Alpha v beta 6-integrin binding cyclopeptides with non-natural amino acids, and conjugates thereof

Abstract

The present invention provides cyclic peptides comprising at least one non-canonical amino acid, which are capable of binding to αvβ6-integrin. Further provided are conjugates, building blocks, and uses thereof, as well as synthetic intermediates and methods for manufacturing the same.

Description

[0001] ALPHA V BETA 6-INTEGRIN BINDING CYCLOPEPTIDES WITH NON-NATURAL AMINO ACIDS, AND CONJUGATES THEREOF

[0002] Technical Field

[0003] The invention relates to the field of peptide ligands targeting cell surface proteins, in particular, to peptides binding to avP6-integrin, and conjugates thereof. The invention furthermore relates to the use of such peptides and peptide conjugates for medical purposes, such as imaging and therapy of human diseases, particularly of cancer.

[0004] Background avP6-integrin is expressed by epithelial cells and only lowly abundant adult human tissues [1]. Its most important function is the activation of transforming growth factor P (TGFP) [2] . TGFp is a powerful growth-inhibiting factor, and in order to control and regulate its signaling, it is secreted into the intracellular space in a latent, inactive complex with another protein called latency-associated peptide (LAP). avP6-integrin activates TGFp by binding to an RGD sequence of LAP, and by transmitting an actual pulling force, the protein complex is deformed and releases TGFp [3,4], Hence, the expression of avP6-integrin is tightly connected to diseases rooted in, or related to, altered TGFp signaling. Owing to its TGFp activation function, avP6-integrin is a driver for invasion and metastasis of epithelial cancers [5], This is because TGFp normally regulates tissue growth by inhibiting several proliferative signaling cascades. Carcinoma cells, however, frequently lose certain components of the respective downstream pathways, for example, p53 [6] or Smad4 [7], and become insensitive to TGFp-induced growth inhibition. Thus, they benefit from a high TGFp level in their surroundings, because it inhibits proliferation of the surrounding normal cells but not their own [8] . Overexpression of avP6-integrin therefore helps carcinomas to invade normal tissues and the highest avP6 expression levels in solid tumors are usually found in their infiltrative margins [9] . avP6-integrin is a valuable theranostic target. It potentially enables a precise delineation of carcinoma margins and / or assessment of their invasiveness by molecular (nuclear) imaging, as well as therapeutic intervention with targeted radioligands, antibody-drug conjugates (ADCs), small-molecule drug conjugates (SMDCs), or peptide-drug conjugates (PDCs), at the most critical locations. It is found in many carcinomas, such as squamous cell, basal cell, lung adeno, and colon

[0010] , and also in pulmonary fibrosis

[0011] , which expands the potential of avP6-targeted imaging beyond oncology. Notably, one of the cancers with the worst prognosis, the pancreatic ductal adenocarcinoma (PDAC), has been shown to be most closely associated with avP6-integrin, which is found in 88% of primary tumors, virtually all metastases, and also in its immediate precursor lesions (PanIN3)

[0012] , Addressing avP6-integrin allows to guide theranostic agents, such as radiopharmaceuticals, drug conjugates, fluorescent agents, contrast agents, or similar agents, to the tumor cells. av[36-integrin can furthermore be exploited for the transmembrane transfer of targeted agents, such as radiopeptides or peptide-drug conjugates, because such constructs rapidly internalize into cells, such as tumor cells

[0013] , av[36-integrin thus is a suitable target for molecular imaging, and furthermore for all therapeutic schemes which benefit from a specific homing of the respective agents to carcinoma cells, such as radioligand therapy (RLT), targeted drug delivery, targeted photodynamic or photothermal therapy, and other comparable approaches.

[0005] State of the art

[0006] Several types of avP6-integrin ligands have been reported in the literature [14-17], Some of them have been used as a basis for tracers for single-photon computed emission tomography (SPECT) [18-20] or positron emission tomography (PET) imaging [21-25], Some of these radiopharmaceuticals have been evaluated in humans for imaging of various carcinomas [26-31] or idiopathic pulmonary fibrosis (IPF) [32,33], Furthermore, avP6-integrin targeting peptides have been used in PDCs for tumor targeting in animal tumor models

[0034] , avP6-integrin targeting cyclic nonapeptides with a high av[36-integrin selectivity and metabolic stability

[0035] , such as cyclo-[FRGDLAFp(AMe)K], have been conjugated to the68Ga chelator TRAP

[0036] to form monomeric, dimeric, and trimeric conjugates

[0037] , The trimer showed a high degree of nonspecific uptake in the bowel organs (intestines and liver), whereas various monomeric conjugates showed insufficient tumor accumulation

[0038] , A TRAP-based trimer of cyclo- [YRGDLAYp(AMe)K], referred to as68Ga-Trivehexin, was later used for imaging of patients with PDAC and HNSCC [39-42],

[0007] Summary of the invention

[0008] During the use of peptides and peptide-derived compounds as pharmaceutical agents for diagnostic imaging and therapeutic intervention, the pharmacodynamic (target binding) and pharmacokinetic parameters (absorption, distribution, metabolism, and elimination, abbreviated as ADME) are decisive for the clinical application and the use in healthcare schemes. The desired purpose is generating a high- contrast image or a diseases-specific pharmacological effect. This is commonly achieved by selective accumulation of the peptide-derived agent at the site where its target is abundant. At the same time, the accumulation in other parts of the body, such as specific organs or tissues, may exert unwanted effects. In case of diagnostic application, for example in medical imaging, the unwanted effects can be false readout (false negatives or false positives) which limits diagnostic accuracy or sensitivity. A primary concern in this case is the residual amount of diagnostic agent circulating in the blood, as this causes a generally higher background signal which can obstruct diagnostically relevant signals, leading to false- negatives. In addition, the readout may then contain signals in areas with an elevated blood perfusion that is not related to disease, which can produce false negatives. In case of a therapeutic intervention, the unwanted effects are commonly referred to as side effects. In case such side effects cause harm to an individuals' health, they are referred to as adverse events, or toxicity. There are two main concerns related to unwanted organ accumulation and toxicity which have been a major concern for many such agents in the past: (i) Renal toxicity can be caused by an excessively high kidney accumulation and retention

[0043] , (ii) Hematological toxicity can be caused by a too high residual activity in the blood, which deposits a high radiation dose to the bone marrow and thus affects the biosynthesis of blood cells

[0044] . The respective measures for the potential suitability of such agents for medical purposes are the tumor-to-kidney ratio and the tumor-to-blood ratio, which must be maximized in order to warrant patient safety and clinical suitability.

[0009] The objective of the present invention is to provide novel cyclopeptides and conjugates comprising the same, which are capable of binding to av[36-integrin allowing to guide therapeutic agents, diagnostic agents or theranostic agents, such as radiopharmaceuticals, drug conjugates, fluorescent agents, contrast agents, or similar agents, to av[36-integrin overexpressing cells such as tumor cells, wherein said cyclopeptides and conjugates comprising the same exhibit a favourable toxicity profde, as expressed for instance by a high tumor-to-kidney ratio and / or a high tumor-to-blood ratio.

[0010] This objective is accomplished by providing novel cyclic nonapeptides containing non-canonical amino acids and conjugates comprising the same, as described herein and as specified in the appended claims. The in-vivo targeting properties on av[36-integrin tumors were investigated. Surprisingly, it was found that these agents were not only accumulated in av[36-integrin expressing tumor xenografts in mouse models, but also exhibited a markedly lower retention in the kidneys and the blood. This resulted in unexpected increase of the tumor-to-kidney ratio, and of the tumor-to-blood ratio. The present invention therefore provides a solution to the aforementioned objectives, namely, avoidance of high and unwanted kidney uptake and blood retention. In other words, the present invention accomplishes the objective of providing diagnostics or therapeutics with a more favorable biodistribution profile that are less likely to cause false readout or adverse events, respectively, in a clinical application.

[0011] In addition, the present invention further provides synthetic intermediates useful for preparing the cyclopeptides and conjugates of the present invention. In addition, the present invention also provides uses of the cyclopeptides and conjugates of the invention in medicine, as specified in the appended claims and as described in more detail below. These uses benefit from the effects accomplished by the cyclopeptides and conjugates of the invention. Detailed description of the invention

[0012] Description of Figures

[0013] Figure 1: Uptakes of68Ga-Trivehexin,68Ga-C17, and68Ga-C18, 90 min after injection ofthe respective radiopharmaceutical, determined by post-mortem dissection and gamma counting (mean values, n = 3, error bars designate standard deviations).

[0014] Figure 2: Intraindividual tumor-to-tissue ratios (mean values, n = 3, error bars designate standard deviations), calculated from ex-vivo biodistribution data shown in Figure 1.

[0015] Figure 3: PET images, 30 min p.i., of a H2009 tumor bearing mouse, being administered68Ga- Trivehexin,68Ga-C17, and68Ga-C18 on consecutive days. A: Images scaled to a maximum value of 5 % injected activity per m (%iA / mL). B: Same PET scans as shown in A, scaled to a maximum value of 70 %iA / mL.

[0016] Figure 4: PET images, 90 min p.i., of a H2009 tumor bearing mouse, being administered68Ga- Trivehexin and68Ga-C18 on consecutive days. A: Images scaled to a maximum value of 8 % injected activity per mL (%iA / mL). B: Same PET scans as shown in A, scaled to a maximum value of 70 %iA / mL.

[0017] Figure 5: Uptakes of68Ga-Trivehexin,68Ga-C17, and68Ga-C18, 30 and 90 min after injection of the respective radiopharmaceuticals, in various organs and tissues, determined from PET imaging data by region-of-interest (ROI) analysis . Bars show mean values of 2 experiments, error bars designate standard deviations.

[0018] Figure 6: PET contrast data (intraindividual tumor-to-blood and tumor-to-kidney ratios), calculated from ROI uptake values (shown in Figure 5). Bars show mean values of 2 experiments, error bars designate standard deviations.

[0019] Figure 7: PET contrast enhancement factors for68Ga-C17, and68Ga-C18 over68Ga-Trivehexin, calculated by dividing the ROI-based tumor-to-blood and tumor-to-kidney ratios at 30 and 90 min of68Ga-C17 and68Ga-C18 by the corresponding ROI-based tumor-to-tissue values of68Ga-Trivehexin (respective data used for calculations are shown in Figure 6).

[0020] Figure 8: Uptakes of177Lu-containing comparative compound C101 and inventive compounds C30 to C34 by tumor and kidney, as well as calculated tumor-to-kidney ratios.

[0021] Figure 9: Uptakes of68Ga-containing comparative compound C102 and inventive compounds C40 to C44 by tumor, blood and kidney, including PET images (A), tumor uptake rates (B), blood uptake rates (C), kidney uptake rates (D), as well as calculated tumor-to-blood (E) and tumor-to-kidney (F) ratios. Figure 10: Uptakes of68Ga-containing comparative compound C102 and inventive compound C45 by tumor, blood and kidney, including PET images (A) as well as calculated tumor-to-blood (B) and tumor- to-kidney (C) ratios for three different points in time.

[0022] Figure 11: Fluorescent microscopy images of av06-integrin expressing BHY cells using inventive compounds C28 and C50 to C55.

[0023] Terms

[0024] Unless specified otherwise, standard amino acid nomenclature is used. Unless specified otherwise, amino acids are L-stereoisomers. Unless specified otherwise, amino acid moieties are linked to each other via peptide bonds.

[0025] Me refers to a methyl group.

[0026] N-Me-amino acid refers to a group derived from the respective amino acid, wherein the a -amino group carries a methyl group; For instance, N-Me-Lys refers to N-methyl-lysine and N-Me-Gln refers to N- methyl -glutamine. Similarly, N-Me-D-Phe refers to the D-enantiomer of N-methyl -phenylalanine.

[0027] Ac refers to an acetyl group.

[0028] Lys(Ac) characterizes a lysine moiety, wherein the amino group in the sidechain is acetylated, so that the Lys(Ac) moiety can be represented by the following formula (when incorporated into a peptide): *-NH-C(C(O)-*)-(CH2)4-NH-C(O)-CH3 wherein the asterisks mark the positions of attachment to the remainder of the peptide.

[0029] Tyr(tBu) characterizes a tyrosine moiety, wherein the 4-OH group in the sidechain forms a tert-butyl- etlier group.

[0030] Asp(tBu) characterizes an aspartic acid moiety, wherein carboxyl group in the sidechain forms a tertbutyl -ester group.

[0031] Unless the context dictates otherwise, references to the “compound of the invention” are to be understood as references not only to the compound of the present invention according to Sequence 1, Formula 10, or all other aspects and embodiments of the inventions described herein below, but also as references to the pharmaceutically acceptable salts, esters, solvates, polymorphs or modified forms thereof as represented by the general formula (II) described herein below.

[0032] The term “amino acid” generally refers to an organic compound comprising both a carboxylic acid group and an amine group. Unless specified otherwise, the term “amino acid” is intended to cover the 20 amino acids encoded by the DNA, and other amino acids, but wherein the use of natural amino acids is preferred. The term “amino acid” is used to refer to free amino acids and also to amino acid residues incorporated into peptides. In the latter case, the reference to an amino acid is to be understood as a reference to a moiety derived from the respective free amino acid, wherein a hydrogen atom of the amino group attached to Ca is replaced by a peptide bond and the hydroxyl group forming part of the carboxyl group attached to Ca is also replaced by a peptide bond. The term “canonical amino acid” and equivalent expressions refer to amino acids coded in the human DNA. Canonical amino acids are alanine (Ala), cystein (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (He), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asp), proline (Pro), glutamine (Gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Vai), tryptophan (Trp), and tyrosine (Tyr). A “non-canonical amino acid” is any amino acid, which is not a canonical amino acid. Preferred non-canonical amino acids are described hereinbelow.

[0033] It will be understood that “carries”, “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. For example, an effector moiety can have six valences or less. The number of n+os of moieties bonded to the effector moiety is specified to be six or less. The above-mentioned implicit proviso means that, if an effector having less than six valences is selected, the number n+os of moieties bonded to the selected effector is implicitly limited to a maximum number that corresponds to the number of valences of the selected effector moiety. As used herein, the term “substituted” is meant to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more. Unless specified otherwise, the term “substituted”, when in association with any of the below groups refers to a group substituted at one or more position with substituents such as alkyl, alkenyl, alkynyl, alkoxy, acyl, amino (including simple amino, mono and dialkylamino, mono and diarylamino, and alkylarylamino), acylamino (including carbamoyl, and ureido), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfmyl, sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonato, phosphinato, oxo, guanidine, imino, formyl and the like. Any of the above substituents can be further substituted if permissible, e.g. if the group contains an alkyl group, an aryl group, or other. Likewise, divalent groups like sulfonyl or sulfinyl can carry an alkyl group, aryl group or the like to satisfy the second valency. Unless specified otherwise, all abbreviations are intended to have their commonly used meaning as represented, for instance, by the IUPAC-IUP Commission on Biochemical Nomenclature in Biochemistry 11, 1972, 942-944.

[0034] Unless specified otherwise, compounds of the present invention are “pharmaceutically acceptable” which means that the respective compounds are suitable for use with humans and / or animals without causing adverse effects (such as irritation or toxicity), commensurate with a reasonable benefit / risk ratio.

[0035] The term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise.

[0036] The chemical structures herein are drawn according to the conventional standards known in the art. Thus, where an atom, such as a carbon atom, as drawn appears to have an unsatisfied valency, then that valency is assumed to be satisfied by a hydrogen atom even though that hydrogen atom is not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0037] The symbol " in general represents a covalent single bond between two atoms in the chain. In addition, the symbol " also represents the point of attachment of the substituent to a compound. Thus for example aryl(Ci-C6)alkyl— indicates an arylalkyl group, such as benzyl, attached to the compound through the alkyl moiety. The symbol "=" in general represents a covalent double bond between two atoms in the chain. In accordance with conventional nomenclature, alternating single and double bonds characterize aromatic bonding if these bonds form a ring system with 4n+2 pi-electrons (n being 0, 1 or 2).

[0038] Where a substituent group is indicated as being attached to a structure in multiple positions, it is to be understood that the substituent can be the same or different in the different positions.

[0039] As used herein, the term “alkyl” refers to saturated hydrocarbons having from one to sixteen carbon atoms, more preferably from one to six carbon atoms, including linear or branched alkyl groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, and the like. The term “Ci-Cnalkyl” refers to an alkyl group having from 1 to the indicated “n” number of carbon atoms. The term “alkylene” group refers to a group derived from an alkyl group as defined above, but having two valencies instead of the single valency of the alkyl group. Preferably, the two free valencies are at opposing termini of the alkylene group.

[0040] As used herein, the term “alkenyl” refers to unsaturated hydrocarbons having from two to sixteen carbon atoms, more preferably from two to six carbon atoms, including linear or branched alkenyl groups, and comprising between one and six carbon-carbon double bonds. Examples of alkenyl groups include, without limitation, vinyl, allyl, 1 -propen-2 -yl, l-buten-3-yl, l-buten-4-yl, 2-buten-4-yl, l-penten-5-yl, l,3-pentadien-5-yl, and the like. The term alkenyl includes both unsubstituted alkenyl groups and substituted alkenyl groups. The term “C2-Cnalkenyl” refers to an alkenyl group having from 2 to the indicated “n” number of carbon atoms. The term “alkenylene” group refers to a group derived from an alkenyl group as defined above, but having two valencies instead of the single valency of the alkenyl group. Preferably, the two free valencies are at opposing termini of the alkenylene group.

[0041] As used herein, the term “alkynyl” refers to unsaturated hydrocarbons having from two to twelve carbon atoms, more preferably from two to six carbon atoms, including linear or branched alkynyl groups, and comprising between one to six carbon-carbon triple bond. Examples of alkynyl groups include, without limitation, ethynyl, l-propyn-3-yl, l-butyn-4-yl, 2-butyn-4-yl, l-pentyn-5-yl, l,3-pentadiyn-5-yl, and the like. The term alkynyl includes both unsubstituted alkynyl groups and substituted alkynyl groups. The term “C2-Cnalkynyl” refers to an alkynyl group having from 2 to the indicated “n” number of carbon atoms. The term “alkynylene” group refers to a group derived from an alkynyl group as defined above, but having two valencies instead of the single valency of the alkynyl group. Preferably, the two free valencies are at opposing termini of the alkynylene group.

[0042] The terms “cycloalkyl”, “carbocyclic” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom) or fused (sharing at least one bond) carbocyclic ring systems, having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-l-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-l-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbomyl, and the like. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The term “Cs-Cncycloalkyl” refers to a cycloalkyl group having from 3 to the indicated “n” number of carbon atoms in the ring structure.

[0043] The term “heterocycloalkyl” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom) or fused (sharing at least one bond) carbocyclic ring systems, having from three to fifteen ring members, where one or more (up to six) ring members are substituted or unsubstituted heteroatoms (e.g. N, O, S, P) or groups containing such heteroatoms (e.g. NH, NRX(Rxis alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2, SO, SO2, and the like). Heterocycloalkyl groups may be C-attached or heteroatom -attached (e.g. via a nitrogen atom) where such is possible. Examples of heterocycloalkyl groups include, without limitation, pyrrolidine, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidine, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3 -azabicyclo [3, l,O]hexanyl, 3- azabicyclo[4,l,0]heptanyl, quinolizinyl, and sugars, and the like. The term heterocycloalkyl includes both unsubstituted heterocycloalkyl groups and substituted heterocycloalkyl groups. The term “C3- Cnheterocycloalkyl” refers to a heterocycloalkyl group having from 3 to the indicated “n” number of atoms (carbon or heteroatom or group) in the ring structure, including at least one hetero group or atom as defined above.

[0044] The terms “aryl” and “aryl ring” refer to aromatic groups having 4n+2 it (pi ) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system (fused or not) and having six to fourteen ring atoms. A polycyclic ring system includes at least one aromatic ring. Aryl may be directly attached, or connected via a Ci-Calkyl group (also referred to as arylalkyl or aralkyl). Examples of aryl groups include, without limitation, phenyl, benzyl, phenetyl, 1 -phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenyl, fluorenyl, phenanthemyl, anthracenyl, and the like. The term aryl includes both unsubstituted aryl groups and substituted aryl groups. The term “Ce-Cnaryl” refers to an aryl group having from 6 to the indicated “n” number of carbons in the ring structure.

[0045] The terms “heteroaryl” and “heteroaryl ring” refer to aromatic groups having 4n+2 7t(pi ) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system (fused or not) and having five to fourteen ring members, including one to six substituted or unsubstituted heteroatoms (e.g. N, O, S) or groups containing such heteroatoms (e.g. NH, NRX(Rxis alkyl, acyl, aryl, heteroaryl or cycloalkyl), SO, and the like). A polycyclic ring system includes at least one heteroaromatic ring. Heteroaryls may be directly attached, or connected via a Ci-Calkyl group (also referred to as heteroarylalkyl or heteroaralkyl). Heteroaryl groups may be C-attached or heteroatom-attached (e.g. via a nitrogen atom), where such is possible. Examples of heteroaryl groups include, without limitation, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrollyl, quinolinyl, isoquinolinyl, indolyl, 3H-indolyl, indolinyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolizinyl, quinolonyl, isoquinolonyl, quinoxalinyl, naphthyridinyl, furopyridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, dibenzofumayl, and the like. The term heteroaryl includes both unsubstituted heteroaryl groups and substituted heteroaryl groups. The term “Cs-Cnheteroaryl refers to an heteroaryl group having from 5 to the indicated “n” number of atoms (carbon or heteroatom or group) in the ring structure, including at least one hetero group or atom as defined above. The terms “heterocycle” or “heterocyclic” or “heterocyclyl” include heterocycloalkyl and heteroaryl groups. Examples of heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,

[0046] 1.2.4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,

[0047] 1.3.4-triazolyl, xanthenyl, and the like. The term heterocycle includes both unsubstituted heterocyclic groups and substituted heterocyclic groups.

[0048] The term “amine” or “amino,” as used herein, refers to an unsubstituted or substituted moiety of the formula -NRaRb, in which Raand Rbare each independently hydrogen, alkyl, aryl, or heterocyclyl, or Raand Rb, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring. The term “amide” or “aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term acylamino refers to an amino group directly attached to an acyl group as defined herein.

[0049] The term “nitro” means -NO2; the term “halogen” refers to bromine, chlorine, fluorine or iodine substituents; the term “thiol” means SH; and the term “hydroxyl” or “hydroxy” means -OH. The term “alkylthio” refers to an alkyl group, having a sulfhydryl group attached thereto. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms. The term “alkylcarboxyl” as used herein means an alkyl group having a carboxyl group attached thereto.

[0050] The term “alkoxy” as used herein means an alkyl group having an oxygen atom attached thereto. Representative alkoxy groups include groups having 1 to about 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, tert-butoxy and the like. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy groups and the like. The term alkoxy includes both unsubstituted or substituted alkoxy groups, etc., as well as halogenated alkyloxy groups.

