNIC(2-QA). NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPP B, (HYNIC)(トリシン)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIM A、IAM B. MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, macropa quin) methyl(macroquin)-SO3 NxS4-x N2S2 N3S N4 MAG3B NOTE NODAGA SCN-Bz-NO TA-R, NOT-P(NOTMP), MA-NOTMP, NOTAM, p-NCS-NOTA, TACN, TACN-TM, NETA, NETA-モノアミンp-SCN-PhPr-NE3TA, C-NE3TA-NCS, C-NETA-NCS, 3p-C-NETA, NODASE, NOPO, NODA, NO2A. N-link-NODA, C-NOTE, BCNOT-link-node -Shammer-Shammer-NOTE NO2A-Shammer NO2A-Shammer NO2AP NO3AP, N-NOTE, LINES-DO3A, p-NH2-Bn-NOTE, p-NH2-Bn-links-DO3A, p-NO2-Bn-sinks, p-S CN-Bn-NOTE p-SCN-Bn-オキソ-DO3A TRAP PEPA BF-PEPA pycup pycup2A pycup1A1Bn pycup2Bn, SarAr-R, DiAmSar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me) TAM A、TAMincluding, but not limited to, B, TAME, TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, TE2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ-HTCPP, DCMC, DEPA, H2ATSM, PCBA, PIH 2,3-HOPO represents 3-hydroxypyridin-2-one; 2C-TETA represents [4,8,11-tris-carboxymethyl-12-(4-isothiocyanato-benzyl)-1,4,8,11-tetraaza-cyclotetradec-1-yl]-acetic acid; 3p-C-DEPA represents 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-NCS represents 2-[(carboxymethyl)][5-(4-thiocyanatophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid; 3p-C-NE3TA-NCS represents {4-[2-(bis-carboxymethylamino)-5-(4-isothiocyanatophenyl)pentyl]-7-carboxymethyl[1,4,7]triazonan-1-yl}acetic acid; 3p-C-NETA represents {4-[2-(bis-carboxymethylamino)-5-(4-nitrophenyl)pentyl]-7-carboxymethyl[1,4,7]triazonan-1-yl}acetic acid; 4-aminobutyl-DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(4-aminobutyl)acetamide; 99m Tc(CO)3- chelating agent refers to a bidentate or tridentate chelating agent capable of forming a stable complex with technetium tricarbonyl fragments; AAZTA stands for 6-amino-6-methylperhydro-1,4-diazepine-N,N',N'',N''-tetraacetic acid; AmBaSar represents 4-((8-amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosan-1-ylamino)methyl)benzoic acid; ATSM represents diacetyl-bis(N4-methylthiosemicarbazone); Azido-mono-amide-DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(azidopropylethylacetamide); BAT 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-hexaone; BCN-DOTA-GA represents 2,2',2''-(10-(4-((2-((((1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; BF-HEHA represents 3-(4-isothiocyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid; BF-PEPA represents 2-(4-thiocyanatobenzoyl)-1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid; Bp44mT represents 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; BPCA represents a bipyridine-chelating agent; Br-Me2HBED represents N-(2-hydroxy-3,5-dimethylbenzyl)-Ar'-(2-hydroxy-5-(bromoacetamido)benzyl)ethylenediamine-N,N'-diacetic acid; Butyn-DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(3-butynylacetamide); CB-DO2A represents 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; CB-TE1A1P represents (1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane), CB-TE1K1P represents 6-amino-2-(11-phosphonomethyl-1,4,8,11-tetraaza-bicyclo[6.6.2]hexadec-4-yl)-hexanoic acid; CB-TE2A represents 4,11-bis-(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane; CB-TE2P represents 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid), CDTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; CHX-A″-DTPA represents [(2-{[2-(bis-carboxymethyl-amino)-cyclohexyl]-carboxymethyl-amino}-ethyl)-carboxymethyl-amino]-acetic acid; C-NOTA represents [4,7-bis-carboxymethyl-2-(4-nitro-benzyl)-[1,4,7]triazonan-1-yl]-acetic acid; CPTA represents 4-((1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)benzoic acid; Cyclam stands for 1,4,8,11-tetraazacyclotetradecane; Cyclene represents 1,4,7,10-tetraazacyclododecane; CY-DTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, monohydrate; DATA stands for [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid; DCMC represents 1,7-bis(carbamoylmethyl)-1,4,7,10-tetraazacyclodocane; Deferiprone (also known as DMHP, CP20, L1) stands for 3-hydroxy-1,2-dimethyl-4(1H)-pyridone; DEPA stands for 7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid; DEPA stands for diethylenetriaminepentaacetic acid DFO represents the group of desferal or desferrioxamine type 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; DFO-BAC stands for bromoacetyl-desferrioxamine; DFO-HOPO stands for N1-hydroxy-N1-(5-(4-(hydroxy(5-(1-hydroxy-6-oxo-1,6-dihydropyridine-2-carboxamido)pentyl)amino)-4-oxobutanamido)pentyl)-N4-(5-(N-hydroxyacetamido)pentyl)succinamide; DFO-pPhe-NCS (=p-SCN-Bn-DFO) represents 1-(4-isothiocyanatophenyl)-3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-(N-acetylhydroxylamino)-6,11,17,22-tetraazaheptaeicosine]thiourea; DiAmSar represents 1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane; dmEHPG represents N,N-8-ethylene-bis(o-hydroxyphenylglycine) dimethyl ester; dmHBED represents N,N*-bis(o-hydroxybenzyl)ethylenediaminediacetic acid; DM-TE2A represents 1,8-N,N'-bis-(carboxymethyl)-4,11-N'',N'''-bis-(methyl)-1,4,8,11-tetraazacyclotetradecane; DO2A represents 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid; DO2AP represents 4-[phosphorylmethyl]-1,4,7,10-tetrazacyclododecane-1,7-diacetic acid; DO2a2p represents 1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(methylenephosphonic acid); DO3A represents 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; DO3AM-acetic acid represents 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid; DO3AP represents 7-[phosphorylmethyl]-1,4,7,10-tetraazacyclododecane-1,4,10-triacetic acid; DO3A-thiol represents 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(2-thioethyl)acetamide; DOTA (also called tetraxetane) stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTAGA stands for 1,4,7,10-tetraazacyclodocecane, 1-(glutaric acid)-4,7,10-triacetic acid, DOTAM (also called TCMC) stands for 1,4,7,10-tetrakis[carbamoylmethyl]-1,4,7,10-tetracyclodecane; DOTAM-mono-acid represents 1,4,7,10-tetraazacyclododecane-1,4,7-tri(carbamoylmethyl)-10-acetic acid; DOTA-NCS stands for [4,7,10-tris-carboxymethyl-6-(4-isothiocyanato-benzyl)-1,4,7,10-tetraaza-cyclododec-1-yl]-acetic acid; DOTA-NHS stands for [4,10-bis-carboxymethyl-7-(2,5-dioxo-pyrrolidin-1-yloxycarbonylmethyl)-1,4,7,10 tetraaza-cyclododec-1-yl]-acetic acid; DOTA-NHS-ester represents 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; DOTMA stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid); DOTP stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid); DOXP represents (di-2-pyridyl ketone-4,4-dimethyl-3-thiosemicarbazone; Dp44mT represents 2-(di-2-pyridinylmethylene)-N,N-dimethyl-hydrazinecarbothioamide, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone; DpC represents di-2-pyridyl ketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone; DTC stands for diethyldithiocarbamate DTPA stands for diethylenetriaminepentaacetic acid, EDDA stands for ethylenediaminediacetic acid FSC (also known as Fusarin C) 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-hexaone; H2ATSM represents 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), H2CB-TE2A represents 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane; H2CHX-DEDPA represents N,N'-(6-carboxy-2-pyridylmethyl)-N,N'-diacetic acid-1,2-diaminoethane; H2dedpa represents 1,2-[{6-(carboxylato)pyridin-2-yl}methylamino]ethane; H2DO2A represents 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid; H2ODO2A represents 1-oxa-4,7,10-triazacyclododecane-4,10-diacetic acid; H2PTSM represents pyruvaldehyde bis(methyl-thiosemicarbazone); H4octapa represents N,N'-(6-carboxy-2-pyridylmethyl)-N,N'-diacetic acid-1,2-diaminoethane; HBED stands for bis(2-hydroxybenzyl)ethylenediaminediacetic acid; HBED-CC represents N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid; HEHA stands for 1,4,7,10,13,16-hexaazacyclooctadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid; HOPO represents a group of octadentate hydroxypyridinone type chelating agents; HP-DO3A represents 2,2',2''-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetic acid; HYNIC stands for 6-hydrazino-nicotinic acid; HYNIC-Ko-DPPB represents N-ε-(2-(diphenylphosphino)benzoyl)-N-α-(6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinyl)lysine methyl ester; HYNIC-Kp-DPPB represents N-ε-(4-(diphenylphosphino)benzoyl)-N-α-(6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinyl)lysine methyl ester; Macropa represents N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown; MAG3 stands for (N-hydroxysuccinimidyl S-acetylmercaptoacetyltriglycinate; Maleimide-DOTA represents 2,2',2''-(10-(1-carboxy-4-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; Maleimide-DOTA-GA represents 2,2',2''-(10-(1-carboxy-4-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; Maleimide-mono-amide-NOTA represents 1,4,7-triazacyclononane-1,4-bis-acetic acid-7-maleimidoethylacetamide; Maleimide-mono-amine-DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide; MAMA stands for monoamine-monoamide dithiol; MAMA-DA stands for N-[[[(2-mercaptoethyl)amino]carbonyl]methyl]-N-(2-mercaptoethyl)-6-aminododecanoic acid; MAMA-HA stands for N-[[[(2-mercaptoethyl)amino]carbonyl]methyl]-N-(2-mercaptoethyl)-6-aminohexanoic acid; MAMA-HAD stands for N-[[[(2-mercaptoethyl)amino]carbonyl]methyl]-N-(2-mercaptoethyl)-6-aminohexadecanoic acid; MA-NOTMP represents methylaminotriazacyclononane trimethylphosphinate; MM-TE2A represents 1,8-N,N'-bis-(carboxymethyl)-4-N''-(methyl)-1,4,8,11-tetraazacyclotetradecane; N2S2 represents N,N'-bis-(2-amino-ethyl)-propane-1,3-diamine; N3OA represents 4,7,10-tris(carbamoylmethyl)-,4,7,10-triaza-12-crown ether; N3S represents (sulfanylidenehydrazinylidene)azanide; N4 represents N,N'-bis-(2-amino-ethyl)-propane-1,3-diamine; NB-DOTA represents {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid; N-benzyl-NODA represents 1-benzyl-1,4,7-triazonane-1,4-diyl)diacetic acid; NE3TA represents {4-carboxymethyl-7-[2-(carboxymethyl-amino)-ethyl]-[1,4,7]triazonan-1-yl}-acetic acid; NETA represents {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid; NH2-DOTA-GA represents 2,2',2''-(10-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; NH2-PEG4-DOTA-GA represents 2,2',2''-(10-(1-amino-19-carboxy-16-oxo-3,6,9,12-tetraoxa-15-azanonadecane-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; NHS-BAT ester represents the N-hydroxysuccinimide ester of 6-(4'-(4''-carboxyphenoxy)butyl)-2,10-dimercapto-2,10-dimethyl-4,8-diazaundecane; NHS-HYNIC stands for N-hydroxysuccinimidyl hydrazinonicotinic acid hydrochloride; Nitro-DOTA represents 2-(g-nitrobenzyl)-l,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid; Nitro-PA-DOTA represents a-(2-(g-nitrophenyl)ethyl)-l,4,7,10-tetraazacyclododecane-l-acetic acid-4,7,10-tris(methylacetic acid); NO2A represents 1,4,7-triazacyclononane-N,N',N''-triacetic acid; NO2A-Azide represents 1,4,7-triazacyclononane-1,4-bis(acetic acid)-7-(3-azidopropylacetamide); NO2A-butyne represents 1,4,7-triazacyclononane-1,4-bis(acetic acid)-7-(3-butynylacetamide); NO2AP represents triazacyclononane; NO3AP represents 1,4,7-triazacyclononane-N-glutaric acid-N',N''-diacetic acid; NODA represents 4,10-bis(carbamoylmethyl)-4,10-diaza-12-crown ether; 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; NOPO represents 3-{[4,7-bis-(hydroxy-hydroxymethyl-phosphinoylmethyl)-[1,4,7]triazonan-1-ylmethyl]-hydroxy-phosphinoyl}-propionic acid; NOTA represents 1,4,7-triazacyclononanetriacetic acid, NOTAM represents 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetamide; NOTA-NHS stands for 3-hydroxy-2-oxopyridine, NOTA-NHS ester represents 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid; NOTP stands for 1,4,7-triazacyclononane-N,N'N''-tris(methylenephosphonic) acid; NTP stands for {4-carboxymethyl-7-[2-(carboxymethyl-amino)-ethyl]-[1,4,7]triazonan-1-yl}-acetic acid; NxS4-x (N4, N2S2, N3S) represents a group of tetradentate chelating agents with an N atom (basic amine or non-basic amide) and a thiol as donors that stabilize Tc-complexes, especially Tc(V)-oxo complexes; o,p-EDDHA represents ethylenediamine-N(o-hydroxyphenylacetic acid)-N'(p-hydroxyphenylacetic acid) acid; OPTT represents 9-oxa-3,6,12,15,21-pentaazatricyclo[15,3,2,1]trieicosa-1(21),17,19-triene-2,7,11,16-tetradione; OTTA represents 1-oxa-4,7,10-triazacyclododecane-N,N',N''-triacetic acid; Oxo-DO3A represents 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid; PA-DOTA represents 1,4,7,10-tetraaza-N-(1-carboxy-3-(4-nitrophenyl)propyl)-N',N'',N'''-tris(acetic acid)cyclododecane; p-BZ-HTCPP represents 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9-triacetic acid; PCBA stands for 1-[(1,4,7,10,13-pentaazacyclopentadec-1-yl)methyl]benzoic acid; PCB-TE1A1P represents 2-(11-(phosphonomethyl)-1,4,8,11-tetraazabicyclo[6.6.3]heptadecan-4-yl)acetic acid; PCTA represents 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9-triacetic acid; PEPA stands for 1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid; PIH stands for pyridoxal isonicotinoyl hydrazone; p-NCS-Bz-DFO represents N1-hydroxy-N1-(5-(4-(hydroxy(5-(3-(4-thiocyanatobenzoyl)thioureido)pentyl)amino)-4-oxobutanamido)pentyl)-N4-(5-(N-hydroxyacetamido)pentyl)succinamide; p-NCS-Bz-DOTA represents S-2-(4-thiocyanatobenzoyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid; p-NH2-Bn-DOTA represents S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid; p-NH2-Bn-NOTA represents 2-S-(4-aminobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid; p-NH2-Bn-oxo-DO3A represents 1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid; p-NH2-Bn-PCTA represents 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-4-S-(4-aminobenzyl)-3,6,9-triacetic acid; p-NO2-Bn-cyclene represents S-2-(4-nitrobenzyl)-1,4,7,10-tetraazacyclododecane; p-NO2-Bn-DOTA represents S-2-(4-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid; p-SCN-Bn-DFO represents N1-hydroxy-N1-(5-(4-(hydroxy(5-(3-(4-isothiocyanatophenyl)thioureido)pentyl)amino)-4-oxobutanamido)pentyl)-N4-(5-(N-hydroxyacetamido)pentyl)succinamide; p-SCN-Bn-DOTA represents S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid; p-SCN-Bn-NOTA represents 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid; p-SCN-Bn-oxo-DO3A represents 1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-isothiocyanatoobenzyl)-4,7,10-triacetic acid; p-SCN-Bn-PCTA represents 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid; p-SCN-BN-TCMC represents S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane; p-SCN-Bz-DOTA represents S-2-(4-isothiocyanatobenzoyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid; p-SCN-Bz-NOTA represents 2-S-(4-isothiocyanatobenzoyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid; p-SCN-PhPr-NE3TA represents 2,2'-(7-(2-((carboxymethyl)(3-(4-isothiocyanatophenyl)propyl)amino)ethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid; PTSM represents pyruvaldehyde bis(N(4)-methylthiosemicarbazone); pycup represents 1,8-(2,6-pyridinedimethylene)-1,4,8,11-tetraazacyclotetradecane; pycup2Bn represents N1-hydroxy-N1-(5-(4-(hydroxy(5-(3-(4-isothiocyanatophenyl)thioureido)pentyl)amino)-4-oxobutanamido)pentyl)-N4-(5-(N-hydroxyacetamido)pentyl)succinamide; Sar (also known as sarcofazine) stands for 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane; SarAr represents (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), SCN-CHX-A-DTPA-P represents [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid; SCN-TETA represents 6-[p-(isothiocyanato)benzyl]-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid; SHBED represents 3,6,10,13,16,19-hexaazabicyclo(6,6,6)icosane; Tachpyr represents (N,N'N''-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane), tachpyr-(5-Me) represents 1,3,5-cis,cis-triaminocyclohexane-N,N',N''-tri-(5-methyl-2-methylpyridinimine); TACN represents 1,4,7-triazacyclononane; TACN-TM stands for 1,4,7-tris(2-mercaptoethyl)-1,4,7-triazacyclononane; TA-DOTA represents 2,2',2''-(10-(2-((2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; TA-DOTA-GA represents 1,1,1-tris(aminomethyl)ethane; TAM A represents methyl-(2-methyl-3-methylamino-2-methylaminomethyl-propyl)-amine; TAME stands for 1,1,1-tris-(aminomethyl)ethane; TAME-Hex represents (1,8-N,N'-bis(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane; TBPD represents 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-2,10-dione; TCMC stands for 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid; TE2A represents [4,8-bis-carboxymethyl-11-(2,5-dioxo-3-sulfo-pyrrolidin-1-yloxycarbonylmethyl)-1,4,8,11 tetraaza-cyclotetradec-1-yl]-acetic acid; TEAMA represents 6-(p-bromoacetamidobenzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid; TETA represents 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid; TETAM represents 2,2',2'',2''''-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetraacetamide; THP stands for hexadentate tris(3,4-hydroxypyridinone); THPN stands for 1,3-propanediamine-N,N,N',N'-tetrakis[(2-(aminomethyl)-3-hydroxy-1,6-dimethyl-4(1H)-pyridinone)acetamide]; THP-TATE stands for 3,3',3''-(((1,4,7 triazonane-1,4,7-triyl)tris(methylene))tris(hydroxyphosphoryl))triporponic acid; TRAP stands for 3-({4,7-bis-[(2-carboxy-ethyl)-hydroxy-phosphinoylmethyl]-[1,4,7]triazonan-1-ylmethyl}-hydroxy-phosphinoyl)-propionic acid; Triapine represents dipyridyl thiosemicarbazone, Tricine stands for picolylamine diacetic acid; TRITA represents 2,2',2'',2''''-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid; TRITRAM stands for 2,2',2''-(1,4,7,10-tetraazacyclotridecane-1,4,7-triyl)triacetamide.

[0422] HYNIC, DTPA, EDTA, DOTA, TETA, bisaminobisthiol (BAT) based chelators are disclosed in U.S. Pat. No. 5,720,934; desferrioxamine (DFO) is disclosed in Doulias et al. (Doulias et al., Free Radic Biol Med, 2003, 35:719); tetrapyridine, and N3S, N2S2, and N4 chelators are disclosed in U.S. Pat. Nos. 5,367,080 A, 5,364,613 A, 5,021,556 A, 5,075,099 A, and 5,886,142 A, 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) is disclosed by Pfister et al. (Pfister et al., EJNMMI 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); and macropas and analogs are disclosed by Thiele et al. (Thiele et al., Angew Chem Int Ed Engl, 2017, 56: 14712), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA) and PEPA analogs are disclosed by Price and Orvig (Price et al., Chem Soc Rev, 2014, 43: 260), pycup and analogs are disclosed by Boros et al. (Boros et al., Mol Pharm, 2014, 11: 617), N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED), 1,4,7,10-tetrakis(carbamoylmethyl)-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, 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), and 1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA) were obtained from Price and Orvig (Price et al., Chem.). Soc Rev, 2014, 43: 260), 1-hydroxy-2-pyridone ligands (HOPO) are disclosed by Allott et al. (Allott et al., Chem Commun (Camb), 2017, 53: 8529), [4-carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl-[1,4]diazepan-1-yl]-acetic acid (DATA) is disclosed by Tornesello et al. (Tornesello et al., Molecules, 2017, 22: 1282), tetrakis(aminomethyl)methane (TAM) and analogs are disclosed by McAuley 1988 (McAuley et al., Canadian Journal of Chemistry, 1989, 67: 1657), and hexadentate tris(3,4-hydroxypyridinone) (THP) and analogs are disclosed by Ma et al. (Ma et al., Dalton Trans, 2015, 44: 4884).

[0423] 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 111 It is used in Octreoscan® to complex 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 described by Tweedle et al. (U.S. Pat. No. 4,885,363); other polyazamacrocycles for chelating trivalent metal isotopes have been described by Eisenwiener et al. (Eisenwiener et al., Bioconjug Chem, 2002, 13: 530); 99m N4-chelators, such as Tc-N4-chelators, have been used for peptide labeling in the case of minigastrins to target the CCK-2 receptor (Nock et al., J Nucl Med, 2005, 46:1727).

[0424] In one embodiment, the chelating agent is DOTA, DOTAGA, DOTAM, DOTP, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, CHX-A″-DTPA, DFO, macropa, HOPO, TRAP, THP, DATA, NOPO, NOTP, PCTA, sarcofadin, FSC, NETA, NE3TA, H4octapa, pycup, HYNIC, NxS4-x(N4, N2S2, N3S), 99m The metal chelator is selected from the group including, but not limited to, Tc(CO)3-chelators, and analogs thereof.

[0425] The chemical structure of the chelating agent is as follows:

[0426] [ka]

[0427] [ka]

[0428] In preferred embodiments, the metal chelator is selected from the group consisting of DOTA, DOTAGA, DOTAM, NOTA, NODAGA, NODA-MPAA, NOPO, HBED, DTPA, CHX-A″-DTPA, CB-TE2A, Macropa, PCTA, N4, and analogs thereof.

[0429] In a more preferred embodiment, the metal chelator is selected from the group consisting of DOTA, DOTAGA, NODAGA, and Macropa, and their analogs.

[0430] It will be appreciated by those skilled in the art that in one embodiment, the chelator further comprises one or more functional groups or functionalities that allow for its attachment to a compound of the present invention.

[0431] It will be appreciated by those skilled in the art that chelating agents may, in principle, be used regardless of whether the compounds of the invention are used or suitable in diagnosis or therapy, such principles being outlined, among others, in International Patent Application WO 2009 / 109332 A1.

[0432] It will further be appreciated by those skilled in the art that the presence of a chelator in a compound of the present invention, unless otherwise stated, includes the possibility that the chelator may be complexed to any metal complex partner, i.e., any metal that can in principle be complexed by a chelator. Explicitly named chelators of the compounds of the present invention or the general term chelator in connection with the compounds of the present invention refer either to the uncomplexed chelator itself, or to a chelator having any metal complex partner bound thereto, where the metal complex partner is any radioactive or non-radioactive metal complex partner. Preferably, the chelator-metal complex, i.e., the chelator having a metal complex partner bound thereto, is a stable chelator-metal complex.

[0433] Non-radioactive chelator-metal complexes have several applications, for example, for assessing properties such as stability or activity that would otherwise be difficult to determine. One aspect is that cold variants of radioactive versions of the metal complex partner (e.g., non-radioactive indium complexes are described in the Examples) can act as surrogates for radioactive compounds. Furthermore, they are valuable tools for identifying in vitro or in vivo metabolites and for assessing the toxicity properties of compounds of the invention. In addition, chelator-metal complexes can be used in binding assays that take advantage of the fluorescent properties of some metal complexes with individual ligands (e.g., europium salts).

[0434] Chelators can be synthesized or commercially available with a wide variety of (possibly already activated) groups for conjugation to peptides or amino acids.

[0435] Direct conjugation of a chelator to the amino-nitrogen of each compound of the present invention is fully possible for chelators selected from the group consisting of DTPA, DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DFO, DATA, sarcofazine, and N4, preferably DTPA, DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, CB-TE2A, and N4. A preferred linkage in this regard is an amide linkage.

[0436] Direct conjugation of an isothiocyanate-functionalized chelator to the amino-nitrogen of each compound of the present invention is fully possible for chelators selected from the group consisting of DOTA, DOTAGA, NOTA, NODAGA, DTPA, CHX-A″-DTPA, DFO, and THP, preferably DOTA, DOTAGA, NOTA, NODAGA, DTPA, and CHX-A″-DTPA. A preferred linkage in this regard is the thiourea linkage.

[0437] Functional groups on chelators that are preferred precursors for direct conjugation of the chelator to the amino-nitrogen are known to those skilled in the art and include, but are not limited to, carboxylic acids, activated carboxylic acids, e.g., active esters such as NHS-esters, pentafluorophenol-esters, HOBt-esters, HOAt-esters, and isothiocyanates.

[0438] Functional groups on chelators that are preferred precursors for direct conjugation of the chelator to a carboxylic acid group are known to those skilled in the art and include, but are not limited to, alkylamino and arylamino nitrogens. Respective chelator reagents are commercially available for some chelators, for example, DOTA, which has either an alkylamino or arylamino nitrogen.

[0439] Functional groups on chelators that are preferred precursors for direct conjugation of the chelator to a thiol group are known to those skilled in the art and include, but are not limited to, maleimide nitrogens. Respective chelator reagents are commercially available for some chelators, for example, DOTA, which has a maleimide nitrogen.

[0440] Functional groups on chelators that are preferred precursors for direct conjugation of the chelator to the azide group are known to those skilled in the art and include, but are not limited to, acyclic and cyclic alkynes. The respective chelator reagents are commercially available for some chelators, for example, for DOTA with propargyl or butynyl groups.

[0441] Functional groups on chelators that are preferred precursors for direct conjugation of the chelator to an alkyne group are known to those skilled in the art and include, but are not limited to, alkyl and aryl azines. The respective chelator reagents are commercially available for some chelators, for example, azidopropyl-bearing DOTA.

[0442] In one embodiment, the compounds of the invention are present as pharmaceutically acceptable salts.

[0443] According to one embodiment, the effector is a drug, preferably a cytotoxic drug. The cytotoxic drug may optionally be covalently linked to the cyclic peptide structure by a linker moiety, which may be cleavable or non-cleavable. According to this embodiment, the compound of the present invention preferably does not contain a chelating agent. In these embodiments, the drug, preferably a cytotoxic drug, may be covalently linked to the cyclic peptide structure by a linker moiety, such as L1, L3, L4, or L6 (described above).

[0444] The following are exemplary drugs that can be used as effectors in the compounds of the present invention: (A) Anti-neoplastic agents, e.g. (A1) DNA alkylating agents, such as duocarmycin (including its synthetic analogs: adozelesin, carzelesin, bizelesin, KW-2189, and CBI-TMI), nitrogen mustard analogs (e.g., cyclophosphamide, chlorambucil, melphalan, chlormethine, ifosfamide, trofosfamide, prednimustine, bendamustine, chlornaphazine, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride), hydrochloride), mannomustine, mitolactol, novembichine, phenesterine, uracil mustard), alkyl sulfonates (e.g., busulfan, treosulfan, mannosulfan, improsulfan, and piposulfan), ethylenimines (e.g., thiotepa, triaziquone, carboquone), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, chlorozotocin, fotemustine, nimustine, ranimustine), epoxides (e.g., etoglucide), other alkylating agents (e.g., mitobronitol, pipobroman, temozolomide, dacarbazine); (A2) Topoisomerase inhibitors, such as doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, etoposide, etoposide phosphate, irinotecan and its metabolites such as SN-38, teniposide, topotecan, resveratrol, epipodophyllins (e.g., 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, mitoxantrone, novantrone, retinoic acid (retinol), 9-nitrocamptothecin (RFS 2000)); (A3) RNA polymerase II inhibitors, such as alpha-amanitin, other amatoxins; (A4) DNA cleaving agents, such as calicheamicin; (A5) Antimitotic or microtubule disrupting agents, such as vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinorelbine, navelbine, vinflunide, vintafolide), taxanes (e.g., paclitaxel, docetaxel, paclitaxel, poliglumex), polyglumex), cabazitaxel) and their analogs, maytansinoids (e.g., DM1, DM2, DM3, DM4, maytansine, and ansamitocin) and their analogs, cryptophycins (e.g., cryptophycin 1 and cryptophycin 8), epothilones, eleutherobin, discodermolide, bryostatin, dolostatin, auristatins (e.g., monomethylauristatin E (MMAE), monomethylauristatin F), tubulysin, cephalostatin; pancratistatin, sarcodictyin, spongistatin, demecolcine, mitomycin; (A6) Antimetabolites, such as DHFR inhibitors (e.g., methotrexate, trimetrexate, denopterin, pteropterin, aminopterin (4-aminopteroic acid) or other folic acid analogs, e.g., raltitrexed, pemetrexed, pralatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea, deferoxamine), pyrimidine analogs (e.g., cytarabine, fluorouracil, 5-fluorouracil), uracil and its metabolites, tegafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, fluorouracil combinations, tegafur combinations, trifluridine combinations, cytosine arabinoside, ancitabine, floxuridine, doxifluridine), uracil analogs (e.g., 6-azauridine, deoxyuridine), cytosine analogs (e.g., enocitabine), purine analogs (e.g., azathioprine, fludarabine, mercaptopurine, thiamiprine, thioguanine, cladribine, clofarabine, nelarabine), folic acid supplements such as folinic acid; (A7) Kinesin spindle protein inhibitors, such as filanesib; (A8) Kinase inhibitors, such as ipatasertib, BIBW 2992 (anti-EGFR / Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, afatinib, vemurafenib, crizotinib, regorafenib, masitinib, dabrafenib, trametinib, ibrutinib, ceritinib, lenvatinib, nintedanib, cediranib, palbociclib b), osimertinib, alectinib, rociletinib, cobimetinib, midostaurin, olmutinib, E7080 (anti-VEGFR2), mubritinib, ponatinib (AP24534), bafetinib (INNO-406), bosutinib (SKI-606), cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, tivozanib, ispinesib, temsirolimus, everolimus, ridaforolimus; (A9) Nicotinamide phosphoribosyltransferase inhibitors, such as CAS number 2241014-82-2; (A10) matrix metallopeptidase 9 inhibitors, such as derivatives of CGS27023A; (A11) Phosphatase inhibitors, such as microcystin-LR; (B) immunomodulatory agents, including immunostimulants, immunosuppressants, cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids (e.g., amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone, danazol, dexamethasone, prednisone, triamcinolone acetonide, beclomethasone propionate), DHEA, hydroxychloroquine, meloxicam, methotrexate, mofetil, mycophenylate, sirolimus, tacrolimus, everolimus, fingolimod, ibrutinib, imiquimod, resiquimod, cytokines, peptide immunomodulators, e.g., TLR agonists (e.g., CpG oligonucleotides); (C) Anti-infectious disease agents, including antibacterial, antimycobacterial, and antiviral agents. Non-limiting examples of antibiotics used in antibiotic-antibody drug conjugates are rifalogues, i.e., rifamycin derivatives; (D) A radioisotope, metabolite, pharmaceutically acceptable salt, and / or prodrug of any of the aforementioned active substances (A) to (C).