[0051] The term “carbonyl” or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

[0052] The term “acyl” refers to a carbonyl group that is attached through its carbon atom to a hydrogen (z.e., formyl), an aliphatic group (Ci-Cnalkyl, Ci-Cnalkenyl, Ci-Cnalkynyl, wherein n is an integer from 2 to 10; e.g. acetyl, a cycloalkyl group (e.g. G-Gcycloalkyl). a heterocyclic group (e.g. G- Gheterocycloalkyl and G-G,hctcroar l). an aromatic group (e.g. Cearyl, e.g., benzoyl), and the like. Acyl groups may be unsubstituted or substituted acyl groups (e.g. salicyloyl).

[0053] The term “solvate” refers to a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, hemiethanolates, and the like, preferably hydrates.

[0054] A "pharmaceutically acceptable salt" of a compound means a salt of a compound that is pharmaceutically acceptable. Desirable are salts of a compound that retain or improve the biological effectiveness and properties of the free acids and bases of the parent compound as defined herein or that takes advantage of an intrinsically basic, acidic or charged functionality on the molecule and that is not biologically or otherwise undesirable. Example of pharmaceutically acceptable salts are also described, for example, in Berge etal., “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1-19 (1977). Such salts include:

[0055] (1) acid addition salts, formed on a basic or positively charged functionality, by the addition of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonate forming agents, and the like; or formed with organic acids such as acetic acid, propionic acid, lactic acid, oxalic, glycolic acid, pivalic acid, t-butylacetic acid, - hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylaminosulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 3 -phenyl propionic acid, lauryl sulphonic acid, lauryl sulfuric acid, oleic acid, palmitic acid, stearic acid, lauric acid, embonic (pamoic) acid, palmoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynapthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, and the like;

[0056] (2) base addition salts, formed when an acidic proton present in the parent compound either is replaced by a metal ion, including, an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron and the like; or coordinates with an organic base such as ammonia, ethylamine, diethylamine, ethylenediamine, N,N’- dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, piperazine, chloroprocain, procain, choline, lysine and the like.

[0057] Pharmaceutically acceptable salts may be synthesized from the parent compound that contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Salts may be prepared in situ, during the final isolation or purification of the agent or by separately reacting a purified compound of the invention in its free acid or base form with the desired corresponding base or acid, and isolating the salt thus formed. The term “pharmaceutically acceptable salts” also include zwitterionic compounds containing a cationic group covalently bonded to an anionic group, as they are “internal salts”.

[0058] All acid, salt, base, and other ionic and non-ionic forms of the compounds described are included as compounds of the invention. For example, if a compound is shown as an acid herein, the salt forms of the compound are also included. Likewise, if a compound is shown as a salt, the acid and / or basic forms are also included.

[0059] “Theranostic agents” and “Theranostics” are expressions characterizing agents that can be used in methods in which a step of imaging is combined with a therapeutic step. Depending on the type of effector moiety present in said agents, they may function as diagnostic agents and / or as therapeutic agents in pure diagnostic methods without therapeutic component or vice versa. Unless stated otherwise or the context dictates otherwise, any reference to theranostic agent or the like should be understood as a reference to a diagnostic and / or therapeutic agent (depending on the agent’s functionality). Likewise, unless stated otherwise or the context dictates otherwise, any reference to a diagnostic and / or therapeutic agent should also be understood as a reference to a theranostic agent.

[0060] "Pharmaceutically acceptable vehicle” or "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or carrier with which a compound is administered.

[0061] "Pharmaceutical composition" refers to at least one compound and at least one pharmaceutically acceptable vehicle or carrier, with which the compound is administered to a patient. Unless specified otherwise, all terms should be given their usual meaning as reflected by standard textbooks, encyclopedias and the like. For instance, the term “peptide” is used to characterize a compound in which at least two amino acids are joined via a peptide (amide) bond.

[0062] The term “chelating group” characterizes an atomic group comprising at least 2 and typically 2 to 10 donor atoms, i.e. atoms with one or more free electron pairs such as N, O, or S, and which can form coordinative bonds to metal ions. Said donor atoms are typically connected with adjacent donor atom(s) by 1 to 4, preferably 2 or 3 other heavy atoms, typically carbon.

[0063] The term “linker”, as used herein, is to be understood as referring to moieties connecting two other moieties by at least two covalent bonds. By contrast, moieties that are capable of connecting two other moieties by formation of at least two covalent bonds are referred to as “spacer”. A spacer may be regarded as a precursor of a linker. The spacer contains a functional group at its terminus, which is capable of forming at least one covalent bond with a suitably matched functional group of the moiety to be attached. Said moiety to be attached can be a chelating group, another effector group or it can be another spacer. In this latter case, the linker is the sum of both spacers but with a connecting group that is the reaction product of the two functional groups.

[0064] In detail, if two moieties Ml and M2 are to be connected by a linker L, the resulting conjugate may be characterized by the formula M1-L-M2. Said conjugate may be synthesized in any possible manner using any synthetic approach for forming covalent bonds (also referred to as “coupling”), most preferably using the Click chemistry approach. Said coupling may take place at a terminus or within the linker. The following options are thus conceivable:

[0065] M I -S0 + M2 ^ M I -L-M2 (1)

[0066] M 1 + S0-M2 M 1 -L-M2 (2)

[0067] Ml-Sl + S2-M2 M1-L-M2 (3)

[0068] In reaction (1), the moiety 1 is provided with a spacer SO and it is coupled with M2. Hence, the free terminus of SO and M2 must carry functional groups with compatible functionalities to allow formation of at least one covalent bond.

[0069] In reaction (2), the moiety 2 is provided with a spacer and it is coupled with Ml . Hence, the free terminus of SO and Ml must carry functional groups with compatible functionalities to allow formation of at least one covalent bond.

[0070] In reaction (3), both moieties Ml and M2 carry spacers with mutually compatible functional groups at their free termini to allow formation of at least one covalent bond to thereby generate linker L. Reaction (3) thus shows that linkers may also be formed by coupling two spacers. Such spacers form only part of the final linker but in principle, they are no different than spacers that forming the entire linker via reactions (1) or (2). Hence, they also qualify as spacers in the context of the present application. The terms linker and spacer are thus used to characterize the following moieties:

[0071] Linker - group bound to two moieties or components, e.g., a linker bound to cyclopeptide and chelating group. Covalent bonds to adjacent components may be formed via reactions of functional groups, as described for instance in reactions (1) and (2). Alternatively, the linker may be attached to an adjacent moiety by a covalent bond between non-fimctionalized groups. Such an attachment of the linker to the adjacent moiety without functional group may be present in cases in which the adjacent moiety can be purchased or synthesized in a form that already carries a spacer. A typical example is a chelating group of formula (IVd), as shown below, which may already be provided with a spacer that is covalently bonded without functional groups, as shown in the third to sixth formula of chelating groups carrying spacers that are described directly underneath formula (IVd) below.

[0072] Spacer - group bound only to one moiety or component, e.g., a spacer bound to a cyclopeptide. The linker has a functional group at its free terminus to allow coupling with another functional group. The spacers SO in reactions (1) and (2) and SI and S2 of reaction (3) fall into this category.

[0073] Linkers are described in more detail in relation to the conjugate of the third embodiment below. Spacers are described in more detail in relation to the cyclopeptides of first embodiment below. These disclosures are related insofar as the spacers may be regarded as precursors of the linkers. Hence, the disclosure of linkers informs on the structural elements that may be present in the spacers. Likewise, the disclosure of spacers informs on the structural elements that may be present in the linkers. The present disclosure is intended to encompass not only any linker and any spacer as described hereinbelow, but additionally also any linker or any spacer that is functionally related to a spacer or linker described hereinbelow.

[0074] The cyclopeptide of sequence 1 may contain a spacer as group -L4-R4. Hence, the presence and identity of a spacer in a given cyclopeptide can be identified by the presence of a group that can only be identified as a group -L4-R4. For other components and moieties such as chelating groups, central moieties or covalently bonded active atoms or atomic groups, it should in principle not matter for practising the invention whether a particular part of the respective molecule is identified as a spacer. However, if this determination should become relevant, in case of doubt, a spacer may be identified as the part of the molecule, which matches at least one of the definitions provided below for the “spacer attached to other moiety” for anyone of linker formulae (III) to (IIIg”-PEG26).

[0075] As used herein, the term “functional group” refers to any chemical group other than an alkyl group. As described herein, the term “terminus” or “terminal group” refers to the end of a chain of heavy atoms. In case of branched or substituted chains, there will be more than one terminal group. In case of doubt, in the context of the present invention, a reference to a terminal group is intended to refer to a terminal group that is a functional group capable of forming one or more covalent bonds with a suitably matched functional group of the reaction partner. If multiple functional groups of this type are present, the reference to a terminal group is intended to refer to the functional group that is connected to the main part of the molecule via the longest chain of atoms.

[0076] The term “fluorophor” is used to characterize a fluorescent moiety. The present application uses the terms “fluorophore”, “fluorescent dye”, “fluorescent agent” and “fluorescent tracer” as synonyms to characterize such fluorescent moieties. Likewise, the term “chromophore” is meant to characterize a coloured moiety and it is used as having the same meaning as “dye” to characterize such moieties with colour-conveying properties.

[0077] The term “capable of reacting with each other” and related terms imply reactivity that allows to accomplish reasonable yields of 50% or more, preferably 80% or more, more preferably 90% or more and especially 95% or more under conditions that do not result in degradation of the reacting molecules.

[0078] All documents cited herein are incorporated by reference in their entirety.

[0079] In the context of the present specification, the singular forms “a”, “an” and “the” are meant to include also the corresponding plural forms unless the context dictates otherwise. Thus, for example, reference to “a compound” or “the compound” includes two or more compounds. The words “comprise,” “comprises” and “comprising” are to be interpreted inclusively rather than exclusively. Likewise, the terms “contain”, “containing”, “include,” “including” and “or” should all be construed to be inclusive, i.e. as permitting additional unmentioned items, unless the context dictates otherwise. However, the use of these terms should also be understood as a disclosure of the possibility of no further items being present. In other words, a disclosure of an embodiment using the term “comprising” is in one aspect to be understood as a disclosure of “consisting essentially of’ or “consisting of’ the listed items. Likewise, the methods disclosed herein may contain one or more additional steps that are not specifically disclosed herein, but in one aspect, such additional steps are absent in accordance with the terms “consisting essentially of’ or “consisting of’. The term “and / or” used in the context of “X and / or Y” should be interpreted as “X,” or “Y,” or “X and Y.” Where used herein, the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive.

[0080] If a formula contains a variable group or a parameter more than once, the variable group or parameter may for each occurrence be independently selected from the specified possible meanings. Unless specified otherwise or the context dictates otherwise, the possible meanings specified for variable groups or a parameters in relation to one formula or claim may also be applied to other formulae or claims in which this variable group or parameter occurs.

[0081] Compounds of the invention

[0082] The invention relates in a first embodiment to cyclic peptides as described herein. These peptides are advantageous since they can bind to avP6-integrin.

[0083] In a first main aspect of the first embodiment, the invention relates to cyclic peptides which are characterized by the following Sequence 1: cyclo-(A1-Arg-A2-Asp-A3-A4-A5-D-Pro-A6) (Sequence 1), wherein A1,A2,A3,A4,A5,and A6represent amino acids. The variables A1to A6are selected from the following lists of meanings:

[0084] A1: Alanine, Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Tryptophane, Tyrosine, and anon- canonical amino acid.

[0085] A2: Serine, Glycine, and Threonine,

[0086] A3: Leucine, Isoleucine, Norleucine, Valine, and Phenylalanine,

[0087] A4: Glycine, and Alanine,

[0088] A5: Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Lysine, Tyrosine, Tryptophane, Arginine, and a non-canonical amino acid.

[0089] A6: Proline, Pro-Rx3, A'-Mc-amino acid such as A'-Mc-Lys. A'-Mc-Lys(Ac). A'-Mc-L s-Rx4, A'-Mc-Lyy. A'-Mc-Lyy-R'4. A-Me-Gln, A'-Mc-GIn-R4. A'-Mc-Gyy. A'-Mc-Gyy-Rx4. and A'-Mc-ALa-Rx4. with the proviso that at least one of the amino acids A1and A5in Sequence l is a non-canonical amino acid as defined above; and wherein A'-Mc-Gyy represents an amino acid residue derived from A'-Mc-GIn. but having an alkylene chain of 1, 3, 4, 5, 6, 7, 8, 9 or 10 methylene groups in the sidechain; wherein A'-Mc-Lyy represents an amino acid residue derived from A'-Mc-Lys. but having an alkylene chain of 1, 2, 3, 5, 6, 7, 8, 9 or 10 methylene groups in the sidechain; wherein Rx3is selected from -NH2, -OH, -NH-Ac, -NH-L4-R4; wherein Rx4is a spacer group of the formula -L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)n-O-, and -C(O)-O-, with 11 being 1 or 2, and wherein R4 is an alkylene-based group ABG carrying a functional group FG1; and pharmaceutically acceptable salts thereof. In preferred aspects, the non-canonical amino acid is selected from non-canonical amino acids wherein Ca carries a sidechain comprising a C1.4 alkylene group which carries a carbocyclic group, aryl group or heterocyclic group, more preferably non- canonical amino acids wherein Ca carries a sidechain comprising a C1-2 alkylene group which carries a carbocyclic group, aryl group or heterocyclic group and even more preferably non-canonical amino acids wherein Ca carries a sidechain comprising a C1-2 alkylene group which carries an aryl group or heteroaryl group. All these side-chains may optionally carry one or more substituents, preferably at the carbocyclic group, aryl group, heterocyclic or heteroaryl group. Said substituents are independently selected from the list of substituents in the above definition and preferably independently selected from -OH, F, Cl and Br. Of course, the canonical amino acids tryptophan and histidine are not meant to be encompassed.

[0090] The above residue Pro-Rx3represents a proline or proline residue that is functionalized at the C-3, C-4 or C-5 carbon atom and preferably the C-4 carbon atom with a functional group Rx3selected from -NH2, -OH, -NH-Ac, -NH-L4-R4, wherein -L4-R4 is a spacer group in which L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)n-O-, and -C(O)-O-, with 11 being 1 or 2, and wherein R4 is an alkylene based group ABG carrying a functional group FG1, wherein ABG and FG1 are as defined below with respect to formula (III). In specific aspects, it is selected from the group consisting of - (CFbln-CACH and -(CH2)n-N3 with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, such as -butyne, -pentyne, - hexyne, -heptyne, or -R4 represents another spacer group as described herein. Pro-Rx3may further represent aza-proline residues (i.e., proline residues wherein Ca is replaced by N) carrying one of the above -L4-R4 functional groups listed in this paragraph.

[0091] The above residue A-Me-Lys-Rx4represents a residue derived from a A-Me-lysine residue, wherein the co -amino nitrogen atom carries a spacer group Rx4of the formula -L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)n-O-, and -C(O)-O-, with 11 being 1 or 2, and wherein R4 is an alkylene based group ABG carrying a functional group FG1, wherein ABG and FG1 are as defined below with respect to formula (III). In specific aspects, it is selected from the group consisting of-(CH2)n-CACH and -(CH2)n-N3 with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or -R4 represents another spacer group as described herein.

[0092] The above residue N-Me-Lyy represents a residue related to N-methyl-lysine but having a modified length of the side chain. N-Me-Lyy represents in particular the residues covered by the following general

[0093] formula: -N(CH3)-CH(RLyy)-CO-, wherein RLyyrepresents –(CH2)y-NH2 with y = 1, 2, 3, 5, 6, 7, 8, 9 or 10. The above residue N-Me-Lyy-Rx4represents a residue derived from N-Me-Lyy, wherein the side chain amino nitrogen atom carries a spacer group Rx4of the formula –L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)l1-O-, and -C(O)-O-, with l1 being 1 or 2, and wherein R4 is an alkylene based group ABG carrying a functional group FG1, wherein ABG and FG1 are as defined below with respect to formula (III). In specific aspects, it is selected from the group consisting of –(CH2)n-C^CH and –(CH2)n-N3 with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or –R4 represents another spacer group as described herein. The above residue N-Me-Gln-Rx4is a residue derived from N-Me-Gln, wherein the nitrogen atom of the side chain carries a spacer group Rx4of the formula –L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)l1-O-, and -C(O)-O-, with l1 being 1 or 2, and wherein R4 is an alkylene based group ABG carrying a functional group FG1, wherein ABG and FG1 are as defined below with respect to formula (III). In specific aspects, it is selected from the group consisting of – (CH2)n-C^CH and –(CH2)n-N3 with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or –R4 represents another spacer group as described herein. The above residue N-Me-Gyy represents a residue related to N-Me-Gln but having a modified length of the side chain. N-Me-Gyy represents in particular the residues covered by the following general formula: -N(CH3)-CH(RGyy)-CO-, wherein RGyyrepresents –(CH2)y-CO-NH2with y = 1, 3, 4, 5, 6, 7, 8, 9 or 10. The above residue N-Me-Gyy-Rx4represents a residue derived from N-Me-Gyy, wherein the nitrogen atom of the side chain carries a spacer group Rx4of the formula –L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)l1-O-, and -C(O)-O-, with l1 being 1 or 2, and wherein R4 is an alkylene based group ABG carrying a functional group FG1, wherein ABG and FG1 are as defined below with respect to formula (III). In specific aspects, it is selected from the group consisting of –(CH2)n-C^CH and –(CH2)n-N3 with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or –R4 represents another spacer group as described herein. The above residue N-Me-Ala-Rx4represents a residue derived from an alanine residue, wherein the Cβ of alanine carries a spacer group Rx4of the formula –L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)l1-O-, and -C(O)-O-, with l1 being 1 or 2, and wherein R4 is an alkylene based group ABG carrying a functional group FG1, wherein ABG and FG1 are as defined below with respect to formula (III). In specific aspects, it is selected from the group consisting of – (CH2)n-C^CH, –(CH2)n-NH2 and –(CH2)n-N3 with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or –R4 represents another spacer group as described herein. 18 The above-mentioned “another spacer group” can be any spacer group that is capable of forming a linker upon reaction with a suitably matched functional group of the moiety or component to be connected.

[0094] The above spacer may for instance consist of or contain linear, branched and / or cyclic structural elements typically consisting of atoms selected from C, H, N, O, S and P. The total number of heavy atoms (i.e. atoms other than hydrogen) in the spacer (including optionally present substituents) may be within the range of 1 and 250, preferably 2 to 100 and more preferably 3 to 60. In further aspects, the spacer is a linear chain of 1 to 20 and preferably 2 to 10 atoms selected from C, N, O, P and S, preferably alkylene groups, the remaining valences being saturated by hydrogen. This linear chain may be interrupted by one or more cyclic structures preferably such having 5 ring atoms, and more preferably a 1,2, 3 -triazole ring. Bonding to a side chain of the cyclopeptide is typically accomplished by means of an amide bond.

[0095] The above spacer may also carry one or more substituents. Such substituents are preferably selected from the substituents defined above and more preferably from the group consisting of amino, halogen, cyano, nitro, carboxylic acid, carboxylic ester, C1-C20 alkyl, C2-C20 alkenyl, C3-C20 alkynyl, C3-C20 cyloalkyl, C4-C20 cyloalkenyl, C8-C20 cyloalkynyl, C6-C20 aryl, Ci-Ce alkyl-Ce-C2o aryl, heteroaryl, 5-7- membered heterocycle having one or more heteroatoms selected from the group consisting of N, O, S and P.

[0096] Preferred structural elements contained in the above spacer are selected from ethylene glycol, polyethylene glycol (PEG) such as PEG with 2-20 ethylene glycol repeating units, propylene glycol, poly propylene glycol (PPG) such as PPG with 2-15 propylene glycol repeating units, amino acids, oligopeptides such as (Gly)mwith m=2-15 or (Pro)mwith m=2-15, saccharides such as galactose and oligosaccharides such as saccharose and other oligosaccharides with 2-15 monsaccharide repeating units. Further structural elements that may be contained in the spacer are alkylene groups, alkenylene groups or alkynylene groups, each of them preferably having 2-20 carbon atoms and each of them optionally having incorporated therein one or more carbonyl groups and / or optionally being substituted as explained above.

[0097] In other aspects, especially in connection with active atoms or active atomic groups that are suitable for therapeutic purposes, the spacer may contain structural elements allowing the linker derived from the spacer to be cleavable under physiological conditions. The spacer and related linker (hereinafter: “spacer / linker”) may thus contain a hydrolysable group that allows to cleave the two linked moieties of the related conjugate. The use of such a cleavable spacer / linker may be advantageous, e.g. when the cyclopeptide according to Sequence 1, or any more specific structure such as Formula 10 specified hereinbelow, is used in order to target a therapeutically active effector moiety (e.g. a cytotoxic agent) to a cell which expresses the avP6-integrin. Suitable hydrolysable groups can be selected from ester such as - C(O)-O- and -O-C(O)-, amide (peptide) such as -C(O)-NH- and -NH-C(O)-, carbamate such as - NH-C(O)-O- and -O-C(O)-NH-, urea such as -NH-C(O)-NH- and anhydride such as -C(O)-O-C(O)-. It is of course possible to combine two or more of these hydrolysable groups and / or to combine one or more of these hydrolysable groups with one or more of the optionally substituted linker groups specified above.

[0098] As mentioned below, suitable cleavable and non-cleavable linker structures are also disclosed, for instance, in: Khongorzul P, et al., Mol. Cancer Res. 2020;18:3-19, doi: 10.1158 / 1541-7786.MCR-19- 0582; Arano Y, Nucl. Med. Biol. 2021;92: 149-155, doi: 10.1016 / j.nucmedbio.2020.03.001; WO 2009 / 117531 A, WO 2015 / 123679 A, Younes et al. N. Engl. J. Med. 2010;363: 1812-1821; Dorywalska et al. Mol. Cancer Ther. 2016;15(5):958-970, Jain et al., Pharm. Res. 2015;32(l l):3526-3540, Paulus J, et al., J Pept Sci. 2024;30:e3561; doi: 10.1002 / psc.3561, and references cited therein. Further suitable linkers are disclosed in “Ligands for Mapping avP3-Integrin Expression in Vivo” by M. Schottelius et al. in Acc. Chem. Res. 2009, 42, 969-980, especially the linkers forming part of the structures shown in Fig. 12 and 14. ; “Dimerization of a Phage-Display Selected Peptide for Imaging of avP6-Integrin: Two Approaches to the Multivalent Effect” by A.N. Singh et al. in Theranostics 214, 4, 756-760, especially as shown in Scheme 1. A further linker is shown in “Synthesis and biological evaluation of a peptidepaclitaxel conjugate which targets the integrin avP6” by S. Li et al. in Bioorganic & Medicinal Chemistry 2011, 19, 5480-5489, and especially the compounds of Figure 1. Disclosures of linkers in the cited literature should be regarded as disclosing implicitly also the spacers that may be used for forming the linkers. Likewise, disclosure of spacers in the cited literature should be regarded as disclosing implicitly also the linkers that may be obtained when coupling the disclosed spacers with another moiety such as an effector group or a second spacer.

[0099] Of course, it is also possible to combine two or more of the different structural elements mentioned herein as possibly contained in linkers and / or spacers, to thereby form a linker and / or spacer. Generally, the spacer may be characterized by the same structural elements as the above linkers, such that the above linkers are formed upon coupling.

[0100] Spacers carry functional groups FG such as FG 1 or FG2 at their termini to allow bonding to other spacers or other moieties. For example, the spacer attached to the cyclopeptide carries functional group FG1, which reacts with functional group FG2 of for instance an effector moiety, or another spacer to thereby form a linker. Hence, at its free terminus, a spacer contains a functional group FG such as FG1 or FG2 to allow formation of at least one covalent or coordination bond to the adjacent moiety or component to be connected. These functional groups FG1 and FG2 can be any functional groups that are capable of reacting with each other. Suitable functional groups are for instance those which allow to practise synthetic or engineering techniques referred to as conjugation methods or bioconjugate techniques, such as described in Hermanson GT, Bioconjugate Techniques, 3rdEdition 2013, Academic Press, ISBN 978- 0-12-382239-0; Narain R (Ed.), Chemistry of Bioconjugates: Synthesis, Characterization, and Biomedical Applications, John Wiley & Sons, 2014, ISBN:9781118359143; Chauhan P, et al., Chem Soc Rev. 2024;53:380-449. The groups referred to as FG1 and FG2 hereinbelow may be selected from the functional groups described in this literature.

[0101] Preferred functional groups FG which can occur at the terminus of a spacer are: amino group, -NFF; carboxyl group, -COOH; NHS ester group, -C(O)-O-succinimide; maleimide group, ethylene group, - C=CH2; ethyne group, CACH: azide group, -Ns; isonitrile group, -N=C; nitrile group, -ON; thiol group, -SH; hydroxyl group, -OH; phosphate group, -O-P(O)(OH)(OH); phosphonate group, - P(O)(OH)(OH); methylene-bis(phosphonate) group, -CH(P(O)(OH)(OH))2; cyclooctyne group, dibenzo-cyclooctyne group (DBCO), and 1,2,4,5-tetrazine group. The groups referred to as FG1 and FG2 hereinbelow may preferably be selected from this list.

[0102] The adjacent moiety or component to be connected must carry a suitably matched functional group. If, for instance, Click chemistry is used for coupling the spacer to the effector moiety, the functional group of the spacer has to be selected as being complementary to the functional group of the effector moiety as the reaction partner, e.g., if the spacer carries a terminal azide group, an effector moiety as a reaction partner must carry a suitably matched group, typically an ethyne group -OCH. The principle of matched reactivity also applies in other instances as covalent bond formation. For example, in case the functional group has the purpose to enable attachment to a nanoparticle surface or incorporation into the outer layer of a micelle, it has obviously to match the required purpose by providing the right functionality to allow attachment or incorporation. The following Table 1 illustrates possible exemplary functional groups and matching partners, but the present disclosure is not meant to be limited to these groups.

[0103] Table 1

[0104] In preferred aspects, FG1 is selected from the groups described in the above table as FGa and FG2 is selected from the matching groups FGb indicated in the above table. It should however be clear that one or both of these functional groups may be replaced by other functional groups provided the resulting pair of functional groups is capable of reacting with each other.

[0105] In specific aspects, the linker described herein can be characterized by formulae (III), (Illa), (III’), (III”), and (Illa) to (Illgg”). The spacers acting as precursors for these linkers have corresponding structures as described in the following.

[0106] In one aspect, the linker has the formula (III) or, more specifically, formula (Illa):

[0107] *-L4-(ABG)-(CFG)r(ABG)- (III) and

[0108] *-C(O)-(ABG)-(CFG)r(ABG)- (Illa) and the related spacers may have the following structures:

[0109] *-L4-(ABG)-FGl as well as FG2-(ABG)- for formula (III)

[0110] *-C(O)-(ABG)-FGl as well as FG2-(ABG)- for formula (Illa) wherein in formula (III) and related spacer formulae (i.e. formulae of preferred / more specific spacers within the scope of formula (III), such as formula (Illa)), L4 has the same meaning as defined above with respect to Rx3and Rx4, CFG stands for the coupled functional group that is obtained when reacting two functional groups (referred to as FG1 and FG2 herein) and wherein each ABG group is an alkylene- based group. Preferred coupled functional groups CFG are a triazole group derived from coupling of an azide group as FG1 and an ethyne group as FG2, a triazole group with reversed orientation derived from coupling of an ethyne group as FG1 and an azide group as FG2, an amide group derived from coupling of an amino group as FG1 and a carboxyl group as FG2, and an amide group derived from coupling of a carboxyl group as FG1 and an amino group as FG2. The ABG groups may each independently be selected from (CFF , -(CIDpi- O-CFFCIDp- and -(CH2CH2-O)P-(CH2)PI- with k being an integer selected from 0 to 20, preferably 1 to 10, p being an integer selected from 1 to 20, such as 1 to 10, preferably 3 to 10, such as 3 to 8 and more preferably 4 to 8, and pl being 0, 1 or 2. If any of the variables k, p orpl appears multiple times in the formula, then each value may be selected independently. Variable 1 may be 0 or 1. In formula (III) and all related formulae, the asterisk (*) marks the point of attachment of the cyclopeptide. In formula (III) and all related formulae, pl has the same meaning as pl’, as used in the claims. There is an implicit proviso for all linkers described herein that not all elements of the linker may be simultaneously absent (otherwise, there would be no linker; this option is also possible in accordance with the invention, but it is defined in a different manner by specifying that q in the conjugate formulae can be 0). The linker should have a minimum length of two heavy atoms and / or three covalent bonds. As a result, not all structural elements of the linker can be simultaneously absent (e.g., L4 cannot be a covalent bond if all k and 1 are 0 and there is no PEG group). More specifically, there should be at least one coupled functional group, which may either be a CFG group as described above, or a corresponding group at (at least) one of the termini of the linker (in which case the coupled functional group is partly derived from the attached moiety, e.g., the nitrogen of an amide bond being derived from an amino group of a sidechain of a '-Mc-Lys residue in position A6of the cyclopeptide Cp). These indications indirectly apply to the related spacers.

[0111] The more specific formula (Illa) illustrates a preferred aspect of the invention, wherein the spacer / linker is attached to the cyclopeptide via a carbonyl group. However, as indicated in Formula (III), attachment via alternative L4 groups is equally possible.

[0112] The option of 1 in formula (III) or (Illa) representing 0, i.e. absence of a coupled functional group, describes a variant, in which coupling is accomplished in a different position. For instance, an effector moiety may be provided with a methylene spacer terminated by a -COOH group, which may then be bonded to the cyclopeptide via a matching functional group at a sidechain of the peptide, such as an amino group.

[0113] In one aspect, both alkylene-based groups contain only alkylene groups. This linker is represented by formula (III’) and in a preferred variant formula (III”):

[0114] *-C(O)-(CH2)k-(CFG)i-(CH2)k- (III')

[0115] *-C(O)-(CH2)k-(taz)i-(CH2)k- (III") wherein CFG has the same meaning as specified above with respect to formula (III). The more preferred coupled functional group taz stands for a triazole ring with all three nitrogen atoms being adjacent to each other, 1 and k may have the same meanings as specified above with respect to formula (III).

[0116] For the linker of formulae (III), (Illa ), (III’) and (III”), the two spacers acting as precursors may have the following formulae:

[0117] Table 2 wherein ABG and k and m are as defined above with respect to Formula (III), and FG1 and FG2 represent matching functional groups as described above. In a preferred embodiment, FG1 is selected from the FGa groups listed in the above table and FG2 is then selected from the FGb groups specified in the table above as matching with the selected FGa group. More preferably, FG1 and FG2 may be selected from ethyne and azide, but with the proviso that the two functional groups must be different, i.e. while both options are available when selecting the first functional group, the second functional group must be the other functional group, such that the two functional groups are different from each other. This is reflected by the two different spacer options shown in the above table for the formula (III”) linker.

[0118] Further divalent linkers and related spacers may be derived from the following Table 3 :

[0119] Table 3 wherein ABG, CFG, FG1, FG2, taz, k and 1 have the same meanings as indicated above with respect to formula (III), (Illa), (III’) and (III”). As specified above, if any of these variables appears more than once, each of the variables may be selected independently from the above meanings.

[0120] In one further aspect, the atomic group acting as a linker has a structure corresponding any one of the above formulae (III) and (Illa) to (Illg) wherein at least one of the ABG groups is selected to be a polyethylene glycol group -(CH2)PI-(O-CH2CH2)P- or -(CH2CH2-O)P-(CH2)PI- with p = 1 to 20, preferably 1 to 10, and pl = 0, 1 or 2. These linkers may be represented by the formulae (IIIa-PEGl) to (IIIg”-PEG26) provided below. These formulae and related spacers are shown in the following Table 4:

[0121] Table 4

[0122] The variable groups CFG, taz, FG1, FG2 and parameters p, pl, k, and 1 have the same meanings as specified above.

[0123] In a further aspect, the present invention relies on linkers and corresponding spacers as shown in the above table with respect to formulae (IIF-PEG1) to (IIIg”-PEGl), but wherein the -(CFE - group at the right-hand-side of the linker (i.e., in the part originating from the spacer attached to the effector moiety) is also replaced by -(CH2)PI-(O-CH2CH2)P-. The resulting linkers are identified as (IIF-PEG2) to (IIIg”-PEG2), respectively.

[0124] In yet another aspect, the present invention relies on linkers and corresponding spacers as shown in the above table with respect to formulae (IIF-PEG1) to (IIIg”-PEGl), but wherein the -(CH2)k- group in the center of the linker (in linkers with three alkylene-based groups) is also replaced by -(CH2)PI-(0- CH2CH2)P-. The resulting linkers are identified as (III”-PEG3), (IIIa’-PEG3), (IIIa”-PEG3), (Illd’- PEG3), (IIId”-PEG3), (IIIe’-PEG3), (IIIe”-PEG3), (IIIT -PEG3), (Illf ’-PEG3), (IIIg’-PEG3) and (Illg ”- PEG3), respectively.

[0125] In a further aspect, the present invention relies on linkers and corresponding spacers as shown in the above table with respect to formulae (IIF-PEG1) to (IIIg”-PEGl), but wherein the relative orientation of the PEG group is reversed, i.e., wherein -(CH2CH2-O)P-(CH2)PI- is used instead of -(CH2)PI-(0- CH2CH2)P-. The resulting linkers are identified as (IIF-PEG8) to (IIIg”-PEG8), respectively.

[0126] The following Table 5 illustrates and summarizes these and further linkers that may be used in the present invention.

[0127] Table 5 In each of the above series of linkers, the meaning of the parameters k, p and pl is as specified above. For the linkers not having a central ABG group, there is some redundancy in the above table; for instance, there is no difference between the linkers of series PEG2 and PEG3 if the central ABG group is absent. For the sake of clarity, in case of such redundancy, the linker shall be identified as member of the PEG series which comes first in the above table.

[0128] For the sake of simplicity, the above formulae (III’) to (IIIg”-PEG26) all show a carbonyl group in this position. However, it should be clear that in each of these formulae, the carbonyl group may be replaced by another L4 group as described above. For example, with respect to formulae (Illa) to (Illg”), the following linkers are conceivable:

[0129] *-L4-(ABG)-(CFG)r(ABG)- (lllaL4)

[0130] *-L4-(CH2)k-(CFG)i-(CH2)k- (IIFL4)

[0131] *-L4-(CH2)k-(taz)r(CH2)k- (lll"L4)

[0132] *-L4-(ABG)-(CFG)r(ABG)-(CFG)r(ABG)- (HlaL4)

[0133] *-L4-(CH2)k-(CFG)i-(CH2)k-(CFG)i-(CH2)k- (llla'L4)

[0134] *-L4-(CH2)k-(taz)r(CH2)k-(CFG)r(CH2)k- (llla"L4)

[0135] *-L4-(ABG)-NH-CO-(ABG)- (HlbL4)

[0136] *-L4-(CH2)k-NH-CO-(CH2)k- (lllb'L4)

[0137] *-L4-(ABG)-CO-NH-(ABG)- (lllcL4)

[0138] *-L4-(CH2)k-CO-NH-(CH2)k- (lllc'L4)

[0139] *-L4-(ABG)-(CFG)i-(ABG)-CO-NH-(ABG)- (HldL4)

[0140] *-L4-(CH2)k-(CFG)i-(CH2)k-CO-NH-(CH2)k- (llld'L4)

[0141] *-L4-(CH2)k-(taz)i-(CH2)k-CO-NH-(CH2)k- (llld"L4)

[0142] *-L4-(ABG)-(CFG)i-(ABG)-NH-CO-(ABG)- (HleL4)

[0143] *-L4-(CH2)k-(CFG)i-(CH2)k-NH-CO-(CH2)k- (llle'L4)

[0144] *-L4-(CH2)k-(taz)i-(CH2)k-NH-CO-(CH2)k- (llle"L4) *-L4-(ABG)k-C0-NH-(ABG)-(CFG)i-(ABG)k- (HlfL4)

[0145] *-L4-(CH2)k-CO-NH-(CH2)k-(CFG)i-(CH2)k- (lllf'L4)

[0146] *-L4-(CH2)k-CO-NH-(CH2)k-(taz)i-(CH2)k- (lllf"L4)

[0147] *-L4-(ABG)-NH-C0-(ABG)-(CFG)i-(ABG) - (HlgL4)

[0148] *-L4-(CH2)k-NH-CO-(CH2)k-(CFG)i-(CH2)k- (lllg'L4)

[0149] *-L4-(CH2)k-NH-CO-(CH2)k-(taz)i-(CH2)k- (lllg"L4) wherein the meanings of the variable groups and parameters are as defined above. Similar structures having an (other) L4 group in the position of the C(O) are contemplated and meant to be disclosed also with respect to the PEG group-containing linkers as described above by means of formulae (III’-PEGl) to (IIIg”-PEG26).

[0150] In a preferred embodiment, the spacer bonded to the cyclopeptide consists only of an alkylene group, preferably an alkyl group carrying an amino or azide group as functional group, most preferably the sidechain of JV-Me-Lyy or '-Mc-azidolysinc. and, in the bonded state, an amide or a triazine coupled functional group. A specific aspect of this embodiment is characterized by any of the Formulae (Illa) to (Illg”) shown in the above Tables 2 and 3, but wherein the -C(O)-group bonded to the peptide part is simply omitted and / or the above formulae (IIIaL4) to (IIIg”L4), wherein L4 represents a single covalent bond. This includes also those of the PEG-containing linkers specified in the above Formulae PEG5- PEG7, PEG12-PEG14, PEG20 and PEG26, wherein a PEG group is present, but not in the spacer bonded to the cyclopeptide. Formulas of specific interest are shown in the Tables 6 to 9 below.

[0151] Table 6

[0152] In the above table, k has the same meaning as specified above for Formula (III). The linker formed by the above spacers is shown in the following Table 7.

[0153] Table 7

[0154] The variable group taz and parameter k have the same meanings as specified above. The parameter 1 = 1.

[0155] The matching bonding partner can also be an ethyne group or carbonyl group bonded to a moiety that contains a polyethylene glycol group and optionally an alkyl group, as shown in the following Table 8, wherein the variable group taz and parameters p, pl, k, and 1 have the same meanings as specified above in connection with formula (III) and related formulae.

[0156] Table 8

[0157] In a further preferred aspect, the linker may contain a further coupled functional group CFG, preferably an amide bond, linked to another ABG group, as specified above. Such preferred linkers may be characterized by the following formulae, wherein taz, CFG, ABG, FG1, FG2, k, 1, p and pl have the same meanings as specified above in connection with formula (III) and related formulae.

[0158] Table 9

[0159] In the above Tables 6 to 8, or in other descriptions of linkers in the present specification, the spacer bonded to the other moiety may further carry a functional group at its opposite terminus in order to allow convenient binding to a functional group of the other moiety. Depending on the functional group of the other moiety, a matching functional group may be selected based on Table 1. For instance, if the other moiety contains a carboxyl group or derivative thereof, the terminal group of the spacer may be selected to be an amino group to allow bonding of the spacer to the other moiety via an amide group. Linkers employed for bonding between other moieties, such as bonding Cg or Cm to Aa’ or Pm, are preferably also selected from the above Tables 6 to 9 (wherein the asterisk identifies the point of attachment of the outer moiety Aa’ or Pm). Another preferred linker for this purpose is a linker of the following formula (III8):

[0160] *-(CH2)k-[NH-CO-ABG-]pp(NH-CO)-(CH2)k- (III8)

[0161] *-(CH2)k-[NH-CO-(CH2)pi-(O-CH2CH2)p-]pp(NH-CO)-(CH2)k- (III81)

[0162] *-(CH2)k-[NH-CO-(CH2CH2-O)p-(CH2)pi-]pp(NH-CO)-(CH2)k- (III82) wherein pp is 1 or 2, and ABG, k, pl and p are as defined above with respect to formula (III) and derivatives thereof. In case of multiple occurrences, the multiple ABG, k, pl and p may each be selected independently.

[0163] In a preferred aspect of the first embodiment, the one or two non-canonical amino acids, which are present at the positions A1or A5or both positions A1and A5, independently of each other adopt a structure according to Formula 1 or Formula 2:

[0164] Formula 1,

[0165]

[0166] Formula 2, wherein

[0167] * indicates binding to an adjacent carbon atom of a carbonyl group in the peptide chain;

[0168] # indicates binding to an adjacent nitrogen atom of a peptide bond in the peptide chain;

[0169] In one aspect, X1is -C(H)=, and X2, X3, X4, and X5are all -C=, X6, X7, X8, and X9are independently selected from H, -OH, F, Br, and I, wherein at least two of X6, X7, X8, and X9are H, and wherein -C= denotes an aromatic ring carbon atom.

[0170] In another aspect, the above definitions for X1to X9apply, but with the proviso that one of X1, X2-X6, X3-X7, X4-X8, and X5-X9is an aromatic nitrogen atom (-N=);

[0171] X10represents a group selected from -H, -CH3, and -CH2-COOH;

[0172] X11, X12, X13, and X14are collectively selected such that they adopt one of the configurations listed in the following Table 10, wherein -C(H)= denotes an aromatic ring carbon atom with a hydrogen, -C= denotes an aromatic ring carbon atom without a hydrogen, and -N= denotes an aromatic ring nitrogen atom:

[0173] Table 10

[0174] In a more preferred aspect of the first embodiment, at least one of the amino acids A1and A5in Sequence

[0175] 1 is a non-canonical amino acid according to any of the following Formulae la to Ij and 2a to 2d: wherein the meaning of * and # is the same as specified above for Formula 1 and Formula 2, and furthermore all other definitions and specifications pertaining to Sequence 1 of the first embodiment remain the same.

[0176] In one embodiment, at least one of the groups XAand XBis selected such that the resulting amino acid is characterized by a structure selected from the following group consisting of Formulae (la) to (Id), (2a) to (2d), wherein the meanings of * and # are as specified above.

[0177] In a more preferred embodiment, one of the groups XAand XBis selected such that the resulting amino acid is characterized by a structure selected from Formulae (la), (2a) and (2c), wherein the meanings of * and # are as specified above, and the other one of the groups XAand XBis selected such that the resulting amino acid is characterized by a structure selected from Formulae (la), (2a), (2c), Phe, Tyr and Trp.

[0178] In a second main aspect of the first embodiment, the invention relates to a cyclopeptide of Sequence 1, which is characterized by the following Formula 10:

[0179] Formula 10 wherein in Formula 10,

[0180] XArepresents a group selected from Formula A and Formula B, or represents a suitable functional group chosen such that the resulting amino acid in the cyclopeptide is Alanine, Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Tryptophane, Tyrosine;

[0181] XBrepresents a group selected from Formula A and Formula B, or represents a suitable functional group chosen such that the resulting amino acid in the cyclopeptide is Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Lysine, Tyrosine, Tryptophane, or Arginine; with the proviso that at least one of the functional moieties XAand XBis selected from Formula A and Formula B, wherein Formula A and Formula B have the following structures:

[0182] Formula B, wherein in Formula A and Formula B, § denotes the methylene group to which XAor XBis attached. The meanings of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14are the same as specified for Formula 1 and Formula 2.

[0183] Xcin Formula 10 represents a functional group which is chosen such that the resulting amino acid in the cyclopeptide is proline, Pro-Rx3, JV-Me-amino acid such as A'-Mc-Lys. A'-Mc-Lys(Ac). A'-Mc-Lys- Rx4, A'-Mc-Lyy. A'-Mc-Lyy-Rx4. A-Me-Gln, A'-Mc-GIn-R4. A'-Mc-Gyy. A'-Mc-Gyy-Rx4. and A'-Mc-Ala- Rx4, wherein all listed meanings are the same as specified in the definition of A6of Sequence 1, or Xcis another spacer. More specifically, Rx3or Rx4can be any group -L4-R4 or another spacer, as described above with respect to A6of Sequence 1. Likewise, the linkers formed with Xcin Formula 10 may be any of the linkers described above, including especially the linkers of any of formulae (III) to (Illg”) and PEG-containing variants thereof (III’-PEGl) to (IIIg”-PEG26) described above.

[0184] In case of proline and Pro-Rx3, the group Xcis joined with the methyl group of the adjacent N-Me group to form a cyclic structure, i.e., the N-Me group shown in Formula 10 becomes part ofthe five-membered cycle of proline.

[0185] In a preferred aspect, Xcin Formula 10 represents a functional group such that the resulting amino acid is characterized by a structure A'-Mc-Ala-R4. wherein Rx4is represented by the formula -L4-R4, wherein L4 is a covalent bond, and wherein R4 is an alkylene based group carrying a functional group selected from the group consisting of-(CH2)n-C=CH and -(CEEjn-Ns with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein R4 is preferably an alkylene based group carrying a functional group -(CH2)n-Ns with n = 2, 3, or 4, more preferably R4 is -(CH2)n-Ns with n = 3. In other words, in a particularly preferred embodiment, Xcis selected such that the amino acid carrying Xcis A'-Mc-azido-Lys. In another preferred aspect, Xcin Formula 10 represents a functional group such that the resulting amino acid is JV-Me-Lys.

[0186] In case -L4-R4 or Xcin Formula 10 represents another spacer, that spacer group can be any spacer group as described above with respect to Sequence 1.