[0445] According to one embodiment, the effector is a moiety derived from exatecan, PNU-159682, DM4, amanitin, duocarmycin, auristatin, maytansine, tublysin, calicheamicin, SN-38, taxol, daunomycin, vinblastine, doxorubicin, methotrexate, pyrrolobenzodiazepines, pyrrole-based kinesin spindle protein (KSP) inhibitors, indolino-benzodiazepine dimers, or radioisotopes and / or pharmaceutically acceptable salts thereof.

[0446] 4. Use of Compounds or Peptides for Diagnostic and / or Therapeutic Purposes In one embodiment, and as preferably used herein, a diagnostically active compound is a compound that is suitable or useful in the diagnosis of disease.

[0447] In one embodiment, and as preferably used herein, a diagnostic agent or diagnostically active agent is a compound that is suitable or useful in the diagnosis of disease.

[0448] In one embodiment, and as preferably used herein, a therapeutically active compound is a compound that is suitable or useful in the treatment of a disease.

[0449] In one embodiment, and as preferably used herein, a therapeutic agent or therapeutically active agent is a compound that is suitable or useful in the treatment of a disease.

[0450] In one embodiment, and as preferably used herein, a therapeutically diagnostically active compound is a compound that is suitable or useful for both the diagnosis and therapy of a disease.

[0451] In one embodiment, and as preferably used herein, a therapeutic diagnostic agent or therapeutically active agent is a compound that is suitable or useful for both the diagnosis and therapy of disease.

[0452] In one embodiment, and as preferably used herein, a therapeutic diagnostic method is a method for the combined diagnosis and therapy of a disease; preferably, the diagnostically and therapeutically active compounds of the combination used in the therapeutic diagnostic method are radiolabeled.

[0453] In one embodiment, and as preferably used herein, treatment of a disease is the treatment and / or prevention of a disease.

[0454] In one embodiment, and as preferably used herein, pEC50 is determined in a FACS binding assay, which is as described in the Examples part.

[0455] In one embodiment, and as preferably used herein, pIC50 is determined in a FACS binding assay, which is as described in the Examples part.

[0456] In one embodiment, and as preferably used herein, a disease involving CAIX is one in which cells, including but not limited to tumor cells, expressing CAIX, preferably in an upregulated manner, and tissues, either of which express CAIX, preferably in an upregulated manner, respectively, are responsible for the disease and / or symptoms of the disease or are part of the underlying pathology of the disease. Preferred CAIX-expressing cells are tumor cells. In one disease embodiment, preferably when used in the context of therapy, treating the disease and / or influencing the therapy, cells, tissues, and pathology, respectively, results in a cure, treatment, or amelioration of the disease and / or symptoms of the disease. In one disease embodiment, preferably when used in the context of diagnosing and / or diagnosing a disease, labeling CAIX-expressing cells and / or CAIX-expressing tissue allows for the identification or differentiation of said cells and / or tissue from healthy or non-CAIX-expressing cells and / or healthy or non-CAIX-expressing tissue. More preferably, such identification or differentiation forms the basis of said diagnosis and diagnosing, respectively. In one embodiment, labeling refers to the interaction of a detectable label, directly or indirectly, with CAIX-expressing cells and / or with CAIX-expressing tissues or tissues containing such CAIX-expressing cells; more preferably, such interaction involves or is based on the interaction of a label or a compound bearing such a label with CAIX.

[0457] In one embodiment, and as preferably used herein, a target cell is a cell that expresses CAIX and is responsible for the disease and / or symptoms of the disease or is part of the underlying pathology of the disease.

[0458] In one embodiment, and as preferably used herein, non-target cells are cells that do not express CAIX and / or are not responsible for the disease and / or symptoms of the disease or are part of the underlying pathology of the disease.

[0459] In one embodiment, and as preferably used herein, a neoplasm is an abnormal new growth of cells. Cells in a neoplasm grow more rapidly than normal cells and will continue to grow if untreated. Neoplasms can be benign or malignant.

[0460] In one embodiment, and as preferably used herein, a tumor is a mass lesion that can be benign or malignant.

[0461] In one embodiment, and as preferably used herein, cancer is a malignant neoplasm.

[0462] The expression pattern of CAIX in solid tumors makes it a compelling therapeutic and diagnostic target. CAIX is involved in breast cancer (Storci et al., J Pathol, 2008, 214, pp. 25-37), kidney cancer (Luong-Player et al., Am J Clin Pathol, 2014, 141, pp. 219-225), colon cancer (Korkeila et al., Br J Cancer, 2009, 100, pp. 874-880), ovarian cancer (Choschzick et al., Virchows Arch, 2011, 459, pp. 193-200), head and neck cancer (Kappler et al., Strahlenther Onkol, 2008, 184, pp. 393-399), pancreatic cancer (Juhasz et al., Aliment Pharmacol Ther, 2003, 18, pp. 837-846), and lung cancer (Ilie et al., Br J Cancer, 2009, 100, pp. 874-880). It has been reported that IL-1 is upregulated in most types of solid tumors, including but not limited to, IL-1 (Cancer, 2010, 102, 1627-1635).

[0463] One of the most investigated indications for CAIX in the field of renal malignancies is renal cell carcinoma (RCC). CAIX expression in clear cell RCC is out of the hypoxia-induced signaling cascade, in contrast to other neoplasms (Shuin et al., Cancer Res, 1994, 54, pp. 2852-2855). In a study, 317 primary renal tumors were examined for their CAIX expression levels by immunohistochemistry (IHC). High CAIX expression (>85% of tumor cells) was found in 71% of RCC samples (Genega et al., Am J Clin Pathol, 2010, 134, pp. 873-879). This finding, along with the fact that clear cell RCC accounts for the majority of epithelial neoplasms of the kidney, makes clear cell RCC an interesting indication for targeted CAIX compounds.

[0464] Furthermore, a study examined CAIX expression in 166 rectal cancer patients treated with preoperative radiation- or chemo-radiotherapy, or surgery alone (Korkeila et al., British Journal of Cancer, 2009, 100, 874-880). 44% (39 of 80) of tumor samples from surgical patients were found to be CAIX positive.

[0465] In an extensive immunohistochemical study of 1551 cases of tumor and normal samples from various organs, carbonic anhydrase 9 expression was evaluated (Luong-Player et al., Am J Clin Pathol, 2014, 141, 219-225). The indications with the highest amount of CAIX-positive staining were intrahepatic cholangiocarcinoma (90%) and the above-discussed clear cell renal cell carcinoma (90% low-grade and 86% high-grade tumors). Positive CAIX tumor samples were found in a range of 30-70% according to indication: cervical adenocarcinoma (68%), pancreatic adenocarcinoma (58%), squamous cell carcinoma (57%), gastric adenocarcinoma (57%), endometrial carcinoma FIGO II (54%), colon adenocarcinoma (51%), ovarian papillary serous carcinoma (49%), endometrial carcinoma FIGO I (47%), mixed lung adenocarcinoma (46%), esophageal adenocarcinoma (43%), invasive urothelial carcinoma (35%), and papillary renal cell carcinoma (30%).

[0466] Next to its expression on cancer cells, CAIX upregulation on cancer-associated fibroblasts (CAFs) has been reported. CAF cells are one of the most prominent components of the tumor microenvironment (TME), which is central to the tumor's ability to continue growing. Targeting CAFs is a widely accepted strategy for inhibiting tumor growth. CAIX expression in the tumor microenvironment opens up yet another option for targeting malignant tissues. CAIX upregulation has been reported in both pancreatic tumor cells and their surrounding cancer-associated fibroblasts (Fiaschi et al., Cell Cycle, 2013, 12, pp. 1791-1801). Furthermore, a study of lung adenocarcinomas showed CAIX-positive CAF staining using immunohistochemistry in 39 of 158 tissue samples (Nakao et al., Cancer, 2009, 115, pp. 2732-2743). In addition, CAIX expression correlated with significantly worse patient outcomes.

[0467] The compounds of the present invention have high binding affinity to CAIX. Due to 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. As preferably used herein, a targeting agent is an agent that interacts with a target molecule, in this case, the CAIX. Thus, in terms of the cells and tissues targeted and targetable by the compounds of the present invention, any cells and tissues that specifically express the CAIX are targeted and targetable, respectively. As is known from the prior art, apart from specific tissues of the gastrointestinal tract and, to a lesser extent, the CNS (Zamanova et al., Expert Opin Ther Pat, 2019, 29, 509-533), CAIX is highly expressed in the mammalian and human body, especially on some neoplastic cells in some tumor indications, while CAIX expression is low in other tissues of the mammalian and human body. These CAIX-expressing tumor indications include breast cancer (Storci et al., J Pathol, 2008, 214, pp. 25-37), kidney cancer (Luong-Player et al., Am J Clin Pathol, 2014, 141, pp. 219-225), colon cancer (Korkeila et al., Br J Cancer, 2009, 100, pp. 874-880), ovarian cancer (Choschzick et al., Virchows Arch, 2011, 459, pp. 193-200), head and neck cancer (Kappler et al., Strahlenther Onkol, 2008, 184, pp. 393-399), pancreatic cancer (Juhasz et al., Aliment Pharmacol Ther, 2003, 18, pp. 837-846), and lung cancer (Ilie et al., Br J Cancer, 2010, 102, pp. 1627-1635). In clear cell renal cell carcinoma, CAIX expression is unique compared to other cancers because it is generally removed from the hypoxia-induced signaling cascade (Shuin et al., Cancer Res, 1994, 54, pp. 2852-2855).

[0468] Therefore, the compounds of the present invention are particularly suitable and useful in the diagnosis and treatment of these diseases, respectively. To that extent, the above-mentioned indications are indications that can be treated by the compounds of the present invention. It will be understood by those skilled in the art that metastasis, and in particular metastasis of the above-mentioned indications, can also be treated and diagnosed by the compounds of the present invention, and the diagnostic and therapeutic methods that utilize the compounds of the present invention.

[0469] It is also within the scope of the present invention that the compounds of the present invention are used in or for use in a method for treating the diseases disclosed herein. Such methods preferably comprise administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof. Such methods include, but are not limited to, curative or adjuvant cancer treatment. They may be used as palliative treatments where a cure is not possible and the goal is local disease control or symptom relief, or as therapeutic treatments where the therapy has a survival benefit and may be curative.

[0470] The methods for treating the diseases disclosed herein include the treatment of diseases disclosed herein, including tumors and cancers, and can be used as either a first-line therapy or a second-line, third-line, fourth-line, or definitive therapy. It is also within the scope of the present invention to combine the compounds of the present invention with additional therapeutic approaches. It is well known to those skilled in the art that the exact therapeutic intent, including curative, adjuvant, neoadjuvant, therapeutic, or palliative, will depend on the tumor type, location, and stage, as well as the patient's overall health.

[0471] Without wishing to be bound by any theory, the therapeutic effect of the compounds of the present invention is based on the delivery of the radionuclide to diseased CAIX-expressing cells or structures that are destroyed by the radiation emitted by the radionuclide.

[0472] Without wishing to be bound by any theory, the therapeutic use of the compounds of the present invention occurs through binding of said compounds to CAIX-expressing cells, particularly cancer cells, which are destroyed by radiation emitted by the radionuclide. It will also be understood by those skilled in the art that CAIX is a pan-tumor target that is expressed under hypoxic conditions, and such hypoxia is a hallmark of cancer. For this reason, any cancer and tumor, preferably any hypoxic cancer and tumor, can be treated and diagnosed, respectively. In a further embodiment, the disease is a solid cancer, preferably a hypoxic solid cancer.

[0473] Furthermore, the therapeutic use of the compounds of the present invention results from the binding of said compounds to CAIX-expressing cancer-associated fibroblasts (CAFs). It will also be understood by those skilled in the art that CAFs are a cell type present in the tumor microenvironment that promotes tumorigenic properties by initiating extracellular matrix remodeling or by secreting cytokines. For this reason, any tumor, preferably any cancer and tumor containing CAIX-expressing CAFs, respectively, can be treated and diagnosed. Accordingly, in a further embodiment, the disease that can be diagnosed and treated, respectively, by the compounds of the present invention is a cancer containing CAIX-expressing CAFs. Again, without wishing to be bound by any theory, the therapeutic use of the compounds of the present invention results from the binding of said compounds to CAIX-expressing CAFs, which are killed by radiation emitted by the radionuclide generated by the chelator of the compounds of the present invention.