[0187] Preferred feature combination aspect (1): it is of course also preferred that the compound of Formula 10 contains the groups identified above as preferred for XAand XBin combination with groups identified for Xcas being preferred. For instance, in one preferred feature combination aspect, one or both of XAand XBin Formula 10 is selected such that the resulting amino acid is represented by one of Formulae (la) to (Ik), (2a) to (2d), such as (la) to (Id), (2a) to (2d), and Xcis represented by a functional group such that the resulting amino acid is characterized by a structure A'-Mc-Ala-R4. wherein Rx4is represented by the formula -L4-R4, wherein L4 is a covalent bond, and wherein R4 is an alkylene based group carrying a functional group -(CH2)n-N3 with n = 2, 3, or 4, more preferably R4 is -(CFF -Ns with n = 3. In another preferred feature combination aspect, one or both of XAand XBin Formula 10 is selected such that the resulting amino acid is represented by one of Formulae (la) to (Ik), (2a) to (2d), such as (la) to (Id), (2a) to (2d), and Xcis such that the amino acid residue carrying Xcis a A'-Mc-Lys residue.

[0188] Preferred feature combination aspect (2): the preferred compounds of the above preferred feature combination aspect (1) above may also carry a spacer. If Xcis represented by a functional group such that the resulting amino acid is A'-Mc-Lys. the co -amino group of Lys is preferably reacted with a spacer element bonded to a terminal carboxyl group to form an amide bond carrying a spacer element. If Xcis represented by a functional group such that the resulting amino acid is characterized by a structure N- Me-Ala-Rx4, at least apart of said spacer is -L4-R4 as described above, i.e., a functional group -(CH2)n- Ns with n = 2, 3, or 4, more preferably n = 3. Said azide group may be reacted with a further spacer element bonded to a terminal ethyne group to form a longer spacer containing a triazole group as coupled functional group. Said spacer element linked to the coupled functional group (triazole or amide group) may consist of one or more ABG groups connected to each other by coupled functional groups. It preferably consists of one, two, three or four ABG groups connected to each other via zero, one, two or three coupled functional groups. The ABG groups and coupled functional groups are preferably as described above in relation to any one of formulae (III) and variants thereof, as shown for instance in Tables 1 to 10 and especially Tables 6 to 10. More preferably, said spacer element consists of one, two, three or four ABG groups independently selected from (CFF , *-(CH2)PI-(O-CH2CH2)P- and *-(CH2CH2-O)P-(CH2)PI- with k being an integer selected from 1 to 10, p being an integer selected from 1 to 10, preferably 3 to 10, such as 3 to 8 and more preferably 4 to 8, and pl being 0, 1 or 2, * marking the point of attachment to the moiety comprising the cyclic peptide, which are connected to each other via zero, one, two or three coupled functional groups independently selected from triazole groups and amide groups. The orientation of these coupled functional groups is preferably such as shown in the exemplified conjugates, i.e., that the nitrogen in an amide group and the bonding nitrogen in a triazole group are oriented towards the cyclopeptide. The opposite terminus of the spacer element preferably carries another functional group for bonding to another spacer element or the moiety to be linked, such as the chelating group CP or a central moiety Cm.

[0189] Further preferred feature combinations are specified in the following numbered aspects. Unless specified otherwise, references to specific formulae in the below numbered aspects are meant to be references to the respective formulae described in the present specification, wherein the variable groups and parameters may adopt all possible meanings described in the present specification, but only to the extent that they are compatible with the context in which the respective variable groups or parameters appear.

[0190] Aa. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in appended claims 3, 4 and / or 5, wherein the cyclic peptide or pharmaceutically acceptable salt thereof is further characterized by at least one of XAand XB, and optionally both, being selected from Table 10 and / or such that the resulting amino acid is anyone of Formulae (la) to (2d).

[0191] Ab. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in appended claims 3, 4 and / or 5 or numbered aspect Aa, wherein one of XAand XBis selected such that the resulting amino acid is characterized by a structure selected from Formulae (la), (2a) and (2c), and the other one of the groups XAand XBis selected such that the resulting amino acid is characterized by a structure selected from Formulae (la), (2a), (2c), Phe, Tyr and Trp.

[0192] Ac. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in numbered aspect Aa or Ab, wherein Xcis selected such that the amino acid carrying Xcis A'-Mc-Lys or A'-Mc-azido-Lys.

[0193] Ad. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in anyone of numbered aspects Aa to Ac, wherein the groups XAand XBare selected in accordance with the groups XAand XBof at least one specific cyclic peptide exemplified in the present specification.

[0194] Ae. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in anyone of numbered aspects Aa to Ad, but wherein Xcis selected such that the amino acid carrying Xcis derived from A'-Mc-Lys. which is bonded via an amide bond to a spacer element consisting of one, two or three ABG groups independently selected from (CFLjk, *-(CH2)PI-(O-CH2CH2)P- and * -(CH2CH2-O)p- (CFFjpi- with k being an integer selected from 1 to 10, p being an integer selected from 1 to 10, preferably 3 to 10, such as 3 to 8 and more preferably 4 to 8, and pl being 0, 1 or 2, * marking the point of attachment to the moiety comprising the cyclic peptide, which are connected to each other via zero, one or two coupled functional groups independently selected from triazole groups and amide groups, and the spacer being terminated by a functional group selected from the groups specified in Table 1, preferably an amino group, a carboxyl group, an ethyne group or an azide group.

[0195] Af. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in numbered aspect Ae, wherein spacer element consists of ABG group (CfTf with k being an integer selected from 1 to 10, and the spacer is terminated by a functional group selected to be an amino group.

[0196] Ag. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in anyone of numbered aspects Aa to Ad, but wherein Xcis selected such that the amino acid carrying Xcis derived from '-Mc-azido-Lys. which is bonded via a triazol group to a spacer element consisting of one, two or three ABG groups independently selected from (CIDk, *-(CH2)PI-(O-CH2CH2)P- and *-(CH2CH2- O)P-(CH2)PI- with k being an integer selected from 1 to 10, p being an integer selected from 1 to 10, preferably 3 to 10, such as 3 to 8 and more preferably 4 to 8, and pl being 0, 1 or 2, * marking the point of attachment to the moiety comprising the cyclic peptide, which are connected to each other via zero, one or two coupled functional groups independently selected from triazole groups and amide groups, and the spacer being terminated by a functional group selected from the groups specified in Table 1, preferably an amino group, a carboxyl group, an ethyne group or an azide group.

[0197] Ah. The cyclic peptide or pharmaceutically acceptable salt thereof as specified in numbered aspect Ag, wherein the spacer element consists of one ABG group selected from *-(CH2)PI-(O-CH2CH2)P- with p being an integer selected from 3 to 8, and pl being 0, 1 or 2, * marking the point of attachment to the moiety comprising the cyclic peptide, the spacer being terminated by a functional group selected to be an amino group.

[0198] In a preferred aspect of the first embodiment of the present invention, the cyclopeptide is characterized by one of the following structural formulae:

[0199] wherein Xchas the same meaning as described above in the definition of Formula 10.

[0200] Of particular interest are cyclopeptides of the structural formulae shown above, wherein Xcadopts the following structures: wherein § denotes the methylene group to which Xcis attached. Hence, the first meaning of Xcresults in the amino acid being N-Me-Lys, the second meaning results in N-Me-Lyy. The remaining four meanings result in the amino acid being N-Me-Ala-RX4with RX4having varying meanings for -L4-R4. In principle, the first and second meaning could also be regarded as forming the amino acid N-Me-Ala- RX4with RX4having varying meanings for -L4-R4. However, for the sake of clarity and in case of doubt, in this case (and other cases) where multiple definitions give rise to the same group, the most concrete definition (i.e. the definition that adheres most closely to conventional amino acid definitions) shall be decisive, and this is the above-mentioned definition referring to N-Me-Lys and N-Me-Lyy. In other words, the definition of a group by -L4-R4 is to be treated as subsidiary to other definitions provided herein and to be applied only if there is no other definition characterizing the respective group.

[0201] Specific cyclopeptides of the invention are:

[0202]

[0203] Specific cyclopeptides functionalized with spacers are: Protected peptides and synthetic intermediates

[0204] In a second embodiment, the invention relates to synthetic intermediates which are used to generate the cyclopeptides of the invention according to Sequence 1 and Formula 10. Such synthetic intermediates include linear peptides with 4 to 9 amino acids, which are typically bound to resins during solid-phase peptide synthesis. These linear peptides may carry suitable protecting groups, such as Pbf on the terminal nitrogen atom of the side chain of arginine, tert-butyl on the phenolic oxygen of tyrosine or the carboxyl group of aspartic acid, acetonide on the catecholate group of dopa, or Dde on the terminal nitrogen atom of the side chain of lysine or ornithine. The group of synthetic intermediates furthermore encompasses cyclic peptides according to Sequence 1 and Formula 10, which carry one or more of the mentioned protecting groups on the respective amino acid side chains.

[0205] Specific synthetic intermediates have the following sequences:

[0206] HO-Gly-Arg(Pbf)-DOPA(ac2)-(M\4e)-azidolysine-D-Pro-DOPA(ac2)-Ala-Leu-Asp(tBu)-Fmoc

[0207] HO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-I)-Pro-4-Pal-Ala-Lcii-Asp( / Bii)-Fmoc

[0208] HO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-I)-Pro-7-AW-Ala-Lcii-Asp( / Bii)-Fmoc

[0209] HO-Gly-Arg(Pbf)-4-Pal-(AMe)Lys(Boc)-D-Pro-7-AW(Boc)-Ala-Leu-Asp(tBu)-Fmoc

[0210] HO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-7-AW-Ala-Lcii-Asp( / Bu)-Fmoc

[0211] HO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-7-AW(Boc)-Ala-Lcii-Asp( / Bii)-Fmoc

[0212] HO-Gly-Arg(Pbf)-Tyr( / Bii)-(AMc)-azidolysinc-d-Pro-7-AW-Ala-Lcii-Asp( / Bii)-Fmoc

[0213] HO-Gly-Arg(Pbf)-Tyr( / Bii)-(AMc)-azidolysinc-d-Pro-7-AW(Boc)-Ala-Lcii-Asp( / Bii)-Fmoc

[0214] HO-Gly-Arg(Pbf)-Phc-(AMc)-azidolysinc-D-Pro-4-Pal-Ala-Lcii-Asp( / Bu)-Fmoc

[0215] HO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-Trp-Ala-Lcii-Asp( / Bii)-Fmoc

[0216] HO-Gly-Arg(Pbf)-DOPA(ac2)-(AMe)-azidolysine-D-Pro-DOPA(ac2)-Ala-Leu-Asp(tBu)-NH2

[0217] HO-Gly-Arg(Pbf)-4-Pal-(AMe)Lys(Boc)-D-Pro-4-Pal-Ala-Leu-Asp(tBu)-NH2

[0218] HO-Gly-Arg(Pbf)-4-Pal-(AMe)Lys(Boc)-D-Pro-7-AW-Ala-Leu-Asp(tBu)-NH2

[0219] HO-Gly-Arg(Pbf)-4-Pal-(AMe)Lys(Boc)-D-Pro-7-AW(Boc)-Ala-Leu-Asp(tBu)-NH2

[0220] HO-Gly-Arg(Pbf)-4-Pal-(AMe)-azidolysine-D-Pro-7-AW-Ala-Leu-Asp(tBu)-NH2

[0221] HO-Gly-Arg(Pbf)-4-Pal-(AMe)-azidolysine-D-Pro-7-AW(Boc)-Ala-Leu-Asp(tBu)-NH2

[0222] HO-Gly-Arg(Pbf)-Tyr( / Bii)-(AMc)-azidolysinc-l)-Pro-7-AW-Ala-Lcii-Asp( / Bii)-NH2

[0223] HO-Gly-Arg(Pbf)-Tyr( / Bii)-(AMc)-azidolysinc-D-Pro-7-AW(Boc)-Ala-Lcii-Asp( / Bii)-NH2

[0224] HO-Gly-Arg(Pbf)-Phc-(AMc)-azidolysinc-D-Pro-4-Pal-Ala-Lcii-Asp( / Bu)-NH2 HO-Gly-Arg(Pbf)-4-Pal-( VMe)-azidolysine-D-Pro-Trp-Ala-Leu-Asp(tBu)-HN2, wherein in the above listed sequences, 4-Pal has the meaning 4-pyridylalanine, 7 -AW has the meaning 7-aza-tryptophane, and D0PA(ac2) has the meaning l-DOPA-(acetonide), Pbf means 2, 2, 4,6,7- pentamethyldihydrobenzofuran-5 -sulfonyl group (Pbf).

[0225] Specific protected peptides are:

[0226]

[0227] Conjugates

[0228] In a third embodiment, the invention relates to a conjugate of a peptide according to Sequence 1 and / or Formula 10. In principle, such a conjugation can be done by covalent bonding to any amino acid side chain of the cyclopeptide. It is however preferred that the conjugation is effected via covalent bonding to the sidechain of A6. In a preferred aspect of the third embodiment, such conjugates are derived from peptides according to Formula 10, wherein the conjugation is effected via covalent bonding to the group Xc.

[0229] The general structure of such conjugates of the present invention may be characterized by the following formula (I)

[0230] E((L)q-Cp)n(OS)os (I) wherein each Cp represents a cyclopeptide according to the part of Sequence 1 or Formula 10 (without R4-L4 or Xc), L represents an optional linker, q is 0 or 1, wherein, if present, at least part of L is derived from R4-L4 or Xc, such that Cp-L is derived from a cyclopeptide according to the Sequence 1 or Formula 10 wherein R4-L4 or Xcis a spacer that is coupled with E, or another spacer carried by E, to form the linker L; n is an integer selected from 1 to 6, preferably from 2 to 4, such as 2, 3, or 4, and E represents an effector moiety. OS is an optional further substituent, which may for instance be a pharmacokinetic modifier or an active atom or atomic group and which is further defined as the moieties bonded to Cg or Cm (other than CP-L) with respect to the more specific formulae of the conjugates provided below; in further aspects, OS may also be a linker bonded to a nanocarrier, microbead or medical device as described herein; os is an integer selected from 0 to 5, wherein n and os are selected such that n+os=6 or less. Hence, such a conjugate of formula (I) can comprise 1, 2, 3, 4, 5, or 6 cyclopeptide moieties or further substituents, however with the proviso that the number of these groups, i.e., n+os, does not exceed the number of free valences of E. This proviso applies in an analogous manner to all of the more specific conjugate formulae described hereinbelow. Most preferably, the conjugate of formula (I) contains 3 cyclopeptide moieties. The linker L is a linker as defined above and below, for instance in preferred aspects according to any one of formulae (III) to (IIIg”-PEG26), which means that it has at least one covalent bond at each of the two termini, connecting the linker to the adjacent groups E and Cp. In-between, there may be any bivalent atomic group wherein the shortest distance between the two atoms forming the covalent bonds to adjacent groups is from 3 to 60 covalent bonds, preferably from 5 to 40 covalent bonds, more preferably from 8 to 30 covalent bonds.

[0231] The above linker L may consist of or contain linear, branched and / or cyclic structural elements typically consisting of atoms selected from C, H, N, O, S and P. The total number of heavy atoms (i.e. atoms other than hydrogen) in the linker (including optionally present substituents) may be within the range of 2 and 250, preferably 4 to 100 and more preferably 7 to 60.

[0232] The above linker L may also carry one or more substituents. Such substituents are preferably selected from the substituents defined above and more preferably from the group consisting of amino, halogen, cyano, nitro, carboxylic acid, carboxylic ester, C1-C20 alkyl, C2-C20 alkenyl, C3-C20 alkynyl, C3-C20 cyloalkyl, C4-C20 cyloalkenyl, C8-C20 cyloalkynyl, C6-C20 aryl, Ci-Ce alkyl-Ce-C2o aryl, heteroaryl, 5-7- membered heterocycle having one or more heteroatoms selected from the group consisting of N, O, S and P.

[0233] Preferred structural elements contained in the above linker are selected from ethylene glycol, polyethylene glycol (PEG) such as PEG with 2-20 ethylene glycol repeating units, propylene glycol, poly propylene glycol (PPG) such as PPG with 2-15 propylene glycol repeating units, amino acids, oligopeptides such as (Gly)mwith m=2-15 or (Pro)mwith m=2-15, saccharides such as galactose and oligosaccharides such as saccharose and other oligosaccharides with 2-15 monsaccharide repeating units. Further structural elements that may be contained in the linker are alkylene groups, alkenylene groups or alkynylene groups, each of them preferably having 2-20 carbon atoms and each of them optionally having incorporated therein one or more carbonyl groups and / or optionally being substituted as explained above. Said structural elements advantageously carry functional groups at their termini to allow bonding to the cyclopeptide, an effector moiety, or to other linker structural elements. Said functional groups are preferably derived from hydroxyl groups, amino groups, carboxyl groups and click chemistry functions groups such as azide and ethyne groups.

[0234] Preferred linkers are disclosed in “Ligands for Mapping avP3-Integrin Expression in Vivo” by M. Schottelius et al. in Acc. Chem. Res. 2009, 42, 969-980, especially the linkers forming part of the structures shown in Fig. 12 and 14. ; “Dimerization of a Phage-Display Selected Peptide for Imaging of avP6-Integrin: Two Approaches to the Multivalent Effect” by A.N. Singh etal. in Theranostics 214, 4, 756-760, especially as shown in Scheme 1. A further linker is shown in “Synthesis and biological evaluation of a peptide-paclitaxel conjugate which targets the integrin avP6” by S. Li et al. in Bioorganic & Medicinal Chemistry 2011, 19, 5480-5489, and especially the compounds of Figure 1. Of course, it is also possible to combine two or more different structural elements mentioned above to form a linker.

[0235] At its termini, the above linker may contain active functional groups to facilitate bonding to the cyclic peptide compound of the invention and bonding to an effector moiety. If, for instance, click chemistry is used for coupling the linker to the peptide and / or for coupling the linker to the effector moiety, the functional groups of the linker have to be selected as being complementary to the functional groups of the reaction partner (peptide and / or effector moiety).

[0236] In some aspects, especially in connection with active atoms or active atomic groups that are suitable for therapeutic purposes, the linker may be cleavable under physiological conditions. The linker may thus contain a hydrolysable group that allows to cleave the two linked moieties. The use of such a cleavable linker may be advantageous, e.g. when the cyclopeptide according to Sequence 1, or any more specific structure such as Formula 10 specified hereinbelow, is used in order to target a therapeutically active effector moiety (e.g. a cytotoxic agent) to a cell which expresses the avP6-integrin. Suitable hydrolysable groups can be selected from ester such as -C(O)-O- and -O-C(O)-, amide (peptide) such as -C(O)-NH- and -NH-C(O)-, carbamate such as -NH-C(O)-O- and -O-C(O)-NH-, urea such as -NH- C(O)-NH- and anhydride such as -C(O)-O-C(O)-. It is of course possible to combine two or more of these hydrolysable groups and / or to combine one or more of these hydrolysable groups with one or more of the optionally substituted linker groups specified above.

[0237] Further suitable cleavable and non-cleavable linker structures are disclosed, for instance, in: Khongorzul P, et al., Mol. Cancer Res. 2020;18:3-19, doi: 10.1158 / 1541-7786.MCR-19-0582; Arano Y, Nucl. Med. Biol. 2021;92: 149-155, doi: 10. 1016 / j.nucmedbio.2020.03.001; WO 2009 / 117531 A, WO 2015 / 123679 A, Younes et al. N. Engl. J. Med. 2010;363: 1812-1821; Dorywalska et al. Mol. Cancer Ther. 2016;15(5):958-970, Jain et al., Pharm. Res. 2015;32(l l):3526-3540, Paulus J, et al., J Pept Sci. 2024;30:e3561; doi: 10.1002 / psc.3561, and references cited therein. The linker structures disclosed in this literature can be used when practicing the present invention. The disclosures of linker structures in these references is therefore incorporated herein.

[0238] In further aspects, the linker is a linear chain of 2 to 20 and preferably 3 to 10 atoms independently selected from C, N, O, P and S, preferably alkylene groups, which optionally carry one or more substituents, the remaining valences being saturated by hydrogen. This linear chain may be interrupted by one or more cyclic structures preferably such having 5 ring atoms, and more preferably a triazole ring. Bonding to a side chain of the cyclopeptide is typically accomplished by means of an amide bond or a triazole group formed by click chemistry cycloaddition. Bonding of the linker to the active atom or atomic group Aa’ in formula (la’), (lb), (1c) or (Id) can also be accomplished by means of an amide bond or a triazole group formed by click chemistry cycloaddition, but a direct covalent bond is also possible. In some aspects, the atomic group acting as a linker may be characterized by a structure selected from formulae (III), (Illa ), (III’) and (III”), (Illa) to (Illg”), and (III’-PEGl) to (IIIg”-PEG26) as described above.

[0239] According to another aspect, one or more of the linkers, as described herein, may carry one or more independently selected substituents. Each of these substituents is not particularly restricted. According to a preferred aspect, the substituent is itself a moiety containing a linker and a cyclopeptide and / or active atom or group of atoms, preferably a linker L and a cyclopeptide Cp and / or active atom or group of atoms Aa or Aa’, as described herein. It is even possible that the linker part of said substituents is further substituted to form a dendrimeric structure, which may have up to 3 generations of substituents attached to the 0 generation linkers as depicted for instance in formulae (III), (Illa ), (III’), (III”) and (Illa) to (Illg”) and (III’-PEGl) to (IIIg”-PEG26). In other aspects, the linker does not carry such substituents containing a linker and a cyclopeptide Cp, or the linker does not carry any substituents.

[0240] If the conjugate of the present invention comprises two or more cyclopeptide moieties, these multiple cyclopeptide moieties according Sequence 1 or Formula 10 may be the same or different from each other.

[0241] It is furthermore possible to use a polymeric or dendritic effector moiety. In this case, n may be an integer selected from 2 to 100, preferably 10 to 30. Suitable polymeric scaffolds include polyethyleminines, polysaccarides, polyamides, polypeptides, poly(amidoamine) (PAMAM) dendrimers, polypropylene imine) (PPI) dendrimers, polyether-copolyester (PEPE) dendrimers, polyether dendrimers, polyester dendrimers, and polyaryl ether dendrimers. Said conjugates may comprise only copies of the same cyclopeptide according to Sequence 1 or Formula 10, or a mixture of different cyclopeptides according to Sequence 1 or Formula 10. The cyclopeptides may be attached to the polymer backbone via linkers as described above. The resulting polymeric conjugates may for instance be represented by the formulae (Ic’) and (Ic”), wherein the central moiety Cm represents the above-mentioned polymeric scaffold and the variable n is 2 to 100 and preferably 10 to 30, as specified above. Active atoms or atomic groups, as described herein, may optionally be bonded to the polymer backbone via linkers as described above.

[0242] Effector Moiety

[0243] The effector moiety E is an atomic group having from 1 to 1000 heavy atoms, preferably from 6 to 200 heavy atoms and more preferably from 30 to 150 heavy atoms. It is further characterized by the following characteristics:

[0244] (a) it has 1 to 6, preferably 3 or 4 valences, i.e. functional groups, optionally bonded via spacers, which are capable of reacting with functional groups of other moieties to be connected, such as other spacers, cyclopeptides, pharmacokinetic modifiers Pm, or active atoms or groups of atoms Aa’;

[0245] (b) it optionally contains an active atom or group of atoms that is capable of exercising the desired physiological, pharmacological or physical effect, e.g., a radioisotope-containing moiety or a chromophore for diagnostic purposes or a therapeutically active moiety for therapeutic purposes.

[0246] Considering that the cyclopeptide itself is capable of binding to avP6-integrin, and may thereby exercise some physiological effect, one aspect of the invention relates to conjugates wherein the cyclopeptide itself acts as an active group of atoms in the sense of item (b) above, which means that a further active atom or group of atoms is not strictly required. For this reason, condition (b) is indicated to be optional. These aspects are further illustrated below with by means of formulae (la”), (la’”), (lb’), (lb”), (Ic’), (Ic”), (Ibb’), (Tai’), (Ibl’), (Ib2’) and (IfT).

[0247] The effector may in some aspects be characterized by the following general formulae (II) and (II’).

[0248] Aa(Cg) (II)

[0249] Aa'(Cg) (If) wherein Aa stands for an active atom or active atomic group that is capable of being bonded via chelation, Aa’ stands for an active atom or active atomic group that is capable of being bonded via covalent bonding, Cg stands for a chelating group.

[0250] Specific conjugate structures

[0251] Combining formula (II) with formula (I) yields the following formula (la):

[0252] Aa(Cg)((L)qCp)n(la) wherein Aa, Cg, L, Cp, q, and n have the same meanings as defined above with respect to formulae (I) and (II).

[0253] In a related aspect, an active atom or active atomic group Aa’ is covalently bonded to the chelating group or to the linker or cyclopeptide. The conjugate of this aspect is characterized by the following formula (la’):

[0254] Aa'(Cg)((L)qCp)n (la') wherein Aa’ is an active atom or active atomic group capable of forming covalent bonds, Cg, L, Cp, q, and n have the same meanings as defined above with respect to formulae (I) and (II’). In case the cyclopeptide acts as the active group of atoms, the conjugate may be characterized by the following formula (la”):

[0255] (Cg)((L)qCp)„ (la") wherein the meanings of Cg, L, Cp, q and n are the same as specified above with respect to formulae (I), (II) and (IP). Such conjugates like formula (la”), having a chelating group Cg but no chelated active atom or atomic group Aa, may serve a dual function since they may also be used as radiolabeling precursors.

[0256] It is possible that the number of cyclopeptide groups is smaller than the maximum number of valences of the chelating group. In this case, further valences may simply be saturated by hydrogen atoms. In a further aspect, such free valences may be provided with a spacer as described herein. The respective conjugates may be characterized by the following formula (la’”):

[0257] (Cg)((L)qCp)„Ss (la'") wherein the meanings of Cg, L, Cp, q and n are the same as specified above with respect to formulae (I), (II) and (II’), S represents a spacer as described herein, and s is an integer selected from 1 to 5, wherein n and s are selected such that n+s = 6 or less, preferably s is 1 or 2 and n+s = 3 or 4.

[0258] The present invention also contemplates conjugates, wherein an active atom or group of atoms as well as a spacer are simultaneously present. Such conjugates are characterized by the following formulae (la*) and (la**)

[0259] Aa(Cg)((L)qCp)nSs (la*)

[0260] Aa'(Cg)((L)qCp)nSs (la**) wherein the variable groups Aa, Aa’, Cg, L, Cp and S and the parameters q, n and s have the same meanings as specified above with respect to formulae (I), (la’”), (II) and (IT)

[0261] In another aspect, it is possible to attach a second active atom or active atomic group to one of the linkers (instead of one of the cyclopeptides), such that the conjugate is represented by the following formula (lb):

[0262] Aa(Cg)((L)qCp)n (LAa') (lb) wherein Aa, Cg, L, q, and Cp have the same meanings as in formula (la) above, and wherein Aa’ is an active atom or active atomic group different from Aa insofar as it is covalently bonded to the linker and not via a chelating group, n’ is 1 to 5 and preferably 1, 2 or 3 with the proviso that n’+l is the number of free valences of the chelating group or less. Of course, when carrying a group Aa’ instead of a cyclopeptide Cp, the above information regarding the linker may be applied in an analogous manner insofar as the asterisk (*) does not mark the point of attachment of Cp, but may instead be understood as an indication of the point of attachment of Aa’ .

[0263] In yet another aspect, linkers and / or cyclopeptides may be connected via a non-chelating central moiety. In these cases, the active atom or active atomic group is covalently bonded to any part of the molecule, which can be the central moiety, a linker or a cyclopeptide. The conjugate of this aspect is characterized by the following formulae (Ic), (Id), and (le). In the conjugates of formula (If), Cm or Cg is completely absent, so that the active atom or active atomic group is bonded to the cyclopeptide, either directly or via a linker. These formulae are shown below:

[0264] Aa'(Cm)((L)qCp)n (Ic)

[0265] (Cm)((L)qCp)n(L(Aa')p'(Cp)m)o (Id)

[0266] (Cm)((L)qCp)(n-i)-(LCp(Aa')p )o’ (le)

[0267] Cp((L)qAa')p- (If)

[0268] The formula (Ic) corresponds to the above formula (la’), but wherein the chelating group is replaced by a central moiety Cm. Aa’, L, Cp, q, and n have the same meanings as defined above with respect to formulae (I), (la), (II) and (II’), i.e., L represents a linker as described herein, Cp represents a cyclopeptide as described herein with respect to Sequence 1 or Formula 10, but without spacer group - L4-R4 or Xc, q is 0 or 1 and n is selected from the range of 1 to 6, preferably 2 to 4. Aa’ is an active atom or active atomic group that is capable of forming covalent bonds.

[0269] In one aspect, the conjugate may contain a chelating group bonded via a linker to a central moiety. This structure is represented by the following formula (Id’), wherein Cm is the central moiety, each L is independently selected to be a linker as described herein, Cp is a cyclopeptide as described herein, Cg is a chelating group as described herein, Aa is the active atom or atomic group as described herein, q, n, m and o have the same meanings as defined above with respect

[0270] (Cm)((L)qCp)n(L(Cg(Aa))m)o (Id')

[0271] The central moiety Cm in formulae (Ic) to (le) or any other conjugate of the present invention that carries a central moiety can be any atom or atomic group having at least n+1 valences to accommodate n linker- cyclopeptide moieties and 1 active atom or active atomic group. Cm preferably has 1 to 30 atoms selected from C, N, O, S and P. The remaining valences are saturated by hydrogen. Preferred Cm groups are aromatic groups such as phenyl, naphthyl, or groups derived from larger condensed aromatic groups containing 3 or 4 6-membered rings such as anthracene, phenanthrene, benzpyrene, etc.; non-aromatic cyclic groups including C5-7 carbocycles such as cyclopentane, cyclohexane, cycloheptane, condensed groups containing 2, 3 or 4 rings, each consisting of 5 to 7 ring members such as fully or partially hydrogenated forms of naphthalene, anthracene, phenanthrene, benzpyrene, etc., bi- or tricyclic groups having 7 to 10 carbon atoms such as norbomene or adamantane. Further preferred central moieties may be heterocyclic groups containing 1, 2, 3 or 4 condensed rings each having a ring size independently selected from 5, 6 or 7 ring members. These groups may be aromatic, partially or fully saturated and combinations thereof in case of condensed rings. Another preferred central moiety is derived from tris(hydroxymethyl)aminomethane (TRIS, tromethamin), wherein the three oxygen atoms may be bonded to linkers in the form of ether or ester groups and the nitrogen may be bonded to a linker in the form of an amide bond. Alternatively, the central moiety may be a single atom selected from C, N and P.

[0272] Formula (Id) characterizes conjugates, wherein the cyclopeptide moieties and the active atom or active atomic group Aa’ are all linked to the central moiety. The active atom or active atomic group Aa’ is covalently bonded to one of the linkers while the cyclopeptide Cp may be bonded directly to the central moiety or via a linker. The meanings of Cm, Aa’, L, Cp, q, and n are the same as explained above with respect to formula (I), (II), (IF), (la) and (Ic). Optionally, the linker carrying the active atom or active atomic group Aa’ may additionally carry a cyclopeptide Cp; hence, m may be 0 or 1. If an additional Cp is present, the active atom or active atomic group Aa’ and its point of attachment should be selected such that detrimental interactions with the cyclopeptide are avoided or at least minimized, e.g. by attaching the two moieties to different atoms of the linker, which are at least 5 covalent bonds apart from each other. The number of linkers carrying the active atom or atomic group Aa’ is characterized by o and it can be any integer from 1 to 5 with the proviso that n and o are selected such that n+o = 6 or less, preferably n+o = 3 or 4. Preferably, n is 2 and o is 1; or n is 3 and o is 1 or n is 2 and o is 2. The number of active atoms or atomic groups Aa’ bonded to an individual linker is characterized by p’ and it can be 1 or 2.

[0273] Formula (Id’) is characterized by a central moiety Cm, such as a TRIS-derived group, carrying n cyclopeptide moieties bonded via a linker L, as well as o chelating groups carrying an active atom Aa and being bonded via a linker L, wherein each L is independently selected to be a linker as described herein, Cp is a cyclopeptide as described herein, Cg is a chelating group as described herein, Aa is the active atom or atomic group as described herein, and q, n, m and o have the same meanings as defined above with respect to formula (Id), preferably q is 1, n is 3, m is 1 and o is 1.

[0274] Formula (le) is characterized by the active atom or active atomic group Aa’ being bonded to the cyclopeptide Cp. The meanings of Cp, Cm, Aa’, L, Cp, q, and n are the same as explained above with respect to formula (I), (II), (IF), (la) and (Ic). The variable o’ indicates the number of cyclopeptides Cp carrying an active atom or group Aa’. o’ can be any integer from 1 to 6 with the proviso that n and o’ are selected such that n+o’ = 7 or less, preferably n+o’ = 4 or 5. Preferably, n is 3 and o’ is 1; or n is 4 and o’ is 1 or n is 3 and o’ is 2. The variable p’ characterizes the number of active atoms Aa’ bonded to an individual cyclopeptide and it can be 1 or 2.

[0275] The compounds of formula (If) may have a dual function: as long as the binding of Aa’ does not lead to significant deterioration of the affinity to avP6-integrin, i.e. as long as binding affinity of the Aa’- carrying cyclopeptide remains to be 5 nM or higher (wherein the term "higher" is referring to a lower numerical value in the context of binding affinities) when determined in accordance with the methods described in Kapp TG, et al., Sci Rep. 2017 Jan 11 ;7:39805. doi: 10.1038 / srep39805, they may serve as conjugates of the present invention. In addition, they may also be incorporated into larger conjugates, e.g. of formula (le), and thus serve as a building block of the invention. The meanings of Aa’, Cp, q and p’ are the same as explained above with respect to formula (le).

[0276] Conjugates of the invention according to formula (lb) or (Ic), but not having the Aa bonded to Cg or Aa’ bonded to Cm, are also in accordance with the invention. Such formulae are shown below:

[0277] (Cg)((L)qCp)„ (LAa') (lb')

[0278] (Cg)((L)qCp)„ (LAa')Ss (lb")

[0279] (Cm)((L)qCp)n (Ic')

[0280] (Cm)((L)qCp)nSs (Ic")

[0281] (Cm)((L)qCp)n(L(Cg)m)o (Id ) wherein the meanings of Aa', Cg, Cm, L, Cp, S, q, n, n', s, m and o are the same as specified above with respect to formulae (lb), (Ic) and (Id'), s' is selected from the range 1-4, preferably 1-2, such that n'+s'+l=6 or less.

[0282] Further conjugates including active atom or atomic group as well as a spacer are characterized by the formulae (lb*) and (Ic*) below:

[0283] Aa(Cg)((L)qCp)n (LAa')Ss' (lb*)

[0284] Aa'(Cm)((L)qCp)nSs (Ic*) wherein the meanings of Aa, Aa', Cg, Cm, L, Cp, S, q, n, n', s and s' are the same as specified above with respect to formulae (lb), (lb"), (Ic) and (Ic"). The modes of binding active atoms and active groups Aa and Aa’ described above by means of formulae (la) to (If) and related formulae (la’), (la”), (la’”), (lb’), (lb”), (Ic’), (Ic”), (la*), (la**), (lb*), and (Ic*) may be freely combined. For instance, a compound of formula (la) or (la’) may carry one or more cyclopeptides which themselves carry one or more active atoms or active groups Aa’ . In particular, the present invention also relates to conjugates of formula (la) or (la’), wherein one or more of the cyclopeptides carries an iodine atom, wherein, specifically, the cyclopeptides of Sequence 1 comprise an amino acid of Formula 2 wherein X13or X14represents iodine. Such cyclopeptides and conjugates comprising the same may be suitable as contrast agents for imaging purposes. The iodine atom may thus be regarded as a covalently bonded active group Aa’. In the context of formula (I) and all related formulae, n has the same meaning as n*, as used in the claims.

[0285] Active atom or active atomic group

[0286] The active atom or active atomic group Aa, Aa’ may include moieties containing one or more of the following: chromophors and particularly fluorescent or luminescent groups; radiolabelled prosthetic groups; chelators; magnetic resonance imaging agents; enzyme inhibitors; chemotherapeutics and particularly cytostatics, topoisomerase inhibitors, alkylating agents, antimetabolites, anti-microtubule agents, cytotoxic antibiotics, taxanes, intercalating agents, platinum compounds, mitosis inhibitors, tyrosine kinase inhibitors; peptides and particularly peptide receptor ligands; functional building blocks for surface grafting, particularly on medical devices, nanoparticles, micelles, magnetic particles, or quantum dots; functional proteins such as antibodies, antibody fragments, nanobodies, or affibodies; pharmacokinetic modifiers and particularly albumin binders, sugars, oligo- and polysaccarides; metalcontaining or metal-free compounds suitable for photodynamic therapy, and specifically compounds that generate reactive oxygen species upon irradiation with light (visible or near-infrared wavelength range).

[0287] Specifically, active atom or active atomic group Aa, Aa’ may include the following:

[0288] (Ila) a non-radioactive isotope or a radioisotope of a metal ion selected from La3+, Ce3+, Pr34, Nd3, Sm3+, Eu24, Gd34, Tb34, Dy34, Ho34, Er34, Tm34, Yb34, Lu34, Sc34, Y34, Ga34, Fe34, Co24, Co34, Si44, Ge44, In34, Sn24, Sn44, Bi34, Rh34, Ru34, Ru44, Ag4, Au34, Pb24, Pd24, Pd44, Pm34, Ac34, Ti44, Zr44Al34, Cr34, Cu24, Zn24, Th34, and mixtures thereof. Particularly preferred is a metal ion selected from the group consisting of Ga34, Gd34, Cu24, Sc34, Y34, and Lu34and mixtures thereof. The radioisotope may specifically be selected from43Sc,44Sc,46Sc,47Sc,55Co, "mTc,203Pb,66Ga,67Ga,68Ga,72As,i nIn,113mIn,114mIn,97Ru,62Zn,61Cu,62Cu,64Cu,52Fe,52mMn,51Cr,186Re,188Re,77As,86Y,9CY,67Cu,169Er,117mSn,121Sn,127Te,134Ce,142Pr,143Pr,198Au,199Au,149Tb,152Tb,155Tb,161Tb,109Pd,165Dy,149Pm,151Pm,153Sm,157Gd,166Ho,172Tm,169Yb,175Yb,177Lu,105Rh,i nAg,88Zr,89Zr,212Pb,212Bi,213Bi,225Ac,227Th and mixtures thereof, wherein these radioisotopes are preferably used in the form of metal ions in the respective oxidation states listed above. Particularly preferably the radioisotope is selected from the group consisting of68Ga,44Sc, ""mTc. ”’ln,64Cu,89Zr,90Y,177Lu,212Pb,225Ac, and mixtures thereof. All non-radioactive isotopes or radioisotopes of metal ions mentioned herein are preferably bound as coordination compounds (chelates), which means that they preferably represent active atoms or active atomic groups according to the definition of Aa.

[0289] In a specific embodiment of (Ila), the non-metal radionuclide18F is furthermore incorporated as chelate, more precisely, in form of a chelated complex fragment comprising of1 SF bound to a non-radioactive metal ion according to the formula |l sFMcll|'cl1 1' . wherein ch represents the oxidation state or charge of M. Said complex fragment can be bound like a metal ion via chelate formation and thus represents, in its entirety, an active atomic group according to the definition of Aa. Mch+can be any metal ion, but preferably is a polyvalent metal ion, which means that ch is >1, preferably 2, 3, or 4. Preferred metallic elements M are selected from the elements of the groups 2, 3, 4, and 13 of the periodic system, and from lanthanides. Specifically, Mch+can be selected from Ca2+, Sc3+, Y3+, Ti4+, Zr4+, Ga3+, or Al3+.

[0290] (lib) a non-metal radioisotope which is selected from ”C,13N,15O,18F,123I,124I,125I,131I, or211At, preferably18F or21’At. In addition to its presence as Aa, Aa’ or part thereof in the above formulae, said non-metal radioisotope may also be an active atom Aa’ that is present anywhere else within the molecule, where it may replace any other covalently bonded atom that already exists as part of the remaining molecule, and which has an appropriate number of bonding partners. All non-metal radioisotopes mentioned under (lib) are preferably bound in a covalent manner, which means that they preferably represent active atoms or active atomic groups according to the definition of Aa'.

[0291] (lie) a fluorescent or non-fluorescent dye and preferably moieties derived from ThermoFisher’s commercially available Cy® series such as Cy® 3, 5, 5.5, 7, 7.5 and the AlexaFluor® series such as AlexaFluor® 350, 405, 488, 532, 546, 555, 568, 594, 647, 680, and 750 as well as Fluorescein, Pyren, Rhodamin, BODIPY dyes and their analogues; near-infrared (NIR) fluorescent dyes such as indocyanine green (ICG), IR800CW, IR780, IR-783, IR-820, IR825, squaraine dyes, porphyrins such as Pheophorbidea and Chlorin e6 (as described, for example, in Int. J. Nanomed. 2021;16:2147, Chem. Soc. Rev., 2022;51:8957, or Biomaterials 201 l;32:7127e7138), ZW800-1 (as described in Nat Commun 2019;10:3118), dyes or fluorophors with absorption and emmission bands at wavelengths >1000 nm (NIR2), such as FD-1080, IR-26, IR-1061, Flav7, ICR-Qu, Chrom7, JuloChrom7, l,7-AMe2PHC5, BTC1070, LZ1105, 5H5, CX3, as described in Chen X, et al., Adv. Healthcare Mater. 2024;2304506. The moiety derived from a dye is preferably covalently linked (i.e. via a linker) to the chelating group, the central moiety or the cyclopeptide, or it is bonded directly to the cyclopeptide without linker.

[0292] (lid) a contrast agent for magnetic resonance imaging (MRI), preferably comprising Gd3+, Fe3+, Mn2+, or fluorine as the source of the MRI signal or MRI signal enhancement, most preferably Gd in the form of Gd(III). The contrast agent is preferably provided in the form of a chelate complex; (lie) an atom or atomic group suitable for enhancement of imaging by X-ray based technology, such as planar X-ray imaging or computed tomography (CT), preferably iodine or atomic groups containing iodine.

[0293] (llf) an agent suitable for ribonucleic acid (RNA) interference (RNAi), for example, using small interfering RNA (siRNA) or other oligonucleotides as described in Setten RL, et al., Nature Reviews Drug Discovery 2019; 18:421.

[0294] (llg) an atom or atomic group derived from a therapeutic agent. Said atom or atomic group may have therapeutic activity as such or after cleavage of cyclopeptide -containing moieties to thereby release the underlying therapeutic agent. Preferably, said therapeutic agent is a therapeutic agent suitable for the treatment of cancer or fibrosis.

[0295] If the treatment indication is cancer, the therapeutic agent is preferably selected from alkylating agents, anti-metabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors and other anti-tumor drugs. More specifically, the following can be mentioned: platinum based compounds, antibiotics with anticancer activity, anthracyclines, anthracenediones, alkylating agents, antimetabolites, Antimitotic agents, taxanes, taxoids, microtubule inhibitors, Vinca alkaloids, folate antagonists, topoisomerase I inhibitors (Topi inhibitors), topoisomerase II inhibitors (TopIl inhibitors), etoposide, etoposide phosphate and teniposide, antiestrogens, antiandrogens, aromatase inhibitors, GnRh analogs, inhibitors of 5 a- reductase, bisphosphonates, a metabolic inhibitor, preferably a mTOR inhibitor; an epigenetic inhibitor, preferably a DNMT inhibitor; an anthracy cline antibiotic; a camptothecan; an anthracy cline; histone deacetylase (HDAC) inhibitors, proteasome inhibitors, JAK2 inhibitors, tyrosine kinase inhibitors (TKIs), PI3K inhibitors, Protein kinase inhibitors, Inhibitors of serine / threonine kinases, inhibitors of intracellular signaling, inhibitors of Ras / Raf signaling, MEK inhibitors, AKT inhibitors, inhibitors of survival signaling proteins, cyclin dependent kinase inhibitors, therapeutic monoclonal antibodies, TRAIL pathway agonists, anti-angiogenic agents, metalloproteinase inhibitors, cathepsin inhibitors, inhibitors of urokinase plasminogen activator receptor function, immunoconjugates, antibody drug conjugates, antibody fragments, bispecfic antibodies, bispecific T cell engagers (BiTEs). Said anticancer drug is preferably selected from the group consisting of 5 -fluorouracil, cisplatin, irinotecan, hydrochloride, epirubicin, paclitaxel, docetaxel, camptothecin, exatecan, deruxtecan, doxorubicin, rapamycin, 5 -azacytidine, doxorubicin, the primary active metabolite of irinotecan SN-38, govitecan, topotecan, amsacrin, UFT, capecitabine, CPT-II, oxaliplatin, cyclophosphamide, methotrexate, aminopterin, permetrexed, navelbine, epirubicin, mitoxantrone, raloxifen, mitomycin, carboplatinum, gemcitabine, etoposide, topotecan, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), vedotin, mertansine (DM1), emtansine, soravtansine, calicheamicins, ozogamicin, maytansinoides, maytansin, a-amanitin, mafotodin, exotoxin a, pasudotox, pyrrolobenzodiazepines, tesirine, sarotalocan, siRNA therapeutics, such as patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, fitusiran, QPI-1002, olpasiran, ARO-APOC3, Tivansiran, MIR19, revusiran, fazirsiran, cemdisiran, and thapsigargin.