[0474] In one embodiment of the invention, the disease is neoplasia nos (not otherwise specified), neoplasia, benign, neoplasia, uncertain whether benign or malignant, neoplasia, malignant, neoplasia, metastatic, neoplasia, malignant, uncertain whether primary or metastatic, tumor cells, benign, tumor cells, uncertain whether benign or malignant, tumor cells, malignant, malignant tumor, small cell type, malignant tumor, giant cell type, malignant tumor, spindle cell type, epithelial neoplasia nos, epithelial tumor, benign, carcinoma in situ nos, carcinoma nos, carcinoma, metastatic nos, carcinomatosis, epithelioma, benign, epithelioma, malignant, large cell cell carcinoma nos, carcinoma, undifferentiated type nos, carcinoma, anaplastic type nos, pleomorphic carcinoma, giant cell and spindle cell carcinoma, giant cell carcinoma, spindle cell carcinoma, pseudosarcomatous carcinoma, pleomorphic cell carcinoma, spherical cell carcinoma, small tumor (tumorlet), small cell carcinoma nos, oat cell carcinoma, small cell carcinoma, spindle cell types, papillary and squamous neoplasms, papilloma nos, papillary carcinoma in situ, papillary carcinoma nos, warty papilloma, verrucous carcinoma nos, squamous papilloma, papillary squamous carcinoma, papilloma varus, papillomatosis nos, squamous carcinoma in situ nos, squamous carcinoma nos, squamous cell type Squamous cell carcinoma, metastatic nos, squamous cell carcinoma, keratinizing type nos, squamous cell carcinoma, large cell, non-keratinizing type, squamous cell carcinoma, small cell, non-keratinizing type, squamous cell carcinoma, spindle cell type, adenoid squamous cell carcinoma, squamous intraepithelial carcinoma with suspicious stromal invasion, squamous cell carcinoma, microinvasive, Queyrat's erythroplasia, Bowen's disease, lymphoepithelial carcinoma, basal cell neoplasm, basal cell tumor, basal cell carcinoma nos, multicentric basal cell carcinoma, basal cell carcinoma, morphea type, basal cell carcinoma, fibroepithelial type, basosquamous cell carcinoma, variant carcinoma, Yadaszo Jadassohn's epithelioma in situ, trichoepithelioma, trichofolliculoma, trichilemmomas, calcifying epithelioma, transitional cell papilloma and carcinoma, transitional cell papilloma NOS, urothelial papilloma, transitional cell carcinoma in situ, transitional cell carcinoma NOS, Schneiderian papilloma, transitional cell papilloma, inverted type, Schneiderian carcinoma, transitional cell carcinoma, spindle cell type, basaloid cell carcinoma, cloacal carcinoma, papillary transitional cell carcinoma, adenoma and adenocarcinoma, adenoma NOS, bronchial adenoma NOS, adenocarcinoma in situ, adenocarcinoma NOS, adenocarcinoma, metastatic NOS, scirrhous adenocarcinoma, linitis plastica plastica), superficial spreading adenocarcinoma, adenocarcinoma, intestinal type, carcinoma, diffuse type, monomorphic adenoma, basal cell adenoma, islet cell adenoma, islet cell carcinoma, insulinoma nos, insulinoma, malignant, glucagonoma nos, glucagonoma, malignant,Gastrinoma nos, gastrinoma, malignant, mixed islet cell and exocrine adenocarcinoma, bile duct adenoma, cholangiocarcinoma, bile duct cystadenoma, bile duct cystadenocarcinoma, hepatocellular adenoma, hepatocellular carcinoma nos, hepatocholangioma, benign, combined hepatocellular carcinoma and cholangiocarcinoma, trabecular adenoma, trabecular adenocarcinoma, embryonal adenoma, eccrine cutaneous cylindroma, adenoid cystic carcinoma, cribriform carcinoma, adenomatous polyp nos, adenocarcinoma in adenomatous polyp, tubular adenoma nos, tubular adenocarcinoma, adenomatous polyposis coli, adenocarcinoma in adenomatous polyposis coli, multiple adenomatous polyps, solid carcinoma nos, simple carcinoma, carcinoid tumor nos, carcinoid tumor, malignant, carcinoid tumor, argyrophilic nos, carcinoid tumor, argyrophilic, malignant, carcinoid tumor, non-argyrophilic nos, carcinoid tumor, non-argyrophilic, malignant, mucocarcinoid tumor tumor), malignant, composite carcinoid, pulmonary adenomatosis, bronchioloalveolar adenocarcinoma, alveolar adenoma, alveolar adenocarcinoma, papillary adenoma NOS, papillary adenocarcinoma NOS, villous adenoma NOS, adenocarcinoma in villous adenoma, villous adenocarcinoma, tubulovillous adenoma, chromophobe adenoma, chromophobe carcinoma, acidophilic adenoma, acidophilic carcinoma, mixed acidophilic-basophilic adenoma, mixed acidophilic-basophilic carcinoma, eosinophilic adenoma, eosinophilic adenocarcinoma, basophilic adenoma, basophilic carcinoma, clear cell adenoma, clear cell adenocarcinoma NOS, hyperplastic renal cell tumor (hypernephroid tumor), renal cell carcinoma, clear cell adenofibroma, granular cell carcinoma, chief cell adenoma, aqueous clear cell adenoma, aqueous clear cell adenocarcinoma, mixed cell adenoma, mixed cell adenocarcinoma, adenolipoma, follicular adenoma, follicular adenocarcinoma NOS, follicular adenocarcinoma, well differentiated type, follicular adenocarcinoma, trabecular type, small follicular adenoma, large follicular adenoma, papillary and follicular adenocarcinoma, non-encapsulated sclerosing carcinoma, multiple endocrine adenoma, juxtaglomerular tumor, adrenocortical adenoma NOS, adrenocortical carcinoma, adrenocortical adenoma, dense cell type, adrenocortical adenoma, high Highly pigmented variant, adrenocortical adenoma, clear cell type, adrenocortical adenoma, glomerulosa cell type, adrenocortical adenoma, mixed cell type, endometrioid adenoma nos, endometrioid adenoma, borderline malignant, endometrioid carcinoma, endometrioid adenofibroma nos, endometrioid adenofibroma, borderline malignant, endometrioid adenofibroma, malignant, adnexal and skin appendage neoplasms, skin appendage adenoma, skin appendage carcinoma, sweat gland adenoma, sweat gland tumor nos, sweat gland adenocarcinoma, apocrine adenoma, apocrine adenocarcinoma, eccrine acrohidradenoma, eccrine spiral adenoma, sweat gland cyst, papillary hidradenoma,Papillary syringoma, syringoma nos, sebaceous adenoma, sebaceous gland carcinoma, ceruminous adenoma, cerumen carcinoma, mucoepidermal neoplasm, mucoepidermoid tumor, mucoepidermoid carcinoma, cystic, mucinous, and serous neoplasm, cystadenoma nos, cystadenocarcinoma nos, serous cystadenoma nos, serous cystadenoma, borderline malignant, serous cystadenocarcinoma nos, papillary cystadenoma nos, papillary cystadenoma, borderline malignant, papillary cystadenocarcinoma nos, papillary serous cystadenoma nos, papillary serous cystadenoma, borderline malignant, papillary serous cystadenocarcinoma, serous superficial papilloma nos, serous superficial papilloma, borderline malignant, serous superficial papillary carcinoma, mucinous cystadenoma nos, mucinous cystadenoma tumor, borderline malignant, mucinous cystadenocarcinoma NOS, papillary mucinous cystadenoma NOS, papillary mucinous cystadenoma, borderline malignant, papillary mucinous cystadenocarcinoma, mucinous adenoma, mucinous adenocarcinoma, pseudomyxoma peritonei, mucin-producing adenocarcinoma, signet ring cell carcinoma, metastatic signet ring cell carcinoma, tubular, lobular, and medullary neoplasms, intraductal carcinoma in situ NOS, invasive ductal carcinoma, comedocarcinoma, noninvasive, comedocarcinoma NOS, juvenile carcinoma of the breast, intraductal papilloma, intraductal papillary adenocarcinoma in situ, intracystic papillary adenoma, intracystic carcinoma in situ, intraductal papillomatosis NOS, subareolar ductal papillomatosis, medullary carcinoma NOS, medullary carcinoma with amyloid stroma, lymphoid infiltration medullary carcinoma with stroma, lobular carcinoma in situ, lobular carcinoma in situ (nos), invasive tubular carcinoma, inflammatory carcinoma, Paget's disease of the breast, Paget's disease and invasive ductal carcinoma of the breast, Paget's disease, extramammary, acinic cell neoplasm, acinic cell adenoma, acinic cell tumor, acinic cell carcinoma, mixed epithelial neoplasm, adenosquamous carcinoma, adenolymphoma, adenocarcinoma with squamous metaplasia, adenocarcinoma with chondral and osseous metaplasia, adenocarcinoma with spindle cell metaplasia, adenocarcinoma with apocrine metaplasia, thymoma, benign, thymoma, malignant, specialized gonadal neoplasm, sex cord-stromal tumor, theca cell tumor (nos), theca cell carcinoma, luteinoma (nos), granulosa Cell tumor nos, granulosa cell tumor, malignant, granulosa cell-theca cell tumor, androblastoma, benign, androblastoma nos, androblastoma, malignant, Sertoli-Leydig cell tumor, ginandroblastoma, tubular androblastoma nos, Sertoli cell carcinoma, tubular androblastoma with lipid storage, Leydig cell tumor, benign, Leydig cell tumor nos, Leydig cell tumor, malignant, hilar cell tumor, lipid cell tumor of the ovary, adrenal rest tumor, paraganglioma and glomus tumor, paraganglioma nos, paraganglioma, malignant,Sympathetic paraganglioma, parasympathetic paraganglioma, jugular bulb tumor, aortic body tumor, carotid bulb tumor, extra-adrenal paraganglioma NOS, extra-adrenal paraganglioma, malignant, pheochromocytoma NOS, pheochromocytoma, malignant, glomangiosarcoma, glomus tumor, glomus angiomoma, nevus and melanoma, pigmented nevus NOS, malignant melanoma NOS, nodular melanoma, balloon cell nevus, balloon cell melanoma, halo nevus, nasal fibrous papule, nerve nevus, large cell nevus, amelanocytic nevus, amelanotic melanoma, junctional nevus, malignant melanoma in junctional nevus, precancerous melanosis NOS, 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 and spindle cell nevi, epithelioid cell melanoma, spindle cell melanoma NOS, spindle cell melanoma type a, spindle cell melanoma type b, mixed epithelioid and spindle cell melanoma, blue nevi NOS, blue nevi, malignant, cellular blue nevi, soft tissue tumors and sarcomas NOS, soft tissue tumors, benign, sarcoma NOS, sarcomatosis NOS, spindle cell sarcoma, giant cell sarcoma, small cell sarcoma, epithelioid cell sarcoma, fibromatous neoplasms, fibroma NOS, fibrosarcoma NOS, fibromyxoma, fibromyxoid sarcoma, periosteal fibroma, periosteal fibrosarcoma, fascial fibroma, fascial fibrosarcoma, infantile fibrosarcoma, elastic fibroma, aggressive fibromatosis, abdominal fibromatosis, desmoplastic fibroma fibroma), fibrous histiocytoma nos, atypical fibrous histiocytoma, fibrous histiocytoma, malignant, fibroxanthoma nos, atypical fibroxanthoma, fibroxanthoma, malignant, dermatofibroma nos, dermatofibroma protuberans, dermatofibrosarcoma nos, myxomatous neoplasm, myxoma nos, myxosarcoma, lipomatous neoplasm, lipoma nos, liposarcoma nos, fibrolipoma, liposarcoma, well differentiated type, fibromyxoid lipoma, myxoid liposarcoma, round cell liposarcoma, pleomorphic liposarcoma, mixed type liposarcoma, intramuscular lipoma, spindle cell lipoma, angiomyolipoma, angiomyoliposarcoma, angiolipoma nos, angiolipoma, invasive, myelolipoma, brown lipoma, lipoblastomatosis, leiomyomatous neoplasm, leiomyoma nos, intravascular leiomyomatosis, leiomyosarcoma nos, epithelioid leiomyoma, epithelioid leiomyosarcoma, cellular leiomyoma, deforming leiomyoma, angiomyoma, angiomyosarcoma, myoma, myosarcoma, rhabdomyoma nos, rhabdomyosarcoma nos, pleomorphic rhabdomyosarcoma, mixed rhabdomyosarcoma,Embryonal rhabdomyoma, adult rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, complex mixed and stromal neoplasm, endometrial stromal sarcoma, endolymphatic stromal myosis, adenomyoma, pleomorphic adenoma, mixed tumor, malignant nos, mixed müllerian tumor, mesodermal mixed tumor, mesodermal nephroma, nephroblastoma nos, epithelial nephroblastoma, mesenchymal nephroblastoma, hepatoblastoma, carcinosarcoma nos, carcinosarcoma, embryonal type, myoepithelioma, mesenchymoma, benign, mesenchymoma nos, mesenchymoma, malignant, embryonal sarcoma, fibroepithelial neoplasm, Brenner tumor nos, Brenner tumor, borderline malignant, Brenner tumor, malignant, fibroadenoma nos, intraductal fibroadenoma nos, periductal Peripheral fibroadenoma, adenofibroma NOS, serous adenofibroma, myxoid adenofibroma, intracellular fibroadenoma, cystosarcoma phyllodes NOS, cystosarcoma phyllodes, malignant, juvenile fibroadenoma, synovial neoplasm, synovium, benign, synovial sarcoma NOS, synovial sarcoma, spindle cell type, synovial sarcoma, epithelioid cell type, synovial sarcoma, biphasic type, clear cell sarcoma of tendons and aponeuroses, mesothelial neoplasm, mesothelioma, benign, mesothelioma, malignant, fibrous mesothelioma, benign, fibrous mesothelioma, malignant, epithelioid mesothelioma mesothelioma), benign, epithelial mesothelioma, malignant, mesothelioma, biphasic type, benign, mesothelioma, biphasic type, malignant, adenoid tumor nos, germ cell neoplasm, dysgerminoma, seminoma nos, seminoma, anaplastic type, spermatocytic seminoma, germinoma, embryonal carcinoma nos, endodermal sinus tumor, polyembryoma, gonadoblastoma, teratoma, benign, teratoma nos, teratoma, malignant nos, teratocarcinoma, malignant teratoma, anaplastic type, malignant teratoma, intermediate type, dermoid cyst, dermoid cyst with malignant transformation, ovarian goiter nos, ovarian goiter, malignant, goiter (strumal) carcinoid, trophoblast Blast neoplasm, hydatidiform mole nos, invasive hydatidiform mole, choriocarcinoma, choriocarcinoma combined with teratoma, malignant teratoma, trophoblastic, mesonephroma, mesonephroma, benign, mesonephric tumor, mesonephroma, malignant, endosalpingioma, vascular tumor, hemangiomas nos, angiosarcoma, cavernous hemangiomas, venous hemangiomas, botryoid hemangiomas, Kupffer cell sarcoma, hemangioendothelioma, benign, hemangioendothelioma nos, hemangioendothelioma, malignant, capillary hemangiomas, intramuscular hemangiomas, Kaposi's sarcoma, angiokeratoma, verrucous hemangiomas, hemangiopericytoma, benign, hemangiopericytoma nos, hemangiopericytoma, malignant, angiofibroma nos,Hemangioblastoma, lymphangioma, lymphangiomas nos, lymphangiosarcoma, capillary lymphangioma, cavernous lymphangioma, cystic lymphangioma, lymphangioleiomyoma, lymphangioleiomyomatosis, angiolymphangioma, osteoma and osteosarcoma, osteoma nos, osteosarcoma nos, chondroblastic osteosarcoma, fibroblastic osteosarcoma, angioectatic osteosarcoma, osteosarcoma in Paget's disease of bone, parosteal osteosarcoma, osteoid osteoma nos, osteoblastoma, chondromatosis nos, osteochondroma, osteochondromatosis nos, chondrosarcoma nos, parosteal chondroma, parosteal chondrosarcoma, chondroblast cell tumor nos, chondroblastoma, malignant, mesenchymal chondrosarcoma, chondromyxoid fibroma, giant cell tumor, giant cell tumor nos of bone, giant cell tumor of bone, malignant, giant cell tumor nos of soft tissue, malignant giant cell tumor of soft tissue, mixed bone tumor, Ewing's sarcoma, adamantinoma of long bone, ossifying fibroma, odontogenic tumor, odontogenic tumor, benign, odontogenic tumor nos, odontogenic tumor, malignant, dentinoma, cementoma nos, cementoblastoma, benign, cementogenic fibroma, giant cementoma, odontoma nos, aggregate odontoma, complex odontoma, ameloblastic fibro-odontoma, enamel, Melanoblastoma, adenoid odontogenic tumor, calcifying odontogenic cyst, ameloblastoma NOS, ameloblastoma, malignant, odontogenic ameloblastoma, flat odontogenic tumor, odontogenic myxoma, odontogenic fibroma NOS, ameloblastoma, ameloblastoma, calcifying odontogenic tumor, mixed tumor, craniopharyngioma, pinealoma, pineocytoma, pineoblastoma, melanotic neuroectodermal tumor, spinal chordoma, glioma, glioma, malignant, gliomatosis cerebrum, mixed glioma, subependymal glioma, subependymal giant cell astrocytoma, choroid plexus papilloma nos, choroid plexus papilloma, malignant, ependymal nos, ependymal tumor, anaplastic type, papillary ependymoma, myxopapillary ependymoma, astrocytoma nos, astrocytoma, anaplastic type, plasmatic astrocytoma, gemistocytic astrocytoma astrocytoma), fibrous astrocytoma, pilocytic astrocytoma, spongioblastoma nos, polar spongioblastoma polare), astroblastoma, glioblastoma nos, giant cell glioblastoma, glioblastoma with sarcomatous components, primitive polar cavernoblastoma, oligodendroglioma nos, oligodendroglioma, anaplastic type, oligodendroglioblastoma, medulloblastoma nos, desmoplastic medulloblastoma, medulloblastoma, cerebellar sarcoma nos, giant cell sarcoma (monstrocellular) sarcoma, neuroepitheliomatous neoplasm, ganglioneuroma, ganglioneuroblastoma, ganglioneuromatosis, neuroblastoma NOS, medulloepithelioma NOS, teratoid medulloepithelioma, neuroepithelioma NOS, spongioneuroblastoma, ganglioglioma, neurocytoma, Pacinian tumor, retinoblastoma NOS, retinoblastoma, differentiated type, retinoblastoma, undifferentiated type, olfactory neurogenic tumor, esthesioneurocytoma, esthesioneuroblastoma, esthesioneuroblastoma, esthesioneuroepithelioma, meningioma, meningioma NOS, meningioma NOS, meningioma, malignant, meningotheliomatous meningioma, fibrous meningioma, psammomatous meningioma, hemangiomatous meningioma, hemangioblastic meningioma, hemangiopericytic meningioma), transitional meningioma, papillary meningioma, meningeal sarcomatosis, nerve sheath tumor, neurofibroma nos, neurofibromatosis nos, neurofibrosarcoma, melanotic neurofibroma, plexiform neurofibroma, schwannoma nos, schwannomatosis, schwannoma, malignant,Neuroma NOS, Granular cell tumor and alveolar soft part sarcoma, Granular cell tumor NOS, Granular cell tumor, Malignant, Alveolar soft part sarcoma, Lymphoma, NOS or Diffuse, Lymphomatous tumor, Benign, Malignant lymphoma NOS, Malignant lymphoma, Non-Hodgkin's type, Malignant lymphoma, Anaplastic cell type NOS, Malignant lymphoma, Stem cell type, Malignant lymphoma, Rotating cell type NOS, Lymphosarcoma NOS, Malignant lymphoma, Lymphoplasmacytic type, Malignant lymphoma, Immunoblastic type, Malignant lymphoma, Mixed lymphocytic-histiocytic NOS, Malignant lymphoma, Germinocyte-Centrocytic, Diffuse, Malignant lymphoma , follicular center cell nos, malignant lymphoma, lymphocytic, well differentiated nos, malignant lymphoma, lymphocytic, moderately differentiated nos, malignant lymphoma, centrocytic, malignant lymphoma, follicular center cell, cleaving nos, malignant lymphoma, lymphocytic, poorly differentiated nos, prolymphocytic lymphosarcoma, malignant lymphoma, centroblastic type nos, malignant lymphoma, follicular center cell, non-cleaving nos, reticulum cell sarcoma, reticulum cell sarcoma nos, reticulum cell sarcoma, pleomorphic cell type, reticulum cell sarcoma, nodular, Hodgkin's disease, Hodgkin's disease nos, Hodgkin's disease, lymphocyte predominant, Hodgkin's disease, mixed cell type, Hodgkin's disease, lymphocyte depletion type nos, Hodgkin's disease, lymphocyte depleted type, diffuse fibrosis, Hodgkin's disease, lymphocyte depleted type, reticular type, Hodgkin's disease, nodular sclerosis nos, Hodgkin's disease, nodular sclerosis, cellular phase, Hodgkin's granuloma, Hodgkin's granuloma, Hodgkin's sarcoma, lymphoma, nodular or follicular, malignant lymphoma, nodular nos, malignant lymphoma, mixed lymphocytic-histiocytic, nodular, malignant lymphoma, centrocytic-centrocytic, follicular, malignant lymphoma, lymphocytic, well differentiated, nodular, malignant lymphoma, lymphocytic, moderately differentiated, nodular, malignant lymphoma, follicular centrocyte, cleaved, follicular, malignant lymphoma lymphoma, lymphocytic, poorly differentiated, nodular, malignant lymphoma, germinal center cell type, follicular, malignant lymphoma, follicular center cell, non-cleaving, follicular, mycosis fungoides, mycosis fungoides, Sézary disease, mixed reticuloendothelial neoplasm, microglioma, malignant histiocytosis, histiocytic medullary reticulosis, Letterer-Sciewe disease, plasma cell neoplasm, plasma cell myeloma, plasma cell neoplasm, benign, plasmacytoma nos, plasma cell neoplasm, malignant, mast cell tumor, mastocytoma nos, mast cell sarcoma, malignant mastocytosis, Burkitt's tumor, Burkitt's tumor, leukemia, leukemia nos, acute leukemia nos, subacute leukemia nos,Chronic leukemia NOS, non-leukemic leukemia NOS, combined leukemia, combined leukemia, lymphocytic leukemia, lymphocytic leukemia NOS, acute lymphocytic leukemia, subacute lymphocytic leukemia, chronic lymphocytic leukemia, non-leukemic lymphocytic leukemia, prolymphocytic leukemia, plasma cell leukemia, erythroleukemia, acute erythrocyte, chronic erythrocyte, lymphosarcoma cell leukemia, myeloid leukemia, myeloid leukemia NOS, acute myeloid leukemia, subacute myeloid leukemia, chronic myeloid leukemia, non-leukemic myeloid leukemia, neutrophilic leukemia, acute prolymphocytic leukemia The patient is selected from the group comprising myelocytic leukemia, basophilic leukemia, eosinophilic leukemia, monocytic leukemia, monocytic leukemia nos, acute monocytic leukemia, subacute monocytic leukemia, chronic monocytic leukemia, non-leukemic monocytic leukemia, mixed leukemia, mast cell leukemia, megakaryocytic leukemia, megakaryocytic myelopathy, myeloid sarcoma, hairy cell leukemia, mixed myeloproliferative and lymphoproliferative disorder, polycythemia vera, acute panmyelosis, chronic myeloproliferative disorder, myelosclerosis with myeloid metaplasia, idiopathic thrombocythemia, chronic lymphoproliferative disorder,