[0296] Further suitable therapeutic agents for the treatment of cancer are disclosed, for instance, in “Cancer Drugs” by Judith Matray-Devoti, Chelsea House, 2006; “Physicians' Cancer Chemotherapy Drug Manual 2015” by Edward Chu, Vincent T De Vita, Jr., Jones & Bartlett Learning 2015; “Cancer Chemotherapy and Biotherapy: Principles and Practice” by Bruce A. Chabner, Dan L. Longo, Wolters Kluwer, 2011; “Drugs in Cancer Care” by Rachel Midgley, Mark R. Middleton, Andrew Dickman, David Kerr (Eds.), Oxford University Press 2013; Khongorzul P, et al., Mol. Cancer Res. 2020;18:3- 19, doi: 10.1158 / 1541-7786.MCR-19-0582; Dumontet C, et al., Nat. Rev. Drug Discovery 2023 ;22: 641, doi: 10.1038 / s41573-023-00709-2; Metrangolo V, Engelholm LH, Cancers 2024;16:44, doi: 10.3390 / cancersl6020447; Choi Y, et al, Adv. Drug Delivery Rev. 2024;209: 115306, doi: 10.1016 / j.addr.2024.115306. The drugs disclosed in this literature can be used as therapeutic agents when practicing the present invention. The disclosures of therapeutic drugs in these references is therefore incorporated herein.

[0297] If the treatment indication is fibrosis, the therapeutic agent is preferably selected from therapeutic drugs suitable for the treatment of fibrosis. Such therapeutic drugs are disclosed, for instance, in “Cystic Fibrosis in the 21st Century” by Andrew Bush (Ed.), S. Karger, 2006; “Liver Fibrosis: New Insights for the Healthcare Professional: 2013 Edition” by Q. Ahton Acton, ScholarlyEditions, 2013; “Idiopathic Pulmonary Fibrosis: A Comprehensive Clinical Guide” by Keith C. Meyer, Steven D. Nathan, Springer, 2014; “New Insights into the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis: A Potential Role for Stem Cells in the Lung Parenchyma and Implications for Therapy” by M. Gharaee-Kermani et al. in Pharmaceutical Research, 2007, 24, 819-841; “Pulmonary Fibrosis: pathogenesis, etiology and regulation” by M.S. Wilson and T.A. Wynn in Mucosal Immunol. 2009, 2, 103-121. Specific preferred therapeutic drugs are preferably selected from the drugs and drug classes disclosed listed in Table II of the review article by Gharaee-Kermani et al. cited above.

[0298] If the active atom is18F, attachment can be accomplished by formally replacing any other covalently bonded atom that already exists as part of the remaining molecule and which has one bonding partner. Depending on the position of the formal replacement, the resulting conjugate may be a conjugate of one of formulae (la’), (la**) (lb), (lb*), (Ibl), (IbU), (Ib2), (Ib2’), (Ic), (Ic*), (Id), (le), (If), (Ifl), (lb’), (lb”), (Idd), (Idd’), (lee), (lee’), or (Iff) as described herein. Preferably, the formally replaced atom is a hydrogen atom. For clarity, the formal replacement can be accomplished by a suitable chemical reaction whose mechanism does not involve an actual replacement of an atom in the compound of the invention by a fluorine atom. Preferred are typical reactions of organic and inorganic synthetic chemistry, such as substitutions, additions, eliminations, cycloadditions, isotope exchange reactions, or formation of Lewis acid-base adducts. The18F can furthermore be introduced to the conjugate also as a part of another moiety, which is covalently or non-covalently bound to any part of the conjugate by means of a suitable chemical reaction. In this case, the18F-containing moiety is referred to as a prosthetic group. Bond formation between the18F atom or the18F-containing prosthetic group and the compounds of the invention can, in principle, be accomplished by any chemical reaction suitable for formation of covalent bonds or coordination bonds. Preferred are reactions and methods commonly referred to as Click Chemistry (as described in Bauer D, et al., Bioconjug Chem. 2023;34: 1925. doi: 10.1021 / acs.bioconjchem.3c00286 or elsewhere hereinabove or below), fluorinations utilizing18F- substituted tetrazines (as described in Andersen IV, et al., Molecules. 2022;27:4022. doi: 10.3390 / molecules27134022), fluoroglycosylation (as described in Shinde SS, et al., Pharmaceuticals 2021;14: 1175. doi: 10.3390 / phl4111175), fluorinations employing Silicon Fluoride Acceptors, abbreviated SiFA (as described in Gower-Fry L, et al., Pharmaceuticals 2021; 14:701. doi: 10.3390 / phl4070701),18F-trifluoromethylation (as described in Francis F, et al., Molecules 2021 ;26:6478. doi: 10.3390 / molecules26216478), or by using other specific radiofluorination reactions as described in the following literature: doi: 10. 1002 / cmdc.202100303. The18F for radiofluorination is preferably used for the radiolabeling of the compounds of this invention, or of prosthetic groups used for said radiolabeling, in a reactive form that can be obtained by suitable methods described in Haveman LYF, et al., EJNMMI Radiopharm Chem. 2023;8:28. doi: 10.1186 / s41181-023-00203-5. Furthermore,18F can be incorporated as chelate, more precisely, in form of a chelated complex fragment comprising ofl sF bound to a non-radioactive metal ion according to the formula |l sFMcll|'cl1 1' . wherein ch represents the oxidation state or charge of M. Said complex fragment can be bound like a metal ion via chelate formation and thus represents, in its entirety, an active atomic group according to the definition of Aa. Mch+can be any metal ion, but preferably is a polyvalent metal ion, which means that ch is >1, preferably 2, 3, or 4. Preferred metallic elements M are selected from the elements of the groups 2, 3, 4, and 13 of the periodic system, and from lanthanides. Specifically, Mch+can be selected from Ca2+, Sc3+, Y3+, .+, 2r4+, Qa;orl Particularly preferred are such approaches which make use of the complex fragment [18FA1]2+, sometimes referred to as aluminium fluoride (A1F) radiofluorination (as described in Fersing C, et al., Molecules 2019;24:2866. doi: 10.3390 / molecules24162866; Archibald SJ, Allott L, EJNMMI Radiopharm Chem. 2021;6:30 doi: 10. 1186 / s41181-021-00141-0, or Schmitt S, et al., Coord Chem. Rev. 2023;480:215028, doi: 10.1016 / j.ccr.2023.215028).

[0299] If the active atom Aa is a metal ion or a complex fragment of the formula |l sFMcll|'cl1 1' as described hereinabove, bonding is typically accomplished via a chelating group Cg, for example, as described in Chem. Soc. Rev. 2011;40:3019-3049. Binding ofthe metal ion by the chelating group preferably occurs via complex bonds (Lewis acid / base interactions) effected by the N and O atoms of the chelating group. The chelating group is however not particularly limited as long as it is capable of forming a chelate complex with the metal ion of interest, which is preferably stable under physiological conditions for a time period that is sufficiently long for carrying out the intended diagnostic method. Preferred chelators or chelator-containing functional groups are those mentioned in Chem. Soc. Rev. 2014;43:260-290 (DOTA, B-DO2A, 3p-C-DEPA, TCMC, Oxo-DO3A, TETA, E2A, CB-TE2A, CB-TE1A1P, CB-TE2P, MM-TE2A, DM-TE2A, Diamsar, NOTA, NETA, and TACN-TM, DTPA, 1B4M-DTPA, CHX-A"- DTPA, AAZTA, DATA, H2dedpa, JLoctapa, H2azapa, H5decapa, BCPA, CP256, YM103, DFO, PCTA, Hephospha, PCTA, HEEIA, PEPA), bispidines (as mentioned in Dalton Trans. 2018;47: 9202-9220), radiohybrid ligands (as described by Wurzer et al. in J. Nucl. Med. 2019, doi: 10.2967 / jnumed.119.234922), hydroxypyridinone ligands (as described in Dalton Trans. 2019;48:4299-4313 or Bioconjugate Chem. 2015;26:2579-2591), picolinic acid-based chelators (as mentioned in Dalton Trans. 2017;46: 14647-14658, Inorg. Chem. 2016;55: 12544-12558, or Bioconjugate Chem. 2017;28:2145-2159), hydroxamate-derived chelators and catecholate-based chelators such as DFO, HOPO, DFO-SqOEt, DFO*, CTH36, HOPO, BPDETLysH22-3,2-HOPO, THPN, TAM-1, IAM-1, TAM-2, IAM-2, DFO-O3, DFOB-PHB, oxo-DFO, DFOB-PPH, DFO-HOPO, DFOcyclo*, DFO2, C5, C6, C7, TAFC, FSC(succ)3, CTH36, fCTH36, Rousseau 1-4, 4HMS, and related structures (as described in Feiner IVJ, et al., Cancers 2021; 13:4466), PYTA (as described in Simms ME, et al., Chem. Sci. 2024, doi: 10.1039 / D3SC06854D), macrodipa and py-macrodipa (as described in Hu A, et al., J. Am. Chem. Soc. 2021;143: 10429-10440, or Hu A, et al., Inorg Chem. 2022; 61:801-806), Neunpa ligands (as described in Wharton L, et al., Inorg Chem. 2021;60:4076-4092), Bispa / Bispidine based ligands (as described in Kovacs A, et al., Comp Theor Chem. 2022;1212: 113716), PIDAZTA (as described in Farkas E, et al., Chem. Eur. J. 2019;25: 10698-10709), phosphinate- and phosphonate cyclam chelators (as described in David T., et al., Inorg Chem 2015;54: 11751-11766 and David T, et al., J Med Chem. 2018;61:8774-8796), cross-bridged cyclam derivatives bearing two phosphonate, bis(phosphinate), or phosphinate pendant arms (as described in Pazderova L, Inorg Chem. 2020;59:8432-8443), AAZTA- and DATA-like ligands such as AAZ3A- endoHB, AAZ3A-endoHB-NCS, AAZ2A-exoHB, DATA1”. Cy AAZTA (as described in Chem Eur J. 2023;29:e202203798), macropa and its derivatives such as H2BZmacropa, H2BZ2macropa, and H2BZmacropa-NCS (as described in Kadassery KJ, et al., Bioconjugate Chem. 2022;33: 1222-1231), lead-specific chelator (PSC) and its modifications (as described in Li M, et al., Pharmaceutics 2023;15:414 or Lee D, et al., Eur J Nucl Med Mol Imaging. 2024;51: 1147-1162), and especially, chelating groups who allow for conjugation of more than one peptide without additional branched linkers, such as fusarinine c (as described in J. Label. Compd. Radiopharm. 2015;58:209-214), DOTPI (as described in Chem. Eur. J. 2013;19:7748-7757), DOTGA (as described in Chem. Commun. 1998, 1381), NOTGA (as described in Bioconjugate Chem. 2012;23:2229-2238), NODAPA (as described in Bioorg. Med. Chem. Lett. 2008;18:5364-5367), DOTAZA and DOT3AZA (as described in Chem. Asian J. 2014;9:2197-2204), HBED-CC (as described in Eur. J. Nucl. Med. 1986;12:397-404), HBED- NN (as described in J. Org. Chem. 2019;84:7501-7508), (NH2)2sar (as described in Inorg. Chem. 2011;50: 6701-6710), AZA-DFO and AZA-DFO* (as described in Outzen L, et al., ChemMedChem 2023;18:e202300112), or TRAP (as mentioned for instance in Dalton Trans. 2015;44: 11137). Particularly preferred chelating groups are TRAP, its tetravalent homologue DOTPI, NOTGA, DOTAZA, DOT3AZA, and analogues and derivatives of these chelating groups. Typical structures of these chelating groups are represented by formulae (IVa) to (IVd) below: wherein the asterisk (*) marks the point of attachment of the atomic group acting as a spacer or linker. If the number of cyclopeptides and associated linkers (such as characterized by variable n or n’) is less than the number of valences of the chelating group, the remaining valences shown by the asterisk are saturated by hydrogen or another atomic group, preferably a group selected from -CH2-COOH and - CH2-CH2-COOH.

[0300] Specifically, some preferred conjugates of this invention can be constructed using one of the following chelating groups of formulae (Iva), (Ivb) and (Ivd) as shown above, and further carrying spacers:

[0301] Specifically, some preferred conjugates of this invention can furthermore be constructed using one of the following building blocks, consisting of chelating groups of formulae (Iva) and (Ivb) as shown hereinabove, which are carrying longer spacer groups.

[0302] The chelating group may also be an open-chain chelating moiety. A preferred chelating group of this type has the structure -Scr-Scr-Scr-NH-CO-CTT-SH. as shown in exemplified compound C61.

[0303] Pharmacokinetic Modifiers

[0304] Pharmacokinetic modifiers (Pm) are a special variant of Aa‘, which do not give rise to a pharmacological or diagnostic effect themselves, but instead lead to improved pharmacokinetic properties, e.g., reduced clearance due to bonding to plasma proteins. They are advantageously used in conjugates having at least one further active atom or active atomic group Aa or Aa’ . However, even the conjugates without active atom or active group Aa or Aa’, such as shown in Formula (laa), may have therapeutic value since Cp, due to its ability of binding to the avP6-integrin, can exercise pharmacological effects. Incorporating a pharmacokinetic modifier in specific variants gives rise to the following specific forms of the above formulae (la) to (If):

[0305] Pm(Cg)((L)qCp)n(laa)

[0306] Aa(Cg)((L)qCp)n ((L)qPm) (Ibb)

[0307] (Cg)((L)qCp)n ((L)qPm) (Ibb')

[0308] Pm(Cm)((L)qCp)n(Icc)

[0309] (Cm)((L)qCp)n(L(Aa')p'(Cp)m)oi(L(Pm)p (Cp)m)o2 (Idd) (Cm)((L)qCp)(n-i)((L(Cp)m)(Aa')pi(Pm)P2)o’ (lee)

[0310] Cp(Aa')pi((L)qPm)P2 (Iff) wherein the variable groups and parameters are as specified above for formulae (la) to (If) and o 1 and o2 are selected such that o2 is at least 1 and ol+o2=o with o being as defined above, and pl and p2 are selected such that pl is 0 or 1, p2 is 1 or 2 and pl+p2=2 or less.

[0311] In formula (Iff), the cyclopeptide Cp carries one or two pharmacokinetic modifiers Pm, each of which is either bonded directly or via a linker L. Moreover, unless the cyclopeptide carries two pharmacokinetic modifiers, it may optionally carry an active atom or atomic group Aa’ .

[0312] In a specific aspect, the present invention relates to conjugates of the above formulae (laa) to (lee), wherein one or more, preferably one or two cyclopeptide Cp groups are absent, so that the respective linker L becomes a spacer S. These conjugates may be represented by the following formulae (laa’) to (lee’), (Ibb”) and (Ibb’”):

[0313] Pm(Cg)((L)qCp)nSs (laa')

[0314] Aa(Cg)((L)qCp)n’((L)qPm)Ss(Ibb")

[0315] (Cg)((L)qCp)n((L)qPm)Ss (Ibb'")

[0316] Pm(Cm)((L)qCp)nSs (Ice')

[0317] (Cm)((L)qCp)n(L(Aa')p(Cp)m)oi(L(Pm)p(Cp)m)o2Ss (Idd')

[0318] (Cm)((L)qCp)(n-i)((L(Cp)m)(Aa')pi(Pm)p2)o Ss (lee') wherein the meanings of the variable groups and parameters are the same as indicated above for formulae (laa) to (lee) and (Ibb’), s is selected from the range 1 to 5, preferably 1 or 2, with the following provisos:

[0319] • in formulae (laa’) and (Icc’), n and s are selected such that n+s = 6 or less, preferably n+s = 3 or 4;

[0320] • in formulae (Ibb”) and (Ibb’”), n’ and s are selected such that n+s = 5 or less, preferably n+s = 2 or 3; and

[0321] • in formula (Idd’), n, ol, o2 and s are selected such that n+ol+o2+s = 6 or less, preferably n+ol+o2+s = 3 or 4; and

[0322] • in formula (lee’), n, o’ and s are selected such that n+o’+s = 7 or less, preferably n+o’+s = 4 or 5. In formulae (Idd) and (Idd’), one or more cyclopeptides Cp are bonded to central moiety Cm, either directly or via linkers L, one or more linkers L carry an active atom or atomic group Aa’ and optionally a cyclopeptide Cp, one or more linkers L carry a pharmacokinetic modifier Pm and optionally a cyclopeptide Cp. The linkers L and spacers S, if present, are bonded to the central moiety Cm.

[0323] In formulae (lee) and (lee’), one or more cyclopeptides Cp are bonded to central moiety Cm, either directly or via linkers L, one or more linkers L carry an optional cyclopeptide Cp to form a moiety L or LCp, which carries one or two pharmacokinetic modifiers Pm and optionally an active atom or atomic group Aa’. The linkers L and spacers S, if present, are bonded to the central moiety Cm.

[0324] Further preferred conjugates

[0325] In a preferred variant, conjugates are provided with 1-4 (preferably 3) cyclopeptides of Sequence 1 or Formula 10, optionally 1 pharmacokinetic modifier, and optionally 1 fluorophore.

[0326] Such conjugates are advantageously characterized by the following formula (Ibl):

[0327] Aa(Cg)((L)qCp)n((L)qAa')n (Ibl) wherein Cg may be selected from trivalent or tetravalent chelating groups. A related and equally preferred conjugate is characterized by the same structure, but wherein Aa is absent:

[0328] (Cg)((L)qCp)n ((L)qAa')„ (Ibl')

[0329] If Cg is a trivalent chelating group, such as a group of any one of Formulae IVa or IVc, 2 to 3 valences are occupied by a cyclopeptide of Sequence 1 or Formula 10, optionally linked via a linker, and 0 or 1 valences are occupied by Aa’ being a pharmacokinetic modifier or a fluorophore, optionally linked via a linker. Aa, Cp and L are as specified above, q in each occurrence is independently selected to be 0 or 1, n’ is 2 or 3 and n” is 0 or 1. Preferably, Cp is a cyclopeptide of Formula 10, the linker is preferably present (q=l) while n’ is 2 and n” is 1.

[0330] If Cg is a tetravalent chelating group, such as a group of any one of Formulae IVb or IVd, 1 to 4 valences are occupied by a cyclopeptide of sequence 1 or Formula 10, optionally linked via a linker, and 0 to 2 valences are occupied by Aa’ being a pharmacokinetic modifier or a fluorophore, optionally linked via a linker, and 0 or 1 valence is occupied by Aa’, which is as described above but not further limited, optionally linked via a linker. Aa, Cp and L are as specified above, q in each occurrence is independently selected to be 0 or 1, n’ is 1 to 4 and n” is 0 to 3. Preferably, Cp is a cyclopeptide of Formula 10, the linker is preferably present (q=l) while n’ is 3 and n” is 1. In a particularly preferred variant, the Cg is DOTPI, each q is 1, at least one L and preferably each L contains PEG groups of a length of 3 to 10, preferably 4 to 8 repeating units, n’ is 3 and n” is 1. In another preferred variant, conjugates are provided, consisting of a trivalent central chelating moiety, equipped with 3 linkers each bearing a cyclopeptide according to Sequence 1 or Formula 10. This conjugate can be represented by the following formula (lai):

[0331] Aa(Cg)(LCp)3(lai) or, if Aa is absent, by the following formula (lai ’):

[0332] (Cg)(LCp)3(lai') wherein, in formulae (lai) and (lai ’), Aa, Cp and L are as defined above, Cg is a trivalent chelating group. Preferably, at least one of the linkers L contains a PEG group with 3 to 10 repeating units, more preferably 4 to 8 repeating units. Particularly preferably, each of the linkers contains a PEG group with 4 to 8 repeating units. Even more preferably, the cyclopeptide Cp is of Formula 10 and / or the chelating group Cg is a TRAP group.

[0333] Another preferred variant provides conjugates of the following formula (Ib2) or, if Aa is absent, conjugates of the following formula (Ib2’):

[0334] Aa(Cg)(LCp)n(LAa')n” (Ib2)

[0335] (Cg)(LCp)n(LAa')n" (Ib2') wherein Aa is as defined above, Cg is a tetravelant chelating group, n’ is 2 or 3 and n” is 1 or 2, Cp is a cyclopeptide of Sequence 1 or Formula 10, each of the linkers L carrying the cyclopeptides Cp contains a polyethylene glycol PEG with 3 to 10, preferably 4 to 8, repeating units, Aa’ is an active atom or active atomic group as described above and the linker L carrying Aa’ is a cleavable or non-cleavable linker, preferably also containing a PEG with 3 to 10, more preferably 4 to 8, repeating units.

[0336] In a more preferred variant, n’ is 3 and n” is 1 and each of the linkers carrying Cp and Aa’ contains a PEG with 4 to 8 repeating units. Even more preferably, Aa’ is selected from cytostatic agents, siRNA, pharmacokinetic modifiers and fluorophors. Most preferably, Cg consists of a DOTPI moiety. In special variants, the conjugate is a conjugate of Formula ( lb2) or ( lb2’) wherein Aa is as defined above, Cg is DOTPI, which is equipped with 3 linkers containing PEG groups with lengths of 3 to 8 PEG units, each bearing a cyclopeptide according to Sequence 1 or Formula 10, preferably a cyclopeptide of Formula 10, and a fourth non-cleavable or cleavable linker, preferably containing a PEG group with 3 to 8 PEG units, bearing an active atomic group such as a cytostatic agent or a siRNA; a pharmacokinetic modifier such as a 4-(4-iodophenyl)butyric amide (sometimes also referred to as p-iodophenylbutyrate or p- iodobutyl) moiety; a fluorophore such as a IR800CW; a moiety for further functionalization such as a trans-cyclooctene, a tetrazine, a terminal azide, a terminal alkyne, or a cyclooctyne; or a moiety containing a radionuclide such as18F.

[0337] Yet another preferred variant relates to conjugates of the following Formula (Ifl) or (Ifl ’):

[0338] Cp(Aa') (Ifl)

[0339] Cp(Pm) (Ifl') wherein an active atom or atomic group Aa’ or pharmacokinetic modifier Pm is bonded directly, i.e., without linker, to a cyclopeptide Cp of Sequence 1 or Formula 10. Preferably, the cyclopeptide is a cyclopeptide of Formula 10 and / or the active atom or atomic group Aa’ is a cytostatic agent or a siRNA, or a pharmacokinetic modifier, or a fluorophore. In special variants, the conjugate consists of a cyclopeptide according to Sequence 1 or Formula 10, preferably Formula 10, functionalized with an active group such as a cytostatic agent or a siRNA, a pharmacokinetic modifier such as a p- iodophenylbutyrate moiety; a fluorophore such as a IR800CW; a moiety for further functionalization such as a trans-cyclooctene, a tetrazine, a terminal azide, or a terminal alkyne; or a radionuclide such as18F.

[0340] A further preferred aspect of the conjugates of the invention relates to conjugates with a chelated metal ion, as described above, but without metal ion. These conjugates may for instance be conjugates of formula (la), (lb) or (II) or any other conjugate formula described herein having a chelating group Cg, but wherein Aa is absent. Such conjugates may be referred to as radiolabeling precursors.