[0475] In one embodiment of the present invention, the disease is selected from the group consisting of tumors of the pancreas, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, tumors of the head of the pancreas, body of the pancreas, tail of the pancreas, duct of the pancreas, islets of Langerhans, neck of the pancreas, tumors of the prostate, prostate adenocarcinoma, prostate, neuroendocrine tumors, brain tumors, breast cancer, 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, tumors of the axillary process of the breast, border lesions of the breast, juvenile carcinoma of the breast, tumors of the parathyroid gland, myeloma, lung cancer, small cell lung cancer, squamous non-small cell lung cancer (Sq.Non-small cell lung cancer, including but not limited to NSCLC, tumors of the main bronchus, upper lobe, middle lobe, and lower lobe lungs, colorectal cancer, tumors of the ascending colon, hepatic flexure of the colon, transverse colon, splenic flexure of the colon, descending colon, sigmoid colon, colonic junction lesions, small intestine, tumors of the liver, hepatocellular adenoma, hepatocellular carcinoma, hepatocholangiocarcinoma, cholangiocarcinoma, combined hepatocellular carcinoma and cholangiocarcinoma, hepatoblastoma, ovarian cancer, sarcoma, osteosarcoma, fibrosarcoma, gastrointestinal stromal tumors, gastrointestinal, gastric cancer, thyroid cancer, medullary thyroid carcinoma, thyroid, renal cell carcinoma, clear cell renal cell carcinoma Cell carcinoma, renal pelvis, tumor of the bladder, bladder cancer, tumor of the bladder trigone, dome of the bladder, lateral wall of the bladder, posterior wall of the bladder, tumor of the ureteral orifice, urachal tumor, bladder marginal lesions, 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, squamous cell carcinoma of the larynx, cervical cancer, cervical marginal lesions, cervical, isthmic tumor, uterine tumor, ovarian tumor, cervical esophagus, thoracic esophagus, abdominal esophagus, upper third of esophagus, esophagus Tumors of the middle third, lower third, and junctional lesions of the esophagus, endometrial carcinoma, head and neck cancer including but not limited to squamous cell carcinoma of the head and neck (SCCHN), lymphoma, malignant mesothelioma, mesothelial neoplasm, mesothelioma, fibrous mesothelioma, epithelioid mesothelioma, epithelioid mesothelioma, duodenal carcinoma, neuroendocrine tumors, neuroendocrine tumors of the lung, neuroendocrine tumors of the pancreas, neuroendocrine tumors of the foregut, neuroendocrine tumors of the midgut, neuroendocrine tumors of the hindgut, gastroenteropancreatic neuroendocrine tumors, neuroendocrine carcinoma, triple negative The tumors are selected from the group consisting of neuroendocrine tumors of the breast, including but not limited to transmural neoplasia (TNBC), neuroendocrine tumors of the ovary, testicular cancer, thymic carcinoma, tumors of the stomach, fundus, body, antrum, pylorus, lesser curvature of the stomach, greater curvature of the stomach, and marginal junction lesions of the stomach, paraganglioma, ganglioneuroma, melanoma, malignant melanoma, nodular melanoma, amelanotic melanoma, superficial spreading melanoma, epithelioid cell melanoma, spindle cell melanoma, mixed epithelioid and spindle cell melanoma, glioblastoma NOS, giant cell glioblastoma, and glioblastoma with sarcomatous components.

[0476] In one embodiment of the present invention, the disease is selected from the group consisting of non-small cell lung cancer, including Sq. NSCLC, head and neck cancer, including SCCHN, and breast neuroendocrine tumor, including TNBC. Preferably, the disease is selected from the group consisting of Sq. NSCLC, SCCHN, and TNBC.

[0477] In still further embodiments, the aforementioned indications are lesions of outer upper lip, outer lower lip, outer lip nos, upper lip mucosa, lower lip mucosa, lip mucosa nos, lip commissure, lip border lesions, tongue base nos, dorsal surface of tongue nos, tongue border nos, anterior two-thirds of tongue nos, lingual tonsil, border lesions of tongue, tongue nos, upper gums, lower gums, gum nos, anterior floor of mouth, posterior floor of mouth, border lesions of floor of mouth nos, floor of mouth nos, hard palate, soft palate nos, uvula, border lesions of palate, palate nos, buccal mucosa, vestibule of oral cavity, retromolar, border lesions of other and unspecified parts of oral cavity, oral nos, parotid gland, submandibular gland, sublingual gland, border lesions of major salivary glands, major salivary gland nos, tonsillar fossae, tonsillar pillarspillar), tonsillar border lesions, tonsillar nos, vallecula, anterior surface of epiglottis, lateral wall of oropharynx, posterior wall of oropharynx, branchial clefts, oropharynx border lesions, oropharynx nos, superior wall of nasopharynx, posterior wall of nasopharynx, lateral wall of nasopharynx, anterior wall of nasopharynx, nasopharynx border lesions, nasopharynx nos, pyriform sinuses, postcricoid region, hypopharyngeal surface of aryepiglottic folds, posterior wall of hypopharynx, hypopharyngeal border lesions, hypopharyngeal nos, pharyngeal nos, laryngopharynx, Waldeyer's ring, labio-oral and pharyngeal border lesions, cervical esophagus, thoracic esophagus, abdominal esophagus, upper third of esophagus, middle third of esophagus 1, lower third of the esophagus, esophageal border lesions, esophageal nosal membrane, cardia nosal membrane, fundus of the stomach, body of the stomach, gastric antrum, pylorus, lesser curvature nosal membrane, greater curvature nosal membrane, gastric border lesions, gastric nosal membrane, duodenum, jejunum, ileum, Meckel's diverticulum, small intestinal border lesions, small intestinal nosal membrane, cecum, appendix, ascending colon, hepatic flexure of the colon, transverse colon, splenic flexure of the colon, descending colon, sigmoid colon, colon border lesions, colon nosal membrane, rectosigmoid junction, rectal nosal membrane, anal nosal membrane, anal canal, cloacal layer, rectoanal and anal canal border lesions, liver, intrahepatic bile duct , gallbladder, extrahepatic bile duct, ampulla of Vater, bile duct border lesions, bile duct NOS, head of pancreas, body of pancreas, tail of pancreas, pancreatic duct, islets of Langerhans, neck of pancreas, border lesions of pancreas, pancreatic NOS, intestinal NOS, border lesions of digestive system, digestive NOS, nasal cavity, middle ear, maxillary sinus, ethmoid sinus, frontal sinus, sphenoid sinus, border lesions of paranasal sinuses, paranasal sinus NOS, glottis, supraglottis, subglottis, laryngeal cartilage, border lesions of laryngeal duct, laryngeal NOS, trachea, main bronchi, upper lobe lung, middle lobe lung, lower lobe lung, border lesions of lung, lung NOS, thymus, heart, anterior mediastinum, Posterior mediastinum, mediastinal NOS, pleural NOS, border lesions of the heart, mediastinum, and pleura, upper airway NOS, border lesions of the respiratory system and intrathoracic organs, airway NOS, upper limb long bone joints, upper limb short bone joints, lower limb long bone joints, lower limb short bone joints, border lesions of limb bone joints and articular cartilage, limb bone NOS, skull and facial bones, mandible, vertebral column, ribs, sternum, clavicle, pelvic bones, border lesions of bone joints and articular cartilage, bone NOS, blood, bone marrow, spleen, reticuloendothelial system NOS, hematopoietic system NOS, lip skin NOS, eyelid NOS, external ear, facial skin, occipital scalp skinneck), trunk skin, upper limb skin, lower limb skin, head and neck peripheral nerves, shoulder and arm peripheral nerves, leg peripheral nerves, thoracic peripheral nerves, abdominal peripheral nerves, pelvic peripheral nerves, trunk peripheral nerves, boundary lesions of peripheral nerves and autonomic nervous system, autonomic nervous system NOS, retroperitoneum, peritoneum, peritoneal NOS, retroperitoneal and peritoneal boundary lesions, head connective tissue, arm connective tissue, leg connective tissue, chest connective tissue, abdominal connective tissue, pelvic connective tissue, trunk connective tissue NOS, boundary lesions of subcutaneous connective tissue and other soft tissues, connective tissue NOS, nipple, breast center, upper inner quadrant of breast, lower inner quadrant of breast, upper outer quadrant of breast area, lower outer quadrant of breast, axillary process of breast, breast border lesions, breast nos, labia majora, labia minora, clitoris, vulvar border lesions, vulva nos, vagina nos, cervix, ectocervix, cervical border lesions, cervix, uterine isthmus, endometrium, myometrium, fundus of uterus, uterine border lesions, uterine body, uterine nos, ovaries, fallopian tubes, broad ligament of uterus, round ligament, parametrium, uterine adnexa, Wolffian bodies, female genital border lesions, female genital tract nos, penile foreskin, glans penis, penis body, penile border lesions, penile nos, prostate, cryptorchidism, descended testicletestis), testicular nos., epididymis, spermatic cord, scrotum nos., tunica vaginalis testis, male genital tract border lesions, male genital tract nos., kidney nos., renal pelvis, ureter, bladder trigone, bladder dome, bladder lateral wall, bladder posterior wall, ureteral orifice, urachus, bladder border lesions, bladder nos., urethra, paraurethral glands, urinary tract border lesions, urinary system nos., conjunctiva, corneal nos., retina, choroid, ciliary body, lacrimal gland, orbital nos., eye and adnexal border lesions, eye nos., meninges, spinal meninges, meningeal nos., cerebrum, frontal lobe, temporal lobe, parietal lobe, occipital lobe, ventricle nos., cerebellum nos., brainstem, brain border lesions, brain nos., spinal cord, cauda equina, olfactory nerve, optic nerve, auditory nerve, cranial nerve It may occur in organs and tissues selected from the group including: NOS, borderline lesions of brain and central nervous system, nervous system NOS, thyroid gland, adrenal cortex, adrenal medulla, adrenal NOS, parathyroid gland, pituitary gland, craniopharyngeal duct, pineal gland, carotid body, aortic body, borderline lesions of endocrine glands and related structures, endocrine gland NOS, head face or neck NOS, thoracic NOS, abdominal NOS, pelvic NOS, upper extremity NOS, lower extremity NOS, other ill-defined site, borderline lesions of ill-defined site, facial head and neck lymph nodes, intrathoracic lymph nodes, intraperitoneal lymph nodes, arm axillary lymph nodes, leg inguinal lymph nodes, pelvic lymph nodes, lymph nodes in multiple regions, lymph node NOS, and site of unknown origin.

[0478] In one embodiment of the present invention, the cancers recited herein are locally advanced, unresectable, metastatic, or any combination thereof.

[0479] In one embodiment, the compounds of the present invention are used in or for use in a method for treating cancers associated with alterations in the von Hippel-Lindau (VHL) gene. The VHL gene is a tumor suppressor gene that can be inactivated by genetic alterations, including, for example, VHL mutations, promoter hypermethylation, and loss of heterozygosity due to allelic deletion. VHL inactivation has been associated with increased tumor incidence and progression, particularly renal tumor incidence and progression (Wiesener et al., Cancer Res. 2001, 61, pp. 215-222). Furthermore, VHL mutations have reportedly been associated with high levels of CAIX expression, while the absence of VHL mutations has been associated with low CAIX expression and aggressive tumor characteristics (Pantuck et al., Journal of Clinical Oncology 2007, 25(18), pp. 5042; Patard et al., Int J Cancer 2008, 123(2), pp. 395-400). In one embodiment, the cancer is associated with a mutation in the VHL gene.

[0480] The terms "alteration" and "mutation" as used above should be understood to encompass single and multiple alterations and mutations, respectively, i.e., "one or more alterations" and "one or more mutations," respectively.