[0341] Further preferred conjugates of the invention contain a preferred cyclopeptide as described in the preferred feature combination aspects (1) or (2) above is preferably incorporated into a linker as shown in the above Tables 6 to 9. Moreover, when incorporating the preferred compounds with the preferred feature combinations, as described in the preferred feature combination aspects (1) or (2) above, into a conjugate of the present invention, it is preferred not only to use the preferred linkers of Tables 6 to 9, but also to form conjugates of formula (la), (lb), (Ibl) or (Id’), as defined above, if the active atom or group of atoms Aa is bonded via a chelating group Cg, with Cg preferably selected from formulae (IVa), (IVb), (IVc) or (IVd), and to form conjugates of formula (Id), (If) or (Ifl) if the active atom or group of atoms Aa’ is covalently bonded to the remainder of the molecule. In this case, Aa’ is preferably bonded via a linker of formula (III8), (III81 ), (III82) or the linker is absent.

[0342] Further preferred conjugates of the invention are as specified in appended claims 8 to 15 and are further characterized as in the following numbered aspects. Unless specified otherwise, references to specific formulae in the below numbered aspects are meant to be references to the respective formulae described in the present specification, wherein the variable groups and parameters may adopt all possible meanings described in the present specification, but only to the extent that they are compatible with the context in which the respective variable groups or parameters appear.

[0343] Ba. The conjugate of any of appended claims 8 to 15, wherein the cyclic peptide moiety is a moiety derived from a cyclic peptide in accordance with the preferred feature combination aspects (1) or (2) above or anyone of the numbered aspects Aato Ah above.

[0344] Bb. The conjugate of numbered aspect Ba, wherein the conjugate is in accordance with anyone of the conjugate structures described hereinabove in the present section “Further preferred conjugates”.

[0345] Be. The conjugate of numbered aspect Ba or Bb, wherein the conjugate contains two or three cyclic peptides, preferably three cyclic peptides, and the cyclic peptides contained in the conjugate are all the same.

[0346] Bd. The conjugate of numbered aspect Be, wherein the conjugate is selected from Formulae (la), (lb), (Ibb), (Id) or (Id1) as described hereinabove, wherein preferably for Formula (la) q=l, n=3, for Formula (lb) q=l, n’=3, for Formula (Ibb) each q=l, n’=3, for Formula (Id) q=l, n=3, p’=I, m=0, o=l, for Formula (Id’) q=l, n=3, m=l, o=l.

[0347] Be. The conjugate of numbered aspect Be or Bd, wherein, if the conjugate contains a chelating group Cg, the linkers linking the cyclopeptides and the chelating group Cg are all the same, and, if the conjugate contains a central moiety, the linkers linking the cyclopeptides and the central moiety Cm are all the same.

[0348] Bf. The conjugate of numbered aspect Be, Bd or Be, wherein the conjugate is selected from Formula (lb), and the linker linking groups Cg and Aa’ differs from the remaining linkers linking Cg and Cp, or wherein the conjugate is selected from Formula (Id’), and the linker linking groups Cm and Cg differs from the remaining linkers linking Cm and Cp.

[0349] Bg. The conjugate of numbered aspect Bf, wherein the linker differing from the remaining linkers is a linker selected from the Formulae ( II IS). ( II IS 1 ). ( II 182) as described hereinabove.

[0350] Bh. A conjugate as described hereinabove, especially in numbered aspects Ba to Bg, but wherein Aa is absent.

[0351] Bi. The conjugate of numbered aspect Bh, wherein the conjugate is characterized by anyone of Formulae (la”), (lb’), or (Id”) as described above, preferably wherein for Formula (la”) q=l, n=3, for Formula (lb’) q=l, n’=3, for Formula (Id”) q=l, n=3, m=l, o=l.

[0352] Bj. The conjugate of numbered aspect Ba or Bb, wherein the conjugate contains a single cyclopeptide, which is bonded to an effector moiety, optionally via a linker. Bk. The conjugate of numbered aspect Bj, wherein the conjugate is a conjugate of Formulae (If), (Ifl) or (Ifl ’), preferably wherein for Formula (If) q=0, p’=l.

[0353] Most preferably, the conjugates of the invention contain one or more structural elements Cp, L, Cg and / or Cm as shown in the compounds exemplified hereinbelow. Structural elements from different exemplified compounds may be combined. It is particularly preferred to combine two or more structural elements from the same exemplified compound.

[0354] Specific Conjugates of the invention

[0355]

[0356] Further specific conjugates of the present invention are described as compounds C30-C34, C40-C45, C50-C55 and C60-C63 in Example 3 below. Further conjugates of the present invention are conjugates as described as compounds C17-C19, C28 in Example 1 or C30-C34, C40-C45, C50-C55 and C60-C63 in Example 3, but wherein the cyclic peptides are modified such that the amino acid residue with XAis replaced by another amino residue with XAas described herein, preferably by means of Table 10 or one of Formulae la to Ij and 2a to 2d.

[0357] Yet further conjugates ofthe present invention are conjugates as described as compounds C17-C19, C28 in Example 1 or C30-C34, C40-C45, C50-C55 and C60-C63 in Example 3, but wherein the cyclic peptides are modified such that the amino acid residue with XBis replaced by another amino residue with XBas described herein, preferably by means of Table 10 or one of Formulae lato Ij and 2a to 2d.

[0358] Further conjugates of the present invention are conjugates as described as compounds C17-C19, C28 in Example 1 or C30-C34, C40-C45, C50-C55 and C60-C63 in Example 3, but wherein one or more of the linkers is / are replaced by another linker as described herein, preferably a linker characterized by any of the above Formulae (III) to (III82) and / or as described in Tables 3 to 9.

[0359] Further conjugates of the present invention are conjugates as described as compounds C17-C19, C28 in Example 1 or C30-C34, C40-C45, C50-C55 and C60-C63 in Example 3, but wherein the effector moiety is replaced by another effector moiety having the same number of valencies, as described herein, preferably a chelating group as described herein such as a chelating group of Formulae (IVa) to (IVd).

[0360] Fourth embodiment

[0361] A further embodiment of the present invention pertains to nanocarriers containing the cyclopeptide of the first embodiment or conjugate of the third embodiment of the present invention, as described herein. Said nanocarriers are not particularly limited and may be selected from liposomes, micelles, polymer particles. Apart from the cyclopeptide or conjugate of the present invention, the nanocarriers may comprise any material known to be suitable for nanocarrier manufacture, This includes for instance lipids such as phospholipids, polymers, copolymers and polymer mixtures. The nanocarriers are equipped with cyclopeptides according to Sequence 1 or Formula 10. This may be done in the following manners:

[0362] Nanocarriers may encompass the cyclopeptides according to Sequence 1 or Formula 10 or conjugates of the invention containing therapeutic agents as effector moieties, which are intended to act as therapeutic agents. These may be contained within the nanocarriers or be provided on the surface of the nanocarriers.

[0363] In another variant, the nanocarriers may carry the cyclopeptides of Sequence 1 or Formula 10 or the conjugates of the invention such that they are presented on the surface of the nanocarriers. This arrangement is suitable for targeting. Fifth embodiment

[0364] Another embodiment provides targeted microbeads for embolization comprising the cyclopeptide of the first embodiment according to Sequence 1 or Formula 10 or the conjugate of the third embodiment of the invention. Said microbeads preferably carry the cyclopeptide according to Sequence 1 or Formula 10 or the conjugate of the third embodiment of the invention at the surface to accomplish a targeting effect via the avP6-integrin binding of the cyclopeptide.

[0365] Said microbeads may further contain a polymeric hydrogel material such as a poly(vinyl alcohol-co- sodium acrylate) hydrogel.

[0366] Said microbeads of the invention may be used for the treatment of hepatocellular carcinoma (HCC) by transcatheter arterial chemoembolization (TACE). The microbeads of the invention are injected via a catheter directly into the tumor or the vicinity of the tumor. This is intended to give rise to high local concentrations of the agent at or near the tumor while minimizing systemic exposure and side-effects.

[0367] Suitable microbead materials and therapeutic uses thereof are described for instance in Y.M. Nouri et al. in Korean J Radiol. 2019 Jan; 20(1): 34-49; https: / / doi.org / 10.3348 / kjr.2018.0088 and literature cited therein.

[0368] Sixth embodiment

[0369] The present invention also relates to medical devices coated with the cyclopeptide or conjugate or radiolabelling precursor compound of the present invention. Coating can be accomplished using conventional methods and techniques in analogy to those described by M. Kazemzadeh-Narbat et al. in Critical Reviews in Biotechnology, 2021, 41, 94-120, doi: 10. 1080 / 07388551.2020. 1828810. Medical devices can be any indwelling or implanted device and especially those intended for use in patients affected by a disease or condition that is associated with an increase in avP6-integrin expression, such as cancer, fibrosis or COVID-19 and Long-CO VID.

[0370] Manufacture of the Conjugates of the invention

[0371] The conjugates of the invention may be synthesized using standard materials and methods known in the art. If the conjugate is a chelate, the formation of the chelate is typically performed as the last step. That is, a suitable procedure includes one or more steps for forming a precursor, as described below, followed by reaction of the precursor with the atom, atomic group or ion to be chelated. Said final reaction is typically conducted under usual conditions for reactions of this kind which are known to the skilled artisan. In a preferred setting, the reaction is conducted at ambient temperature (room temperature, e.g. 20-25 °C). Also preferred, the reaction is conducted at temperatures ranging from ambient temperature (room temperature) to 37 °C. Said ion may be provided in the form of a salt, wherein the salt-forming counter-ion may be selected from the group consisting of sulfates, fluorides, chlorides, bromides, nitrates, phosphates, carbonates, hydrogencarbonates, sulfonates, acetates, and mixtures thereof. In a further preferred aspect, the ion is provided in the form of a solution.

[0372] The conjugate of the invention is preferably prepared using a modular approach based on Click chemistry to link the chelating group (or central moiety) to the cyclopeptide moiety / moieties. The linker / linkers is / are formed in situ during said coupling reaction. The starting materials contain spacers, i.e., precursors of the linkers with functional groups suitable for Click chemistry couplings at their termini. Preferred chemical reactions for formation of linkers, or attachment of functional molecules to linkers, are copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), strain-promoted alkyne-azide cycloaddition (SPAAC), inverse electron demand diels-alder reaction (IEDDA), staudinger ligation, and related reactions (as described, for example, in Bauer D, et al., Bioconjug Chem. 2023;34: 1925. doi: 10.1021 / acs.bioconjchem.3c00286; Steen EJL,et al., Biomaterials 2018;179:209-245; Bednarek C, et al., Chem Rev. 2020; 120:4301. doi: 10.1021 / acs.chemrev.9b00665; Bilodeau DA, et al., Chem. Rev. 2021;121:6699; Porte K, et al., Chem. Rev. 2021 ; 121 :6718; Worch JC, et al., Chem. Rev.

[0373] 2021;121:6744; Levandowski BJ, et al., Chem. Rev. 2021;121:6777; Heiss TK, et al., Chem. Rev. 2021;121:6802; Deb T, et al., Chem. Rev. 2021; 121 :6850; Fairbanks BD, et al., Chem. Rev.

[0374] 2021;121:6915; Kumar GS, et al., Chem. Rev. 2021;121:6991; Albada B, et al., Chem. Rev.

[0375] 2021;121:7032; Shieh P, et al., Chem. Rev. 2021;121:7059; Fantoni NZ, et al., Chem. Rev.

[0376] 2021;121:7122; Fitzgerald PR, et al., Chem. Rev. 2021 ; 121 :7155; Suazo KF, et al., Chem. Rev. 2021 ; 121 :7178.). All functional groups described in the cited literature as suitable for Click Chemistry reactions can be incorporated as functional groups of the spacers of the cyclopeptide of the first embodiment of the invention and also as functional groups of the spacers of the chelating group or other effectors used as a further starting material to form the conjugate of the third embodiment of the invention. Of course, the functional groups of the two reaction partners must be suitably selected so that the resulting pair of functional groups can react in a Click Chemistry reaction.

[0377] Cyclopeptides carrying spacers, i.e. precursors of linkers, at the A6residue, for example as -L4-R4 groups in A-Mc-Lys-R4or A-Me-Lyy-Rx4, may be obtained by reacting the respective precursor, which carries a carboxyl group at the cyclopeptide-binding terminus, and which may be activated using for instance HATU, HOBt and DIPEA, with the sidechain of the A6residue of the respective cyclopeptide under standard amide coupling conditions, for instance as described in Maltsev OV, et al., Angew. Chem. Int. Ed. 2016;55: 1535-1539 and / or WO 2017 / 046416 Al.

[0378] The cyclopeptide can be synthesized by applying suitably adapted materials and procedures described in the literature, for instance in Quigley NG, et al., Eur J Nucl Med Mol Imaging 2022;49: 1136-1147.

[0379] Kits The conjugates of the present invention, which contain chelating groups, can also be labelled with suitable radionuclides directly by mixing the radionuclide solution and the conjugate in a single vial, preferably containing other necessary excipients such as buffer substances, or radiolysis protection compounds, or stabilizers. Such vials (prior to addition of the radionuclide) may be referred to as kits or single-vial kits. The compounds of the invention and further excipients like buffers, radiolysis protectors, and stabilizers can also be provided in separate vials, whose contents are then transferred into one vial where the labeling reaction takes place. Such combinations of ready-to-use vials are sometimes referred to as multi-vial kits. The present invention also relates to such kits containing a radionuclide-free conjugate compound of the invention serving as radiolabeling precursor in one container and optionally the radionuclide in a separate container, including single-vial kits and multi- vial kits. Further components such as buffers, radiolysis protectors, and stabilizers may optionally be present, either in the same container as the building block compound or in one or more separate containers.

[0380] For all kits, radionuclide chelate complex formation reactions are conducted preferably between 20 and 120 °C, and preferably within times of 1-15 minutes for68Ga, or 1-60 minutes for other radionuclides. These preferred temperatures and times also apply if complexation is carried out without relying on a kit.

[0381] The handling of such kits before, during and / or after complex formation with the radionuclide can be performed manually, or by using automated procedures. Furthermore, all components for using the conjugate compounds of the present inventions for preparation of radiolabelled compounds can be placed in a combination of vials, tubing, manifolds, and separation cartridges, sometimes referred to as cassette, preferably to be used with a robotic system for radiolabeling, frequently referred to as synthesis module. Such cassettes are preferably provided as single-use, sterile, ready-to-use packages.

[0382] The resulting chelate complex may be further used without purification, or be further purified by conventional purification means and methods such as RP-HPLC or solid-phase extraction.68Ga can be provided by elution from a68Ge / 68Ga generator, preferably with nominal activity 1-4 GBq, e.g., as supplied from Eckert&Ziegler (Berlin, Germany), ITM (Garching, Germany), Monrol (Turkey), Rosatom / Isotope (Russia), PARS Isotopes (Iran), iTHEMBA (South Africa), or IRE Elit (Belgium). The pH of the68Ga aqueous solutions may be adjusted with suitable buffers to values ranging from 1 to 7, preferably 2-3, prior to complexation.68Ga can also be provided by synthesizing it using a cyclotron, either using a solid target or a liquid target. The activity of the resulting chelate complex can be very high, for instance up to 300 GBq when using a solid target.

[0383] Pharmaceutical composition of the invention

[0384] The present invention further provides pharmaceutical compositions comprising the cyclopeptide, conjugate, radiolabelling precursor, radiotracer or radiopharmaceutical of the invention as described herein. Said pharmaceutical compositions further comprise one or more excipients. These excipients can be selected by the skilled person as appropriate in view of the intended use, type of administration, and so forth. For instance, details on various types of pharmaceutical compositions including suitable excipients are described in “Aulton’s Pharmaceutics”, Ed. M.E. Aulton and K.M.G. Taylor, Elsevier, 5thEd. 2018 and especially Part 5 thereof. More details on suitable excipients can be found in the “Handbook of Pharmaceutical Excipients”, Ed. R.C. Rowe, P.J. Sheskey and M.E. Quinn, PhP Pharmaceutical Press, 6thEd. 2009. Excipients that are typically used in the pharmaceutical compositions of preferred aspects of the present invention are buffer substances, radiolysis protection compounds, and / or stabilizers.

[0385] If compounds of the present invention are administered, the pharmacokinetic profde and bio-distribution of such pharmaceuticals can be positively influenced by additional infusions, either before, during, or after the administration of the agent. Specifically, such co-infusions can reduce the uptake of the agents in the kidneys, as outlined in Stangl, S, et al., Eur J Nucl Med Mol Imaging 2024, doi: 10.1007 / s00259- 024-06738-2; and W02020224780A1. In such cases, said infusion is referred to as renal protecting agent.

[0386] Of particular interest are renal protecting agents consisting of positively charged amino acids, preferably arginine or lysine, or combinations thereof. Preferably, arginine and lysine are administered in combination, the mixture ratio being between 30% Arg and 70% Lys to 70% Arg and 30% Lys, particularly preferably 50% Arg and 50% Lys. Administered amounts of these amino acids per application, either in combination or alone, can be 10g to 80 g, preferably 50 g.

[0387] Further suitable renal protecting agents are succinylated gelatin, preferably as 4% solutions in injection buffer, such as gelofusine®, gelaspan®, gelafundin®, isoplex® or volplex®; para-aminohippuric acid (PAH) as outlined in Moraitis A, et al., J Nucl Med. 2024, doi: 10.2967 / jnumed.123.266619; or polyglutamic acid (PGA), as outlined in Behe M, et al., J Nucl Med. 2005;46: 1012-5.

[0388] The administration of such renal protecting agents can be done in advance, during, or after the administration of the compounds of the present invention. Possible infusion schemes are described in Buitinga M, et al., J Nucl Med. 2019;60:812-6; or Luo Y, et al., J Pancreatol. 2020;3: 161-6. Preferably, the administration of a renal protecting agent is started before the administration of the compounds of the present invention. Preferably, started 10-60 min before, particularly preferably 15-30 min before. It is preferred that the administration of the renal protecting agent is continued after administration of the compounds of the present invention. Particularly preferably, the renal protecting agent infusion is continued 2h to 4h after the administration compounds of the present invention. Application routes

[0389] In a clinical setting, the compounds of the present invention can be applied via the oral, or parenteral route. If parenteral, the application can be done subcutaneously (s.c.), intramuscularly (i.m.), intraveneously (i.v.), or via an implanted port such as for chemotherapy. A preferred application route is i.v.. In this case, the pharmaceutical composition must be appropriately selected as to be compatible with the i.v. administration route, and preferably is a solution in an acceptable injection buffer, such as saline, phosphate-buffered saline, ringer's solution, saline containing human albumin, or saline containing succinylated gelatin.

[0390] Uses of the invention

[0391] (i-0) Imaging. The use of the invention may be exercised in any forms of medical or biomedical imaging. Materials and entities to be imaged include single cells; multi-cellular bodies such as spheroids; live tissues; conserved tissues such as fresh-frozen tissue sections or formalin-fixed paraffine-embedded (FFPE) tissues; perfused organs; live animals; or humans. The use of the compounds of the invention for imaging purposes can be exercised in the context of in-vitro research; preclinical research using live cells, tissues, organs, laboratory animals; clinical research; or clinical healthcare.

[0392] Said imaging methods generally involve a step of bringing the compound or conjugate of the invention into contact with the material (molecule, cell or tissue) to be imaged, as well as subsequent steps of data collection and data processing. The collected data typically includes information on local concentration of the compound or conjugate of the invention, which is preferably linked to information on the spatial position of the data collection.

[0393] In the context of this description of imaging uses, the expression “compounds and conjugates of the invention” is intended to refer to any of the cyclopeptides of the first embodiment or conjugates of the third embodiment of the invention, which contains at least one atom or atomic group that is suitable for the imaging method of interest. For instance, if it is intended to carry out a CT imaging method, it may be considered to use a cyclopeptide of Sequence 1 or Formula 10, which carries an iodine atom as part of the non-canonical amino acid characterized by Formula 2. If MRI is of interest, it may be considered to use a conjugate of e.g., Formula (la), wherein the chelated active atom Aa is Gd3+.

[0394] Preferred imaging modalities are positron emission tomography (PET), single-photon emission computed tomography (SPECT), planar scintigraphy, X-ray imaging, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), multi-spectral opto-acoustic tomography (MSOT), fluorescence imaging, imaging using the cherenkov radiation emitted by certain nuclides with high decay energy (cherenkov imaging), or autoradiography. The invention also relates to combinations of the aforementioned imaging methods which are preferably exercised with dedicated devices, such as PET / CT, PET / MRI, SPECT / CT, PET / fluorescence. If the use of compounds and conjugates of the present invention encompasses PET, SPECT, or scintigraphy, or any combinations of these modalities with each other or with other imaging modalities mentioned hereinabove, the compounds and conjugates of the invention used for this purpose must contain at least one radioactive atom. In that case, said compound or conjugate is referred to as a radiotracer. The radioactive atoms (sometimes referred to as radionuclides) comprised in the radiotracers of this invention are preferably emitters of gamma radiation or positrons. Preferred radionuclides for use in radiotracers of the present invention are "mTc,inIn,43Sc,44Sc,64Cu,68Ga, and18F.

[0395] The use of the present invention for medical imaging can also be exercised in settings of medical operations or therapeutic regimen where the imaging readout is used to immediately guide medical operations. A preferred setting is the use of a signal consisting of electromagnetic radiation to identify tissue of interest by means of its elevated avP6-integrin expression, using compounds of the invention equipped with suitable reporter molecules to deliver such a signal to a dedicated device. Sometimes, the respective procedures and applications are referred to as image-guided surgery. Preferred applications of this type are:

[0396] (i-A) Fluorescence-guided surgery. An avP6-integrin binding fluorescent tracer, i.e., a cyclopeptide compound according to Sequence 1 or Formula 10, equipped with a fluorescence dye (preferably NIR or NIR2 as described hereinabove), is first administered to a patient. After a time wherein the fluorescent tracer has been allowed to distribute in the body (typically, 30 min - 48 h after administration), the patient undergoes surgery. During surgery, a fluorescence signal can be detected with dedicated intraoperative devices (CCD cameras, visualization monitors) that allows the surgeon to specifically identify the avP6-integrin expressing tissues, for example, to selectively remove them while leaving tissues without avP6-integrin expression in place (as described in Sutton PA, BJS Open. 2023;7:zrad049.).

[0397] (i-B) Radio-guided surgery. If the principle of intraoperative detection and guidance is practiced exploiting gamma radiation originating from radioactive decay, it is referred to as radio-guided surgery. The use and scope of application is the same as described hereinabove in (i-A), or as described in Hermann K, Nieweg OE, Povoski SP (Eds.): Radioguided Surgery. Springer; 1stedition, 2016, ISBN- 13: 978-3319260495.

[0398] (i-C) In another preferred form of imaging application, fluorescence-guided and radio-guided surgery using compounds of the present invention can also be combined during one procedure. In that case, two separate compounds (one with fluorescent properties and one containing a radioactive isotope) can be applied. It is however also possible to use a dedicated agent, comprising one or more fluorophores and one or more radioactive isotopes, within the same molecule. (i-D) In a preferred setting, parts of the applications described in (i-A, i-B, and i-C) are performed using robotic systems (as described in van Oosterom MN, et al., Eur J Nucl Med Mol Imaging 2023; 11:533).