[0481] Tumor profiling can be performed by extracting DNA from formalin-fixed, paraffin-embedded (FFPE) tissue from cancer patients and determining alterations in the von Hippel-Lindau (VHL) gene using known gene sequencing techniques. In some embodiments, VHL mutations can be identified by bidirectional sequencing of all exons and short adjacent intronic sequences. Large genomic and intragenic deletions can be identified by Southern blotting, including quantitative Southern blotting, pulsed-field gel electrophoresis and / or fluorescent in situ hybridization, quantitative real-time PCR (Q-RT-PCR), multiplex ligation-dependent probe amplification (MLPA), or comparative genomic hybridization (CGH) (Decker et al., European Journal of Human Genetics 2014, 22). Preferably, VHL mutations can be identified by sequencing followed by MLPA. In some embodiments, the tumor profiling described above can be used to predict the response of patients diagnosed with cancer to treatment and / or imaging with the compounds of the invention.

[0482] In a further embodiment, the compounds of the invention are used in or for use in a method for the treatment of cancer associated with alterations in the von Hippel-Lindau (VHL) gene, wherein the cancer is selected from the group consisting of clear cell renal cell carcinoma (ccRCC), renal cell carcinoma (RCC), lung cancer, colorectal cancer (CRC), and bladder cancer.

[0483] In yet a further embodiment, the compounds of the invention are used in or for use in a method for the treatment of cancer associated with alterations in the von Hippel-Lindau (VHL) gene, wherein the cancer is clear cell renal cell carcinoma (ccRCC).

[0484] Subjects treated with the compounds of the present invention may be treated in combination with other non-surgical antiproliferative (e.g., anti-cancer) drug therapies. In one embodiment, the compounds may be administered in combination with anti-cancer compounds, such as cytostatic compounds. Cytostatic compounds are compounds (e.g., small molecules, nucleic acids, or proteins) that inhibit cell growth and / or proliferation. In some embodiments, the cytostatic compounds are directed against malignant cells of tumors.

[0485] Suitable antiproliferative or cytostatic compounds that can be used in combination with the compounds of the present invention include anticancer drugs. Numerous anticancer drugs that can be used are known and include 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 mesylate, bizelesin, bleomycin, cefotaxime ... Benzalkonium sulfate;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;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;Diazolidinone Azicon;Docetaxel;Doxorubicin;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Drostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Empromate;Epipropizine;Epirubicin hydrochloride;Elburozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadro hydrochloride zole; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; foskidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitogiline; Mitomarcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Niraparib; Nocodazole; Nogalamycin; Olaparib; O Lumaplatin; 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;Streptonigrin;Streptozocin;Sulofenur;Talazoparib;Tallysomycin;Taxol;Taxotere;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Topotecan hydrochloride;Toremifene citrate;Trestron acetate;Triciribine phosphate;Trimetrexa including, but not limited to, vinblastine sulfate; trimetrexate glucuronate; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; veliparib; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglistine sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0486] Other anticancer drugs include 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-dorsal morphogenetic protein-1; antiestrogens; antineoplastic agents; antisense oligonucleotides; aphidicolin glycinate; apoptotic gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulaculin; atames. Tan; Atlimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azesetron; Azatoxin; Azatyrosine; Baccatin III derivatives; Balanol; Batimastat; BCR / ABL antagonists; Benzochlorins; Benzoylstaurosporines; Beta-lactam derivatives; Beta-arretin; Betaclamycin B; Betulinic acid; bFGF inhibitors; Bisaziridinyl spermine; Bisnafide; Bistraten A; Breflate; Budotitanium; Buthionine sulfoximine; Calcipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Carboxamido-amino-triazoles; Carboxamidotriazoles; CaRest M3; CARN 700; cartilage-derived inhibitor; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; crambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; sipemycin; cytarabine ocfosfate; cytolytic factors; cytostatin; dacliximab; dehydrodidemnin B; deslorelin; dexphosphamide; dexrazoxane;Dexverapamil; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluridine; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflomithine; Elemene; Emiteflu; Epirubicin; Epristeride; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Filgrastim; Finasteride; Flavopiridol; Frezelastine; Fluasterone; Fludarabine; Fluorodaunorunicin hydrochloride hydrochloride); forfenimex; formestane; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulating peptides; insulin-like growth factor-I receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol 4-; Irinotecan; Iropract; Irosogladine; 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; Lissoclinamide 7; Lobaplatin; Lombricine; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lisofylline; Lytic peptides;Maytansine; mannostatin A; marimastat; masoprocol; 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; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A + mycobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressors Suppressor-1-based therapy; mustard anticancer compounds; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpine; nartograstim; nedaplatin; nemorubicin; neridronic...

Claims

1. Cyclic peptide of formula (1a) 【Chemistry 1】 A compound comprising a peptide selected from the group consisting of: In formula (1a), the peptide sequence is drawn from left to right in the N-terminal to C-terminal direction, Y is (iii) Z1, wherein Z1 comprises a linker moiety L1 and an effector E1, such as a chelator, wherein the linker moiety L1 covalently links the effector E1 to Xaa1 when Xaa1 is present, or to Xaa2 when Xaa1 is absent and Xaa2 is present, or to Xaa3 when both Xaa1 and Xaa2 are absent; or (i)R 0a -SO2-, R 0a -CO-, R 0a an N-terminal modifying group A selected from the group consisting of —NH—CO—, wherein R 0a is (C 1 ~C 10 ) alkyl, (C 5 ~C 10 ) aryl, and (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) aryl, and A is selected from the group consisting of 3-methylbutanoyl [Iva], acetyl [Ac], hexanoyl [Hex], benzoyl [Bz], phenylacetyl [Pha], and propionyl [Prp]; or (ii) an effector E1, such as a chelator, wherein effector E1 is covalently linked to Xaa1 when Xaa1 is present, or to Xaa2 when Xaa1 is absent and Xaa2 is present, or to Xaa3 when both Xaa1 and Xaa2 are absent, wherein effector E1 is (α) a moiety derived from a chromophore, the chromophore preferably being selected from (α1) a phosphorophore, and (α2) a fluorophore, such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug Preferably selected from the group consisting of: Xaa1 is absent or present, and when present, is a residue of an aliphatic or polar L-amino acid, preferably Xaa1 is absent or a residue selected from the group consisting of Val, Ile, (2S)-2-amino-3,3-dimethylbutanoic acid [Tle], Ser, and Thr; Xaa2 is present or absent, If Xaa2 is present, (i) Xaa2 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom; or (ii) Xaa2 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2, and has the formula (1b): 【Chemistry 2】 A bicyclic peptide of the formula If Xaa2 is absent, then Xaa1 is also absent; Xaa3 is a group represented by the formula (X) 【Transformation 3】 is a residue of an α-amino acid of During the ceremony, R 3a and R 3b are each and independently H and CH 3 selected from the group consisting of: Xaa3 is preferably a residue of an L-α-amino acid, such as Cys; Xaa4 is a residue of an L-α-amino acid that is optionally N-methylated at the α-nitrogen atom; Xaa5 is the residue of an amino acid optionally attached to Z3, Xaa5 is a D-α-amino acid, N-(C 1 ~C 6 ) a residue of an amino acid selected from the group consisting of alkylglycine, Gly, and α,α-dialkylamino acid; When Xaa5 includes Z3, (i) Z3 is an effector E3 such as a chelator, and Xaa5 is preferably a residue of an amino acid selected from the group consisting of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and the effector E3 is attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; or (ii) Z3 comprises an effector E3 such as a chelator and a linker moiety L3, wherein Xaa5 is preferably a residue of an amino acid selected from the group consisting of Nlys, D-lys, D-orn, D-dab, and D-dap, and the linker moiety L3 is attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; Xaa6 is selected from (i) polar L-α-amino acids, aromatic L-α-amino acids, aliphatic L-α-amino acids, S-alkylated cysteines, oxidized forms of S-alkylated cysteines, and amino acids of formula (3): 【Chemistry 4】 and wherein the amino acid residue is selected from the group consisting of amino acid residues according to During the ceremony, R 6a is H and -(C 5 ~C 10 ) aryl, (C 1 ~C 8 ) alkyl, and (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) an aryl-containing moiety; R 6b is selected from the group consisting of H or methyl; R 6c is H or (C 1 ~C 6 ) alkyl, w is 0 or 1, or (ii) a residue of an L-α-amino acid containing, in addition to an amino group and a carboxy group attached to its α-C atom, a functional group FG3 that forms a covalent linkage B2 with the functional group FG4 of Xaa11, wherein Xaa11 is a residue of an α-amino acid containing, in addition to an amino group and a carboxy group attached to its α-C atom, a functional group FG4, and is represented by formula (1c) 【Transformation 5】 A bicyclic peptide of is formed; Xaa7 is a residue of an amino acid selected from the group consisting of substituted aromatic amino acids, such as substituted heteroaromatic L-α-amino acids, and aromatic amino acids, such as heteroaromatic L-α-amino acids; Xaa8 is a residue of an amino acid selected from the group consisting of L-α-amino acids and cyclic α,α-dialkylamino acids; Xaa9 is a residue of an amino acid selected from the group consisting of L-α-amino acids and Gly; Xaa10 is a residue of a heteroaromatic L-α-amino acid; Xaa11 is (i) a residue of an amino acid selected from the group consisting of an L-α-amino acid and Gly, the L-α-amino acid optionally being linked to Z4, Z4 comprising an effector E4, such as a chelator, and a linker moiety L4; or (ii) is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG2 that forms a covalent linkage B1 with the functional group FG1 of Xaa2, or (iii) a residue of an α-amino acid containing, in addition to the amino and carboxy groups attached to the α-C atom, a functional group FG4 that forms a covalent linkage B2 with the functional group FG3 of Xaa6; Xaa12 is a group represented by formula (XII): 【Transformation 6】 Preferably of formula (XIIa): 【Transformation 7】 is a residue of an aminothiol, During the ceremony, NH of each of formulas (XII) and (XIIa) is bonded to Xaa11; R 12a and R 12b are each and independently H and CH 3 selected from the group consisting of: R 12c -CONH2, -COOH, -CO-Z6, and -CH 2 -Z6, wherein Z6 comprises a linker moiety L6 and an effector E6, such as a chelator, preferably R 12c is -CONH2; X 1 and X 2 are each and independently selected from the group consisting of CH and N, and both are preferably CH; compound.

2. the linker moiety L1 provides (a) a carboxy group that forms an amide bond with the α-amino group provided by Xaa2 when Xaa1 is absent and Xaa2 is present, or with the α-amino group provided by Xaa1 when Xaa1 is present, or with the α-amino group provided by Xaa3 when both Xaa1 and Xaa2 are absent, and (b) an amino group that forms a covalent bond to the effector; preferably, the linker moiety L1 is an optionally cleavable group comprising 1 to 12 amino acids, and / or the effector is as defined in claim 1, the linker moiety L1 is preferably selected from the group consisting of X11 and X11-X12, wherein X11 and X12 are each and individually residues of an amino acid, wherein when linker moiety L1 is X11 the carboxy group is provided by X11, and when linker moiety L1 is X11-X12 the carboxy group is provided by X12, the carboxy group of L1 forming an amide bond with the α-amino group provided by Xaa1 when Xaa1 is present, or with the α-amino group provided by Xaa2 when Xaa1 is absent and Xaa2 is present, or with the α-amino group provided by Xaa3 when Xaa1 and Xaa2 are both absent, and X11 provides the amino group which forms the covalent bond to the effector; X11 and X12 are preferably each and individually selected from 4-carboxymethylpiperazine [PPac], 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and an amino acid according to any one of the following formulae (32) to (34): 【Transformation 8】 and its ortho- and para-substituted isomers, and 【Chemistry 9】 is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formulas (32) and (33) are optionally substituted; The amino acids of formulas (32) and (33) preferably have R at the α-carbon atom covalently bonded to the COOH group in formulas (32) and (33). X11 -CO-NH-, wherein R X11 is (C 1 ~C 10 ) alkyl, (C 5 ~C 10 ) aryl, and (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) aryl; R X11 is preferably methyl, X11 and X12 are preferably each and individually selected from 4-carboxymethylpiperazine [PPac], 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and a compound of formula (35): 【Chemistry 10】 2. The compound of claim 1, wherein the amino acid is a residue of an amino acid selected from the group consisting of ε-amino acids of

3. Xaa2 is a residue of an L-α-amino acid selected from the group consisting of polar amino acids, aromatic amino acids, and charged amino acids; Xaa2 is preferably Gln, Tyr, (S)-N-methyl-tyrosine [Nmy], Phe, Arg, (S)-dimethylornithine [Dmo], Ser, Thr, Asp, Glu, and 【Chemistry 11】 is a residue of an L-α-amino acid selected from the group consisting of: Xaa2 is more preferably a residue of an L-α-amino acid selected from the group consisting of Gln, Tyr, (S)-N-methyl-tyrosine [Nmy], Arg, (S)-dimethylornithine [Dmo], and Ser; The compound of claim 1, wherein Xaa2 is most preferably a residue of Gln.

4. Xaa2 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG1 that forms a covalent linkage B1 with the functional group FG2 of Xaa11, and Xaa11 is a residue of an L-α-amino acid that contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG2, thereby forming a compound of formula (1b): 【Chemistry 12】 A bicyclic peptide of the formula The covalent linkage B1 is preferably selected from the group consisting of an amide linkage, a disulfide linkage, a thioether linkage, a thiourea linkage, a triazole linkage, a carbamate linkage, an amine linkage, a sulfonamide linkage, an ester linkage, a thioester linkage, an ether linkage, a urea linkage, and a hydrocarbon linkage; The covalent linkage B1 is more preferably selected from the group consisting of an amide linkage or a disulfide linkage, The functional group FG1 of Xaa2 which forms the covalent linkage B1 with the functional group FG2 of Xaa11 is preferably NH 2 , NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne; and / or The functional group FG2 of Xaa11, which forms a covalent bond B1 with the functional group FG1 of Xaa2, is NH 2 , NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne; Xaa2 is preferably a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, and Glu; The compound of claim 1, wherein Xaa2 is more preferably a residue of Glu.

5. Xaa11 is a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, and Glu; The compound of claim 4, wherein Xaa11 is preferably a residue of (S)-2,3-diaminopropionic acid [Dap].

6. Xaa4 is a residue of an L-α-amino acid selected from the group consisting of charged amino acids, aliphatic amino acids, and polar amino acids; Xaa4 is preferably Glu, Ala, Ser, (S)-homoserine [Hse], (S)-N-methyl-serine [Nms], Gln, Asn, Asp, Dmo, and 【Chemistry 13】 is a residue of an L-α-amino acid selected from the group consisting of: Xaa4 is more preferably a residue of an L-α-amino acid selected from the group consisting of Glu, Ala, Ser, Gln, and (S)-homoserine [Hse]; The compound of claim 1, wherein Xaa4 is most preferably a residue of Glu.

7. Z3 is absent from Xaa5, Xaa5 is preferably a residue of an amino acid selected from the group consisting of D-pro, Gly, N-methyl-glycine [Nmg], D-ala, (R)-piperidine-2-carboxylic acid [D-pip], (R)-azetidine-2-carboxylic acid [D-aze], (R)-N-methyl-alanine [Nma], and 2-amino-isobutyric acid [Aib]; The compound according to claim 1, wherein Xaa5 is more preferably a residue of D-pro.

8. Xaa5 is an amino acid residue bound to Z3, which comprises an effector E3, such as a chelator, and a linker moiety L3; Xaa5 preferably contains at least one functional group that forms a covalent bond with the linker moiety L3, such as N—(C 1 ~C 4 2. The compound of claim 1, wherein the amino acid is a residue of an amino acid selected from the group consisting of alkylglycine, non-aromatic D-α-amino acid, non-aromatic N-methyl-D-α-amino acid, cyclic D-α-amino acid, and α,α-dialkylamino acid.

9. Z3 is the E3 effector. Xaa5 is preferably a residue of an amino acid selected from the group consisting of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and the effector E3 is covalently attached to an N atom different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; 9. The compound according to claim 8, wherein the bond connecting the effector E3 to the N atom different from the α-nitrogen atom is preferably an amide bond.

10. Z3 comprises an effector E3 and a linker moiety L3, Xaa5 is preferably a residue of an amino acid selected from the group consisting of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and the chelator is covalently attached to an N atom that is different from the α-nitrogen atom of any one of Nlys, D-lys, D-orn, D-dab, and D-dap; and / or The linker moiety L3 preferably provides (a) a carboxy group that forms an amide bond with an N atom different from the α-nitrogen atom of any one of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and (b) an amino group that forms a covalent bond to the effector E3; The linker moiety L3 is preferably selected from the group consisting of X31 and X31-X32, wherein X31 and X32 are each and individually amino acid residues, and when the linker moiety L3 is X31, the carboxy group is provided by X31, and when the linker moiety L3 is X31-X32, the carboxy group is provided by X32, and the carboxy group of L3 forms an amide bond with an N atom other than the α-nitrogen atom of any one of 4-aminobutyl-glycine [Nlys], D-lys, (R)-ornithine [D-orn], (R)-2,4-diaminobutyric acid [D-dab], and (R)-2,3-diaminopropionic acid [D-dap], and X3 provides an amino group that forms a covalent bond to the effector E3; X31 and X32 are preferably each and individually selected from 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and an amino acid according to any one of formulas (32) to (34): 【Chemistry 14】 and its ortho- and para-substituted isomers, and 【Chemistry 15】 is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formulas (32) and (33) are optionally substituted; The amino acids of formulas (32) and (33) preferably have R at the α-carbon atom covalently bonded to the COOH group in formulas (32) and (33). X11 -CO-NH-, wherein R X11 is (C 1 ~C 10 ) alkyl, (C 5 ~C 10 ) aryl, and (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) aryl; R X11 is preferably methyl, or X31 and X32 are preferably each and individually selected from 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and a compound of formula (35): 【Chemistry 16】 9. The compound of claim 8, wherein the amino acid is a residue of an amino acid selected from the group consisting of the ε-amino acids of

11. Effector E3 is (α) a moiety derived from a chromophore, the chromophore preferably being selected from (α1) a phosphorophore, and (α2) a fluorophore, such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug 9. The compound of claim 8, selected from the group consisting of:

12. 2. The compound of claim 1, wherein Xaa6 is a residue of an amino acid selected from the group consisting of Ala, Asp, Asn, (S)-homoserine [Hse], Gln, Glu, Lys, (S)-ornithine [Orn], (S)-2,4-diaminobutyric acid [Dab], N-methyl-Asp, (S)-benzylcysteine ​​[C(Bzl)], (S)-2-amino-3-(quinolin-2-ylmethylsulfanyl)-propionic acid [C(2Quyl)], (S)-benzyl-cysteine-sulfone [Eem], (S)-4-benzyloxy-L-phenylalanine [Tyr(Bzl)], and (S)-2-amino-4-[(naphthalen-1-ylmethyl)-carbamoyl]-butyric acid [E(NHMe2Nph)], and Xaa6 is preferably a residue of Asp.

13. 2. The compound of claim 1, wherein Xaa6 is a residue selected from a residue of a polar N-methylated L-α-amino acid, a residue of a neutral α-amino acid, preferably Ala, a residue of an S-alkylated cysteine, and a residue of a sulfoxide or sulfone of an S-alkylated cysteine.

14. Xaa6 is a residue of an amino acid according to formula (3), R 6a is (C 1 ~C 10 ) alkyl, (C 5 ~C 10 ) aryl, (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) aryl, and (C 3 ~C 7 ) cycloalkyl-(C 5 ~C 10 ) aryl; R 6c is preferably (C 1 ~C 4 ) alkyl.

15. Xaa6 is a residue of an L-α-amino acid that contains, in addition to an amino group and a carboxy group attached to the α-C atom, a functional group FG3 that forms a covalent linkage B2 with the functional group FG4 of Xaa11, and Xaa11 is a residue of an α-amino acid that contains, in addition to an amino group and a carboxy group attached to the α-C atom, a functional group FG4, and has formula (1c) 【Chemistry 17】 A bicyclic peptide of the formula The covalent linkage B2 is preferably selected from the group consisting of an amide linkage, a disulfide linkage, a thioether linkage, a thiourea linkage, a triazole linkage, a carbamate linkage, an amine linkage, a sulfonamide linkage, an ester linkage, a thioester linkage, an ether linkage, a urea linkage, and a hydrocarbon linkage; The covalent linkage B2 is more preferably selected from the group consisting of an amide linkage or a disulfide linkage, The functional group FG3 of Xaa6 which forms the covalent linkage B2 with the functional group FG4 of Xaa11 is preferably NH 2 , NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne; and / or The functional group FG4 of Xaa11, which forms the covalent bond B2 with the functional group FG3 of Xaa6, is NH 2 , NH-, COOH, activated carboxylic acid, chloro, bromo, iodo, SH, OH, SOOH, activated sulfonic acid, sulfonate ester, Michael acceptor, isocyanate, isothiocyanate, azide, alkene, and alkyne; Xaa6 is preferably a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, and Glu, and / or 2. The compound of claim 1, wherein Xaa11 is a residue of an L-α-amino acid selected from the group consisting of (S)-2,3-diaminopropionic acid [Dap], (S)-2,4-diaminobutyric acid [Dab], (S)-ornithine [Orn], Lys, Cys, (S)-homocysteine ​​[Hcy], (R)-penicillamine [Pen], Asp, D-asp, D-glu, and Glu.

16. 2. The compound of claim 1, wherein Xaa7 is a residue of an aromatic amino acid optionally substituted on the aromatic ring system with at least one substituent.

17. Xaa7 is a modified 3-aminophenylalanine [Af3(R 7c )]: [Chemistry 18] Modified 4-aminophenylalanine [Aph(R 7d )]: 【Chemistry 19】 a residue of an amino acid selected from the group consisting of substituted (S)-3-benzothienylalanine [Bta], substituted Trp, and substituted Phe; During the ceremony, the substituted Bta and substituted Trp are each and individually substituted on the aromatic ring with a substituent selected from the group consisting of halogen, methyl, and OH; In the substituted Bta and substituted Trp, one or two of the aromatic carbon atoms may be replaced by a N atom; A substituted Phe is substituted on the aromatic ring with one, two, or three substituents, each and any of the substituents being individually and independently selected from halogen, methyl, OH, NH 2 , OR 7a wherein: R 7a (C 1 ~C 6 ) alkyl, In formula (4a), R 7c HA-CO-R 7e and During the ceremony, R 7e is (C 1 ~C 5 ) alkyl, (C 5 ~C 10 ) aryl, and (C 5 ~C 10 ) heterocyclyl; (C 1 ~C 5 )Alkyl is OH, SO 2 NH 2 , SO 2 NH-R 7f , CO(NHOH), COOH, CONH 2 , and NH 2 optionally substituted with a substituent selected from the group consisting of (C 1 ~C 5 ) alkyl, each of which has an ether oxygen and a sulfone (SO 2 ) moieties, (C 5 ~C 10 ) Aryl is halogen, OH, SO 2 NH 2 , SO 2 NH-R 7f , CO(NHOH), COOH, CONH 2 , and NH 2 optionally substituted with a substituent selected from the group consisting of (C 5 ~C 10 ) Heterocyclyl is a halogen, OH, SO 2 NH 2 , SO 2 NH-R 7f , NH-SO-NH 2 , CO(NHOH), COOH, CONH 2 , and NH 2 optionally substituted with a substituent selected from the group consisting of During the ceremony, R 7f (C 1 ~C 4 ) alkyl, In formula (4b), R 7d HA-CO-R 7g and During the ceremony, R 7g is (C 1 ~C 5 ) alkyl, (C 5 ~C 10 ) aryl, and (C 5 ~C 10 ) heterocyclyl, (C 1 ~C 5 )Alkyl is OH, SO 2 NH 2 , SO 2 NH-R 7h , CO(NHOH), COOH, CONH 2 , and NH 2 optionally substituted with a substituent selected from the group consisting of (C 2 ~C 5 ) alkyl, each of which has an ether oxygen and a sulfone (SO 2 ) moieties, (C 5 ~C 10 ) Aryl is halogen, OH, SO 2 NH 2 , SO 2 NH-R 7h , CO(NHOH), COOH, CONH 2 , and NH 2 optionally substituted with a substituent selected from the group consisting of (C 5 ~C 10 ) Heterocyclyl is a halogen, OH, SO 2 NH 2 , SO 2 NH-R 7h , NH-SO-NH 2 , CO(NHOH), COOH, CONH 2 , and NH 2 optionally substituted with a substituent selected from the group consisting of In the formula, R 7h (C 1 ~C 4 ) alkyl, 2. The compound of claim 1.

18. Xaa7 is the residue of an amino acid, Modified 3-aminophenylalanine [Af3(R 7c )]: 【Chemistry 20】 Modified 4-aminophenylalanine [Aph(R 7d )]: 【Chemistry 21】 and Xaa7 is selected from the group consisting of substituted Trp, substituted (S)-3-benzothienylalanine [Bta], (S)-3-(1-naphthyl)alanine [1Ni], (S)-4-benzyloxy-L-phenylalanine [Tyr(Bzl)], Tyr, substituted Phe, and (S)-benzylcysteine ​​[Cys(Bzl)], and preferably Xaa7 is selected from the group consisting of modified 3-aminophenylalanine [Af3(R 7c )] or modified 4-aminophenylalanine [Aph(R 7d )], Xaa7 is preferably D / L-1-methyltryptophan [1MW], D / L-7-methyltryptophan [7MW], 5-chloro-tryptophan [5Clw], DL-5-methyl-tryptophan [Egc], substituted [Bta], (S)-4-benzyloxy-L-phenylalanine [Tyr(Bzl)], (S)-3-(1-naphthyl)alanine [1Ni], (2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid [Mtf ... amino-3-[4-(trifluoromethyl)phenyl]propanoic acid [Ptf], (S)-3,4-dichlorophenylalanine [Eaa], 4-(tert-butyl)-phenylalanine [Eap], (2S)-2-amino-3-(4-iodophenyl)propanoic acid [Pif], (S)-biphenylalanine [Bip], (S)-3,3-diphenylalanine [Dip], (S)-benzylcysteine ​​[Cys(Bzl)], modified 3-aminophenylalanine of formula (4a) [Af3(R)] 7c )], and modified 4-aminophenylalanine [Aph(R 7d ), In the formula, R 7c teeth, 【Chemistry 22】 and preferably R 7c teeth, 【Chemistry 23】 wherein R 7d teeth, 【Chemistry 24】 is selected from the group consisting of: 7d teeth, 【Chemistry 25】 is selected from the group consisting of Xaa7 is more preferably a modified 3-aminophenylalanine [Af3(R 7c )] and modified 4-aminophenylalanine [Aph(R 7d ), wherein: R 7c teeth, 【Chemistry 26】 wherein R 7d teeth, 【Chemistry 27】 17. The compound of claim 16, selected from the group consisting of:

19. Xaa7 is - modified 3-aminophenylalanine [Af3(R 7c )], where R 7c teeth, 【Chemistry 28】 , preferably 【Chemistry 29】 is, or - modified 4-aminophenylalanine [Aph(R 7d )], where R 7d teeth, 【Transformation 30】 , preferably 【Chemistry 31】 19. The compound of claim 18, wherein:

20. 17. The compound of claim 16, wherein Xaa7 is a residue of an aromatic amino acid selected from the group consisting of (S)-3-benzothienylalanine [Bta], Trp, and Phe.

21. Xaa8 is an aliphatic L-α-amino acid of formula (IX) or an amino acid of formula (XI): 【Chemistry 32】 is a residue of During the ceremony, R 8a is (C 1 ~C 4 ) alkyl, (C 3 ~C 7 ) cycloalkyl, and H; t=0, 1, 2, 3, or 4 s=0, 1, 2, or 3 In the amino acid of formula (XI), one aryl ring is optionally fused to a ring bond that does not include the α-C-atom, In the carbocyclic part of the amino acid of formula (XI), a CH is spaced from the α-carbon atom by at least one carbon atom. 2 groups are optionally replaced by O atoms or NH groups, Xaa8 is preferably a residue of an amino acid selected from the group consisting of Leu, Nle, Npg, Cha, Aic, Thp, Eca, and Egz; The compound of claim 1, wherein Xaa8 is more preferably a Leu residue.

22. Xaa9 is a group represented by formula (XIII): 【Transformation 33】 and Gly, During the ceremony, R 9a H, OH, COOH, CONH 2 , N(R 9b ) 2 , CONH-R 9c , X 9 , and -NH-CO-X 9 is selected from the group consisting of During the ceremony, X 9 is (C 1 ~C 6 ) alkyl, (C 5 ~C 10 ) aryl, and (C 3 ~C 10 ) heteroaryl; and X 9 are each and individually methyl, CONH 2 , halogens, NH 2 substituted with one or two substituents selected from the group consisting of , and OH; u=1, 2, 3, or 4, optionally β-CH 2 and / or γ-CH 2 One or two hydrogens of the group are each and individually replaced by methyl and / or β-CH 2 one of the hydrogens of the group is optionally replaced by OH, R 9b are each and independently (C 1 ~C 4 ) selected from the group consisting of alkyl and H; R 9c is optionally substituted with 1, 2, 3, 4, 5, or 6 OH groups, provided that each carbon atom is not bonded to an O or N atom or is bonded to one O or N atom (C 1 ~C 8 ) alkyl and (C 1 ~C 8 ) cycloalkyl; Xaa9 is preferably Thr, Gly, Ala, His, (S)-dimethylornithine [Dmo], and 【Transformation 34】 is a residue of an amino acid selected from the group consisting of: The compound of claim 1, wherein Xaa9 is more preferably a residue of Thr.

23. Xaa10 is selected from the group consisting of Trp optionally substituted with a substituent selected from the group consisting of methyl, halogen, or OH, and aza-analogs of Trp optionally substituted with methyl, halogen, or OH; 2. The compound of claim 1, wherein Xaa10 is preferably a residue of an amino acid selected from the group consisting of Trp and (S)-7-aza-tryptophan [7Nw].

24. Xaa11 is a residue of an amino acid selected from the group consisting of L-α-amino acids and GIy; Z4 is absent; The compound according to claim 1, wherein Xaa11 is preferably a residue of an L-α-amino acid, and the L-α-amino acid is Ser.

25. Xaa11 is the residue of an L-α-amino acid which, in addition to the amino and carboxy groups attached to its α-C atom, contains a functional group FG2, and Xaa2, in addition to the amino and carboxy groups attached to its α-C atom, contains a functional group FG1 which forms a covalent linkage B1 with the functional group FG2 of Xaa11, thereby forming a compound of formula (1b): 【Chemistry 35】 a bicyclic peptide of the formula: a residue of an L-α-amino acid which contains, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG4, and Xaa6, in addition to the amino and carboxy groups attached to its α-C atom, a functional group FG3 which forms a covalent linkage B2 with the functional group FG4 of Xaa11, and which has the formula (1c): 【Transformation 36】 2. The compound of claim 1, wherein a bicyclic peptide of the formula:

26. Xaa11 is a residue of an amino acid selected from the group consisting of GIy and an L-α-amino acid, and the L-α-amino acid is linked to Z4, which Z4 comprises an effector E4 and a linker moiety L4; Xaa11 is preferably Glu, Gln, and a group of formula (XI): 【Chemistry 37】 and wherein the residue of an L-α-amino acid is selected from the group consisting of: During the ceremony, v=1, 2, 3, or 4, R 11a H, OH, COOH, CONH 2 , NH-(C=NH)-NH 2 , N(R 11b ) 2 , CONH-R 11c , -CO(Z4), X 13 and -NH-CO-X 13 , NH—CO(Z4), O—CO(Z4), Z4, and NH—CS—Z4, wherein X 13 is (C 1 ~C 6 ) alkyl, (C 5 ~C 6 ) aryl, and (C 3 ~C 5 ) heteroaryl; and X 13 are each and individually methyl, CONH 2 , halogens, NH 2 and OH, R 11b are each and independently (C 1 ~C 4 ) selected from the group consisting of alkyl and H; R 11c is optionally substituted by 1, 2, 3, 4, 5, or 6 OH groups, provided that each carbon atom is not bonded to an O or N atom or is bonded to one O or N atom (C 1 ~C 8 ) alkyl and (C 1 ~C 8 ) cycloalkyl; Optionally, β-CH in formula (XI) 2 and / or γ-CH 2 one or two hydrogens of the group are each and individually replaced by methyl; β-CH in formula (XI) 2 one of the hydrogens of the group is optionally replaced by OH, Xaa11 is more preferably Ala, Ser, Gly, Arg, Lys, (S)-dimethylornithine [Dmo], and 【Transformation 38】 is a residue of an amino acid selected from the group consisting of: The compound of claim 1, wherein Xaa11 is most preferably a residue of Ser.

27. the linker moiety L4 covalently links the chelator to the L-α-amino acid at Xaa11; the L-α-amino acid Xaa11 preferably comprises a functional group FG5 different from the carboxyl and amino groups attached to the α-C atom of Xaa11, and the linker moiety L4 covalently links the effector E4 to the functional group FG5 of the L-α-amino acid of Xaa11; Xaa11 is more preferably the residue of an L-α-amino acid of formula (XI) and the functional group FG5 is R 11a Provided by The compound of claim 26, wherein the linker moiety L4 preferably provides (a) a first amino group that forms a covalent bond with the functional group FG5 of the L-α-amino acid of Xaa11, and (b) a second amino group that forms a covalent bond to the effector E4.

28. the linker moiety L4 is either X41 or a residue selected from the group consisting of X41-X42 and X42-X41; X41 is a residue of a diamine that provides the first and second amino groups; X42 is an amino acid residue that provides an amino group and a carboxy group, X41-X42 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the first amino group of X41, the second amino group is the amino group of X42, The second amino group of X41 forms an amide bond with the carboxy group of X42, X42-X41 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the amino group of X42, the second amino group is the second amino group of X41, The carboxy group of X42 forms an amide bond with the first amino group of X41, 27. The compound according to claim 26, wherein X41 is preferably a residue of a linear or cyclic diamine.

29. Xaa11 is the residue of an L-α-amino acid of formula (XI) and R 11a is selected from the group consisting of —CO(Z4), —NH—CO(Z4), —O—CO(Z4), —Z4, and —NH—CS—Z4; R 11a is preferably —CO(Z4), and L4 is connected to R 11a 27. The compound of claim 26, wherein the compound is covalently attached to a carbonyl carbon atom contained in

30. X41 is expressed by equations (35) to (37). 【Chemistry 39】 and a residue of a diamine selected from the group consisting of any one of the diamines During the ceremony, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; f is 0, 1, 2, 3, 4, 5, or 6; g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The diamine of either formula (35) or (36) is -CONH 2 is optionally replaced by J is selected from the group consisting of CH and N; In the diamine of any one of formulas (35) and (36), the carbon atom substituted with a nitrogen atom is preferably -CONH 2 29. The compound of claim 28, further substituted with:

31. X41 is a residue of a diamine selected from the group consisting of 1,3-diaminopropane [Apr], 1,5-diaminopentane [Ape], diaminobutane, and ethylenediamine; and / or X42 is 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and any one of amino acids of formulas (32), (33), and (34): 【Chemistry 40】 and its ortho- and para-substituted isomers, and 【Chemistry 41】 is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formulas (32) and (33) are optionally substituted; The amino acids of formula (32) and (33) preferably have R at the α-carbon atom covalently bonded to the COOH group in formula (32) and (33), respectively. X11 -CO-NH-, wherein R X11 is (C 1 ~C 10 ) alkyl, (C 5 ~C 10 ) aryl, and (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) aryl; R X11 is preferably methyl, X42 is more preferably 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and compounds of formula (35): 【Chemistry 42】 29. The compound of claim 28, wherein the amino acid residue is selected from the group consisting of:

32. Effector E4 is (α) a moiety derived from a chromophore, the chromophore preferably being selected from (α1) a phosphorophore, and (α2) a fluorophore, such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug 27. The compound of claim 26, selected from the group consisting of:

33. The cyclic peptide has the formula (1g): 【Chemistry 43】 is a cyclic peptide of the formula R 12c is preferably the group consisting of -CONH2 and -COOH, or - -CO-Z6 and -CH 2 -Z6 wherein Z6 comprises an effector E6 and a linker moiety L6; The linker moiety L6 is preferably R 12c The effector E6 is covalently linked to the carbon atom of R 12c is more preferably -CO-Z6, and the linker moiety L6 is (a) R 12c and (b) a second amino group that forms a covalent bond to an effector.

34. the linker moiety L6 is either X61 or a residue selected from the group consisting of X61-X62 and X62-X61; X61 is a residue of a diamine providing a first amino group and a second amino group; X62 is an amino acid residue that provides an amino group and a carboxy group, X61-X62 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the first amino group of X61, the second amino group is the amino group of X62, The second amino group of X61 forms an amide bond with the carboxy group of X62, X62-X61 are residues of a diamine, the diamine providing a first amino group and a second amino group; the first amino group is the amino group of X62, the second amino group is the second amino group of X61, The carboxy group of X62 forms an amide bond with the first amino group of X61, X61 is preferably a group represented by the formula (35-37): 【Chemistry 44】 and a residue of a diamine selected from the group consisting of any one of the diamines During the ceremony, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; f is 0, 1, 2, 3, 4, 5, or 6; g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The diamine of either formula (35) or (36) is -CONH 2 and J is selected from the group consisting of CH and N; In the diamine of any one of formulas (35) and (36), the carbon atom substituted with a nitrogen atom is preferably -CONH 2 34. The compound of claim 33, further substituted with:

35. X61 is 1,3-diaminopropane [Apr], 1,5-diaminopentane [Ape], diaminobutane, ethylenediamine, diamine of formula (39), and diamine of formula (40). 【Chemistry 45】 and / or X62 is selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], and amino acids according to any one of formulas (32) to (33): 【Chemistry 46】 and its ortho- and para-substituted isomers, and 【Chemistry 47】 is a residue of an amino acid selected from the group consisting of: During the ceremony, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; The amino acids of formula (32) and formula (33) are each optionally substituted; The amino acids of formula (32) and formula (33) preferably have R at the α-carbon atom covalently bonded to the COOH group in formula (32) and (33). X11 -CO-NH-, where R X11 is (C 1 ~C 10 ) alkyl, (C 5 ~C 10 ) aryl, and (C 1 ~C 5 ) alkyl-(C 5 ~C 10 ) aryl, and R X11 is preferably methyl, X62 is more preferably 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 2-(4-(amino)piperidin-1-yl)acetic acid [APac], 4-carboxymethylpiperazine [PPac], 4-trans-aminomethylcyclohexanecarboxylic acid [4Amc], β-alanine [Bal], γ-aminobutyric acid [Gab], 5-aminopentanoic acid [Ava], 6-aminohexanoic acid [Ahx], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb], and compounds of formula (35): 【Chemistry 48】 and a residue of an amino acid selected from the group consisting of:

35. The compound of claim 34, wherein X62 is most preferably a residue of an amino acid selected from the group consisting of 1,13-diamino-4,7,10-trioxatridecane-succinamic acid [Ttds], 8-amino-3,6-dioxaoctanoic acid [O2Oc], 3-aminomethyl-benzoic acid [Mamb], 4-aminomethyl-benzoic acid [Pamb].

36. Effector E6 (α) a moiety derived from a chromophore, the chromophore preferably being selected from (α1) a phosphorophore, and (α2) a fluorophore, such as fluorescein or rhodamine; and (β) a chelating agent optionally containing a chelated nuclide; and (γ) a moiety derived from a drug, preferably a cytotoxic drug 34. The compound of claim 33, selected from the group consisting of:

37. The compound of the formula Ac-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Glu(NH-Apr-DOTA)-Cys]-NH 2 (3BP-3478): 【Chemistry 49】 The compound of the formula DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-3583): [Transformation 50] The compound of the formula Ac-Lys(DOTA)-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-3840): 【Chemistry 51】 The compound of the formula: DOTA-APAc-Val-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Trp-Leu-Thr-Trp-Dap}-Cys]-NH 2 (3BP-4175): 【Chemistry 52】 The compound of the formula: DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(HO-succinyl)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4237): 【Chemistry 53】 The compound of the formula DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4369): 【Chemistry 54】 The compound of the formula: DOTA-APAc-Val-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4400): 【Transformation 55】 The compound of the formula: DOTA-PPAc-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4448): 【Transformation 56】 The compound of the formula: DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4452): 【Chemistry 57】 The compound of the formula DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4453): 【Chemistry 58】 The compound of the formula DOTA-Rni-Tyr-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4455): 【Chemistry 59】 The compound of the formula DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4501): 【Transformation 60】 The compound of the formula: DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Dap}-Cys]-NH 2 (3BP-4503): 【Chemistry 61】 The compound of the formula: DOTA-PPAc-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Dap}-Cys]-NH 2 (3BP-4504): 【Transformation 62】 The compound of the formula DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Dap}-Cys]-NH 2 (3BP-4505): 【Transformation 63】 is selected from the group consisting of Preferably, the compound of the formula DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4452): 【Chemistry 64】 The compound of the formula DOTA-Gln-[Cys(3MeBn)-Glu-pro-Asp-Aph(SaPr)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4501): 【Transformation 65】 The compound of the formula: DOTA-{Glu-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Dap}-Cys]-NH 2 (3BP-4503): 【Chemical Formula 66】 is selected from the group consisting of More preferably, the compound of the formula DOTA-PPAc-Gln-[Cys(3MeBn)-Glu-pro-Asp-Af3(Cpsu)-Leu-Thr-Trp-Ser-Cys]-NH 2 (3BP-4452): 【Transformation 67】 and In the above compounds, DOTA is DOTAGA, DOTAM, DOTP, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, CHX-A''-DTPA, DFO, macro PA, HOPO, TRAP, THP, DATA, NOPO, NOTP, PCTA, Sarcophagin, FSC, NETA, NE3TA, H4octapa, pycup, HYNIC, NxS4-x(N4, N2S2, N3S), 99m Tc(CO) 3 2. The compound of claim 1, optionally replaced by a chelating agent selected from the group consisting of chelating agents and analogs thereof, preferably from the group consisting of DOTAGA, DOTAM, NOTA, NODAGA, NODA-MPAA, NOPO, HBED, DTPA, CHX-A″-DTPA, CB-TE2A, Macropas, PCTA, N4, and analogs thereof, more preferably from the group consisting of DOTAGA, NODAGA, and Macropas and analogs thereof.

38. Each effector E1, E3, E4, and E6, when present, is independently a chelator optionally comprising a chelated nuclide, the chelator preferably being selected from the group consisting of DOTA, DOTAGA, DOTAM, DOTP, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, CHX-A″-DTPA, DFO, macropa, HOPO, TRAP, THP, DATA, NOPO, NOTP, PCTA, sarcofadin, FSC, NETA, NE3TA, H4octapa, pycup, HYNIC, NxS4-x(N4, N2S2, N3S), 99m Tc(CO) 3 - selected from the group comprising chelating agents and their analogues, The chelating agent is preferably selected from the group comprising DOTA, DOTAGA, DOTAM, NOTA, NODAGA, NODA-MPAA, NOPO, HBED, DTPA, CHX-A″-DTPA, CB-TE2A, Macropa, PCTA, N4, and analogs thereof; The compound of claim 1, wherein the chelating agent is more preferably selected from the group comprising DOTA, DOTAGA, NODAGA, and macropa, and analogs thereof.

39. 38. The compound of claim 37, wherein the chelator comprises a chelated nuclide.

40. The chelated nuclide is a diagnostically active nuclide, The diagnostically active nuclide is preferably a diagnostically active radionuclide; The nuclide is preferably 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, and 125 I, The nuclide is more preferably 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 111 In, 152 Tb, 155 Tb, and 203 Pb, The nuclide is most preferably 64 Cu, 68 Ga, 111 In, and 203 40. The compound of claim 39, selected from the group comprising Pb.

41. The chelated nuclide is a therapeutically active nuclide, The therapeutically active nuclide is preferably a therapeutically active radionuclide, The nuclide is preferably 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, and 211 At is selected from the group including At, The nuclide is more preferably 47 Sc, 67 Cu, 90 Y, 161 Tb, 177 Lu, 212 Pb, 213 Bi, 225 Ac, and 227 selected from the group including Th, The nuclide is most preferably 90 Y, 161 Tb, 177 Lu, 212 Pb, 225 Ac, and 227 40. The compound of claim 39, selected from the group comprising Th.

42. The chelating agent is 111 In and 68 34. The compound of claim 33, comprising a chelated diagnostically active nuclide selected from Ga.

43. The chelating agent is 161 Tb, 177 Lu, 212 Pb, and 225 38. The compound of claim 37, comprising a chelated therapeutically active nuclide selected from Ac.

44. 43. A compound according to any one of claims 1 to 40 and 42 for use in a method for diagnosing a disease.

45. 44. A compound according to any one of claims 1 to 39, 41 and 43 for use in a method for the treatment of a disease.

46. The following methods: - a method for identifying a subject, the subject being likely to respond or not to respond to treatment of a disease, the method for identifying the subject comprising carrying out a method for diagnosing the disease using a compound according to any one of claims 1 to 40 and 42, - a method for the selection of a subject from a group of subjects, the subject being likely to respond or not to respond to treatment of a disease, the method for the selection of a subject from a group of subjects comprising the step of carrying out a method for diagnosing the disease using a compound according to any one of claims 1 to 40 and 42, A method for stratifying a group of subjects into those likely to respond to treatment of a disease and those likely not to respond to treatment of a disease, the use in the method for stratifying a group of subjects comprising carrying out a method for diagnosing a disease using a compound according to any one of claims 1 to 40 and 42.

43. A compound according to any one of claims 1 to 40 and 42 for use in

47. The disease is cancer, The cancer is preferably a solid cancer or solid tumor; More preferably, the cancer is a hypoxic cancer; 45. The compound for use according to claim 44, wherein the cancer is most preferably a carbonic anhydrase IX-expressing cancer.

48. the cancer is selected from the group consisting of clear cell renal cell carcinoma (ccRCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), glioblastoma (GBM), mesothelioma, cholangiocarcinoma (CCA), ovarian cancer, non-small cell lung cancer (NSCLC), brain cancer, pancreatic cancer, thyroid cancer, lung cancer, renal cancer, breast cancer, head and neck cancer, urothelial carcinoma, and bladder cancer; 48. The compound for use according to claim 47, wherein the cancer is preferably selected from the group consisting of squamous non-small cell lung cancer (Sq. NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), clear cell renal cell carcinoma (ccRCC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).

49. 48. The compound for use according to claim 47, wherein the cancer comprises CAIX-expressing cancer-associated fibroblasts (CAFs).

50. The disease is a cancer associated with alterations in the von Hippel-Lindau gene, The cancer is preferably selected from the group consisting of clear cell renal cell carcinoma (ccRCC), renal cell carcinoma (RCC), lung cancer, colorectal cancer (CRC), and bladder cancer; 45. The compound for use according to claim 44, wherein the cancer is more preferably clear cell renal cell carcinoma (ccRCC).

51. 44. A composition, preferably a pharmaceutical composition, comprising a compound according to any one of claims 1 to 43 and a pharmaceutically acceptable excipient.

52. 44. A kit comprising a compound according to any one of claims 1 to 43, and one or more optional excipients, and optionally one or more devices, preferably selected from the group comprising a labelling device, a purification device, a manipulation device, a radiation protection device, an analytical device or an administration device.

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