[0399] (i-E) In-situ or topical imaging, exercised by applying an imaging agent as described hereinabove directly on the site of suspected disease, where avP6-integrin binding occurs and effects a selective accumulation of the imaging agent that allows for a disease-specific imaging readout (as described in de Souza Franca PD, et al., Eur J Nucl Med Mol Imaging. 2021;48:3618).

[0400] (t-0) Therapy. The compounds of the invention can be used to treat medical conditions that are, directly or indirectly, associated with avP6-integrin expression. In one preferred setting, the physiological expression of avP6-integrin by certain cell populations, such as alveolar epithelial cells in the lung, is utilized to direct the compounds of the invention to that cell population in order to exert a therapeutic effect. In another preferred setting, the avP6-integrin expression that is specifically elevated on disease related cell populations is exploited to direct the compounds of the invention to this cell population in order to exert a therapeutic effect.

[0401] In the therapeutic uses of the invention, references to the “compounds of the invention” are to be understood as references to the cyclopeptides of the first embodiment, wherein its avP6-integrin activity is used for accomplishing therapeutic effects, and conjugates of the third embodiment of the invention, wherein the avP6-integrin activity is used for accomplishing therapeutic effects and / or which furthermore carry at least one active atom or active atomic group that has therapeutic efficacy against the disease to be treated. For instance, if the disease to be treated is cancer, the compound of the invention may be a conjugate of Formula (la’), wherein the active atomic group Aa’ is MMAE (see preferred use (t-E) below).

[0402] Preferred applications of this type are:

[0403] (t-A) avP6-integrin ligation with peptides according to Sequence 1 or Formula 10. Such a ligation of avP6-integrin is suitable to influence the integrin-mediated signaling behavior of the avP6-integrin expressing cells. For example, ligation of avP6-integrin can exert a therapeutic effect by downregulating TGF-beta activation, or by restoration the anticancer activity of T-cells. Preferred compounds of the present invention for this purpose possess a high avP6-integrin activity and a long residence time in the biosystem. Preferred classes of compounds of the present invention therefore encompass conjugates of the third embodiment of the invention, which carry two or more cyclopeptides of the first embodiment, because of their generally elevated affinities, or conjugates comprising suitable pharmacokinetic modifiers, such as plasma protein binders or lipophilic side chains that exert a depot effect in subcutaneous adipose tissue. (t-B) Radioligand therapy / radionuclide therapy (RLT). This field of application preferably exploits elevated avP6-integrin expression by disease-related cell population, most preferably, an elevated avP6- integrin expression by cancer cells. In order to practice RLT, compounds of the present invention are used that are equipped with one or more radioactive atoms, which are referred to as radiotherapeutics. Such radiotherapeutics are administered to the diseased living organism, preferably a human patient, by a suitable method that allows the radiotherapeutic to distribute within the organism, preferably by intraveneous (i.v.) injection. By doing so, the radiotherapeutic is enabled to encounter the diseased cell, whereupon the emitted radiation of the contained radioisotopes initiates a cell death, for example, by apoptosis. Altogether, the therapeutic effect is thus achieved by preferential killing of the cell population with elevated avP6-integrin expression, preferably, cancer cells with elevated avP6-integrin expression. The cell-killing effect can be induced by oxidative stress as a result of the production of reactive oxygen species by gamma radiation or beta radiation; by single-strand breaks of the cell's DNA caused by impacting beta- or alpha particles emitted by the radioisotopes comprised in the radiotherapeutics; or by double-strand breaks of the cell's DNA preferentially caused by impacting alpha particles emitted by the radioisotopes of the radiotherapeutics. Suitable radioisotopes in radiotherapeutics of the present invention therefore encompass those emitting beta- or alpha-radiation, as described hereinabove. Preferred radionuclides for use in radiotherapeutics of the present invention are177Lu,90Y,67Cu,47Sc,149Tb,161Tb,225Ac,227Th,212BI,213BI,212Pb,211At.

[0404] (t-C) Radioembolization. Compounds of the invention can be used in combination with micro-particles, such as glass or polymer microbeads, for radioembolization. Such uses are suitable for instance in treating hepatocellular carcinoma (HCC) by transcatheter arterial chemoembolization (TACE).

[0405] (t-D) Targeted therapy using a nanocarrier (NC). NCs are a class of materials consisting of particles or particle-like entities (agglomerates) with several nm to several 100 nm which are frequently used in the context of pharmaceutical preparations, for example, to improve the treatment outcomes of medicines for cancer and viral infections. The compounds of the invention can be used in combination with such techniques, preferably, by attaching compounds of the present invention to the surface of NCs, or incorporating them in any other suitable way that the NC is enabled to bind to avP6-integrin in order to exert a targeting effect to the respective avP6-integrin expressing cells or tissues. Preferred classes of nanocarriers for use with compounds of the present invention are micelles, liposomes, lipid nanoparticles, polymersomes, dendrimers, polymer micelles, nanospheres, silica nanoparticles, quantum dots, iron oxide nanoparticles, gold nanoparticles, core-shell nanoparticles, phosphate-containing nanoparticles, coated nanoparticles, or magnetic nanoparticles, as described in Sher EK, et al., Int J Pharmaceutics 2024, 124345; or ud Din F, et al., Int J Nanomedicine. 2017; 12:7291; or Sabit H., et al., Pharmaceutics. 2022;14: 1566. (t-E) Peptide-drug conjugates (PDC) and targeted delivery. Conjugate compounds of the present invention can be used to selectively deliver pharmaceutically active molecules, materials, or drugs to cells or cell populations with an elevated avP6-integrin expression, as described hereinabove for radioligand therapy using radiotherapeutics (t-B). A preferred field of medical application of targeted delivery is cancer therapy. A high efficiency of avP6-integrin targeted delivery using peptide-drug conjugates with compounds of the present invention results from the fact that such peptide-drug conjugates, if bound to avP6-integrin, are rapidly internalized into respective cells (as outlined in Meecham A & Marshall J, Expert Opin Drug Discov. 2021;16:737. doi: 10.1080 / 17460441.2021.1878143.). Within the cell, the PDC is preferably cleaved, thereby releasing the drug (as described in Paulus J, et al., J Pept Sci. 2024;30:e3561; doi: 10.1002 / psc.3561). Suitable application schemes, therapy regimens, and drugs for use with or in PDCs are disclosed in Wang M, et al., Eur. J. Med. Chem. 2024;265: 116119; Fu C, et al., Acta Pharm Sin B. 2023;13:498; Chavda VP, et al., Molecules. 2022;27:7232. The concepts and methods disclosed in this literature can be used in combination with PDCs based on Sequence 1 and Formula 10, when practicing the present invention. The disclosures of therapeutic schemes and indications in these references is therefore incorporated herein.

[0406] (t-F) Photodynamic therapy / photothermal therapy. Compounds of the present invention can be used to selectively deliver photosensitizing molecules or materials to cells or cell populations with an elevated avP6-integrin expression, as described hereinabove for radioligand therapy using radiotherapeutics (t- B). The general role of such photosensitizers is to exert a cell-killing effect upon irratiation with electromagnetic radiation. Preferred wavelengths are in the visible and infrared light spectrum. A preferred field of medical application of photodynamic therapy in connecion with compounds of the present invention is cancer therapy. Suitable application schemes, therapy regimens, and photosensitizers are disclosed in Li Q, et al., Pharmaceutics 2024;16:218; Correia JH, et al., Pharmaceutics. 2021;13: 1332. The concepts and methods disclosed in this literature can be used in combination with photodynamic therapy agents, which are conjugate compounds of the present invention based on Sequence 1 and Formula 10, when practicing the present invention. The disclosures of photosensitizers, therapeutic schemes, and indications in these references is therefore incorporated herein.

[0407] All imaging and therapeutic modalities described hereinabove in i-0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t- B, t-C, t-D, t-E, and t-F can also be exerted in combination. In this case, suitable compounds of the invention specifically designed for one or more of the purposes mentioned in i-0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t-B, t-C, t-D, t-E, and t-F can be combined freely with each other, or with other agents used to practice the general techniques described in i-0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t-B, t-C, t-D, t-E, and t- F that are not compounds of the present invention. Conditions or clinical settings where the invention is preferentially applied

[0408] (a-A) All concepts and methodologies outlined hereinabove in i-0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t-B, t-C, t-D, t-E, and t-F can be applied with any medical condition that is related to cellular expression of avP6-integrin. However, applications according to i-0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t-B, t-C, t-D, t-E, and t-F are preferentially exercised for diagnosis or therapy of benign or malign neoplasms (frequently referred to as cancer). A preferred field of application are the following cancers: Pancreatic adenocarcinoma (PDAC), head-and-neck cancers (HNSCC), tonsillar carcinoma, urothelial carcinoma, esophageal squamous cell carcinoma, cervical carcinoma (i.e. related to the cervix uteri), endometrial carcinoma, breast cancer, triple-negative breast carcinoma, non-small cell lung cancer, gastric cancer, colorectal cancer, renal cancer, prostate cancer, thyroid cancer, parathyroid gland adenoma, imaging pertinent to hyperparathyroidism (HPT), testicular cancer, hepatocellular carcinoma, cholangiocellular carcinoma, benign and malign salivary gland adenoma.

[0409] Specifically, concepts and methods described in concepts and methodologies outlined hereinabove in i- 0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t-B, t-C, t-D, t-E, and t-F are applied in the context of PDAC and HNSCC (as outlined in Das S, et al., Clinical Nuclear Medicine 2024, doi: 10.1097 / RLU.0000000000005278; or Quigley NG, et al., Eur J Nucl Med Mol Imaging. 2022;49: 1136. doi: 10.1007 / s00259-021-05559-x), of brain metastases (as outlined in Rehm, J, et al., Eur J Nucl Med Mol Imaging 2024, doi: 10.1007 / s00259-024-06750-6), or of parathyroid gland adenoma.

[0410] (a-B) A further preferred field of applications according to i-0, i-A, i-B, i-C, i-D, i-E, t-0, t-A, t-B, t-C, t-D, t-E, and t-F is diagnosis or therapy of fibrosis, such as lung fibrosis, liver fibrosis, cardiac fibrosis (as outlined in Kimura RH, et al., Nat Commun 2019; 10,4673; or Lukey PT, et al., Eur J Nucl Med Mol Imaging. 2020;47:967-79; and Maher TM, et al., Respirat Res. 2020;21:75); CO VID-19 or the post- COVID syndrome (as outlined in Kimura RH, et al., Am J Respir Crit Care Med. 2023;207: 1633-5. doi: 10.1164 / rccm.202206-1107IM.

[0411] Examples

[0412] Example 1: Synthesis of peptides and conjugates

[0413] All syntheses were, if not stated differently, carried out under standard laboratory conditions using standard glass and plastic lab equipment. All solvents and chemicals were obtained from commercial suppliers and used without further purification. Reaction progress and synthesized substances were analyzed via HPLC / MS, using a DIONEX Ultimate 3000 HPLC system coupled to Thermo Fisher ISQ- EM single quad mass spectrometer. HPLC was equipped with single pump gradient system, temperature-controlled column compartment, autosampler unit and DAD. A column Dr. Maisch Reprosil Pur C18 100x4 mm, 5 pm, was used for analytical separations, using a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 10 min, followed by 2 min of 90% acetonitrile. Purifications were carried out on Sykam HPLC system equipped with binary pump and UV / Vis detection unit. Manual injection was used for separation on column Macherey Nagel VP 250 / 30 NUCLEODUR C18 Pyramid, 5 pm using a flow rate of 20 mL / min. Water (+0. 1% TFA) and acetonitrile (+0.1% TFA) served as mobile phases A and B.

[0414] Literature-known Compounds

[0415] The building blocks TRAP (Cl) and TRAP -triazide (C3) were synthesized as described in Baranyai Z, et al., Dalton Trans. 2015;44: 11137.

[0416] Synthesis of TRAP-(PEG8-Alkyne)3(C7)

[0417] Cl (1 eq, 0.8 mmol), PyAOP (6 eq, 4.8 mmol) and DIPEA (8 eq, 6.4 mmol) were dissolved in anhydrous DMSO (5 m ) and preactivated. Propargyl-PEG8-NH2 (4 eq, 3.2 mmol) was added and the reaction was stirred for at least two hours. Afterwards, the mixture was directly purified using preparative HPLC (25-50% B over 45 min) to yield C7 as colorless oil (830 mg, 48%, tR= 6.2 min, m / z = 1748.02 [M+H]+, 874.69 [M+2H]2+.

[0418] Solid Phase Peptide Synthesis

[0419] All solid phase syntheses of cyclic peptides were carried out under similar conditions applied using commercially available building blocks, reactants and solvents. Generally, chloro-trityl resin was used as solid phase and loaded with Fmoc-Glycine (0.8 mmol / g) in DCM catalyzed by an 8-fold excess of DIPEA as base. Free binding sites on resin were capped using methanol / DIPEA (2 / 8 v / v). Couplings were performed using an excess of HATU und HObT as coupling agents and DIPEA as base in DMF. Coupling steps were performed for 3 h at ambient temperature. After each coupling step, a test sample was extracted and the respective sequence was cleaved from resin using HFIP / DCM (2 / 8 v / v) and analyzed via LC / MS. Fmoc deprotection was performed in piperidine / DMF (2 / 8 v / v) for 10 min. This procedure was repeated one more time. Final cleavage of linear peptides from resin was carried out by using HFIP / DCM (2 / 8 v / v) for 10 min. This procedure was repeated twice. Deprotection of any linear peptide sequence was done with TFA / TIPS (95 / 5 v / v) for 24 h at room temperature. Deprotected linear peptides were finally cyclized via amide bond formation using DPPA (3 eq) as reactive component and sodium hydrogen carbonate (5 eq) as inorganic base. This reaction took place in a highly diluted reaction system with DMF as solvent. All peptides were finally purified using HPLC.

[0420] C8

[0421] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-Pal-OH, Fmoc-(A- Me)K(Ns)-OH, Fmoc-D-Pro-OH, Fmoc-(Boc)-Trp-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc- (tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C8L (HO-Gly-Arg(Pbf)-4-Pal-( / VMe)Lys(Boc)-D-Pro-Trp(Boc)-Ala- Leu-Asp(tBu)-Fmoc) was cleaved from resin using HFIP / DCM (tR = 11.5 min, m / z = 1762.25 [M+H]+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C8P (tR = 9.9 min, m / z = 1521.17 [M+H]+, 761.91 [M+2H]2+).

[0422]

[0423] Finally, the crude mixture was deprotected and purified via preparative HPLC (10-60% B over 45 min) to yield C8 as colorless solid (120 mg, 12%, tR = 6.0 min, m / z = 1113.12 [M+H]+, 557.38 [M+2H]2+).

[0424] C9

[0425] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detail and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-DOPA(ac2)-OH, Fmoc- (A-Me)K(N3)-OH, Fmoc-D-Pro-OH, Fmoc-DOPA(ac2)-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc- (tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C9L (HO-Gly-Arg(Pbf)-DOPA(ac2)-( / VMe)-azidolysine-D-Pro- DOPA(ac2)-Ala-Lcii-Asp( / Bii)-Fmoc) was cleaved from resin using HFIP / DCM (tR= 10.3 min, m / z = 1543.41 [M+H]+, 772.43 [M+2H]2+), Fmoc deprotected, and cyclized for 48 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C9P (tR= 12.3 min, m / z = 1525.42 [M+H]+, 735.10 [M+2H]2+).

[0426] Finally, the crude mixture was deprotected and purified via preparative HPLC (15-45% B over 45 min). The deprotected and cyclic peptide C9 was obtained as colorless solid (50 mg, 6%, tR= 6.0 min, m / z = 1136.67 [M+H]+, 568.87 [M+2H]2+).

[0427]

[0428] C10F

[0429] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-4-Pal-OH, Fmoc-(A- Me)K(Boc)-OH, Fmoc-D-Pro-OH, Fmoc-4-Pal-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-(tBu)Asp- OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C10L (HO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-I)-Pro-4-Pal-Ala-Lcii-Asp( / Bii)- Fmoc) was cleaved from resin using HFIP / DCM (tR= 9.6 min, m / z = 1698.21 [M+H]+, 849.29 [M+2H]2+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide CIOP (tR= 7.5 min, m / z = 1458.23 [M+H]+, 729.14 [M+2H]2+). Finally, the crude mixture was deprotected and purified via preparative HPLC (15-20% B over 45 min) to yield CIO as colorless solid (85 mg, 8%, tR=4.1 min, m / z = 1048.52 [M+H]+, 525.42 [M+2H]2+).

[0430] CIO (0.02 mmol) was functionalized with pentynoic acid TFP active ester (1.2 eq) using DIPEA (4 eq) as base in DMSO to yield final compound C10F. C10F was obtained as colorless solid (25 mg, 90%, tR=4.8 min, m / z = 1128.74 [M+]+, 564.99 [M+2H]2+).

[0431] C11

[0432] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-Tyr(tBu)-OH, Fmoc- (A-Me)K(N3)-OH, Fmoc-D-Pro-OH, Fmoc-7AW(Boc)-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc- (tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C11L (HO-Gly-Arg(Pbf)-Tyr( / Bu)-(A'Mc)-azidolysinc-l)-Pro-7- AW(Boc)-Ala-Lcii-Asp( / Bii)-Fmoc) was cleaved from resin using HFIP / DCM (tR= 11.6 min, m / z = 1834.31 [M+H]+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide CUP (tR= 10.4 min, m / z = 1593.25 [M+H]+, 747.64 [M+2H]2+).

[0433] Finally, the crude mixture was deprotected and purified via preparative HPLC (25-45% B over 45 min). The product C17 was obtained as colorless solid (95 mg, 11%, tR= 5.7 min, m / z = 1128.89 [M+H]+, 564.86 [M+2H]2+).

[0434] C12F

[0435] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-4-Pal-OH, Fmoc-(A- Me)K-OH, Fmoc-D-Pro-OH, Fmoc-7-AW-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-(tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C12L (HO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-D-Pro-7-AW-Ala-Lcii-Asp( / Bii)- Fmoc) was cleaved from resin using HFIP / DCM (tR= 9.8 min, m / z = 1736.55 [M+H]+, 868.52 [M+2H]2+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C12P (tR= 7.7 min, m / z = 1496.03 [M+H]+, 748.42 [M+2H]2+).

[0436] Finally, the crude mixture was deprotected and purified via preparative HPLC (15-20% B over 45 min) to yield C12 as colorless solid (45 mg, 4%, tR=4.2 min, m / z = 1087.75 [M+H]+, 544.37 [M+2H]2+). C12 (0.02 mmol) was functionalized with pentynoic acid TFP active ester (1.2 eq) using DIPEA (4 eq) as base in DMSO to yield final compound C12F. C12F was obtained as colorless solid (22 mg, 91%, tR=4.8 min m / z = 1168.39 [M+H]+, 584.98 [M+2H]2+).

[0437] C14

[0438] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-4-Pal-OH, Fmoc-(A- Me)K(Ns)-OH, Fmoc-D-Pro-OH, Fmoc-4-Pal-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-(tBu)Asp- OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C14L (HO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-4-Pal-Ala-Lcii-Asp( / Bu)- Fmoc) was cleaved from resin using HFIP / DCM (tR= 9.4 min, m / z = 1624.05 [M+H]+, 812.76 [M+2H]2+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C14P (tR= 7.6 min, m / z = 1382.90 [M+H]+, 692.02 [M+2H]2+).

[0439]

[0440] Finally, the crude mixture was deprotected and purified via preparative HPLC (10-60% B over 45 min) to yield C14 as colorless solid (150 mg, 17%, tR= 4.9 min, m / z = 1075.14 [M+H]+, 538.14 [M+2H]2+).

[0441] C15

[0442] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-Pal-OH, Fmoc-(A- Me)K(Ns)-OH, Fmoc-D-Pro-OH, Fmoc-(Boc)-7-AW-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc- (tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C15L (HO-Gly-Arg(Pbf)-4-Pal-( / VMe)Lys(Boc)-D-Pro-7-AW(Boc)-Ala- Leu-Asp(tBu)-Fmoc) was cleaved from resin using HFIP / DCM (tR= 10. 1 min, m / z = 1763.68 [M+H]+, 831.62 [M+2H]2+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C15P (tR= 8.4 min, m / z = 1522.62 [M+H]+, 711.97 [M+2H]2+).

[0443] Finally, the crude mixture was deprotected and purified via preparative HPLC (20-40% B over 45 min) to yield C15 as colorless solid (70 mg, 9%, tR= 5.4 min, m / z = 1113.85 [M+H]+, 557.59 [M+2H]2+).

[0444] C16

[0445] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-Phe-OH, Fmoc-(A- Me)K(Ns)-OH, Fmoc-D-Pro-OH, Fmoc-Pal-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-(tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section. The linear peptide C16L (HO-Gly-Arg(Pbf)-Phc-(AMc)-azidolysinc-D-Pro-4-Pal-Ala-Lcii-Asp( / Bu)- Fmoc) was cleaved from resin using HFIP / DCM (tR= 10.5 min, m / z = 1622.17 [M+H]+, 812.48 [M+2H]2+), Fmoc deprotected, and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C16P (tR= 8.8 min, m / z = 1381.93 [M+H]+, 691.39 [M+2H]2+).

[0446] Finally, the crude mixture was deprotected and purified via preparative HPLC (20-50% B over 45 min). The product C16 was obtained as colorless solid (55 mg, 6%, tR= 6.0 min, m / z = 1074.72 [M+H]+, 537.93 [M+2H]2+).

[0447] C17

[0448] C3 (1 eq, 0.0025 mmol) and C10F (3.3 eq, 0.009 mmol) were dissolved in 1.5 mb H2O / / B11OH (1 / 2, v / v). Copper acetate (5 eq, 0.013 mmol), sodium ascorbate (60 eq, 0.15 mmol) and THPTA (0.5 eq, 0.0013 mmol) were dissolved in another reaction vessel and preconditioned. The two mixtures were poured together, and the reaction was stopped after 10 min by direct preparative HPLC (10-40% B over 45 min). After the first HPLC purification the product was demetallated from any residual copper by incubation of NOTA (15 eq, 0.075 mmol) for 1 h at 60 °C at pH 2.4. The crude was finally purified again via preparative HPLC (10-40% B over 45 min) yielding compound C17 as colorless solid (0.0012 mmol, 51%, tR= 4.5 min, m / z = 1404.81 [M+3H]3+, 1053.90 [M+4H]4+, 843.06 [M+5H]5).

[0449] C18

[0450] C3 (1 eq, 0.002 mmol) and C12F (3.5 eq, 0.007 mmol) were dissolved in 1.5 mL H2O / / B11OH (1 / 2, v / v). Copper acetate (5 eq, 0.01 mmol), sodium ascorbate (60 eq, 0.12 mmol) and THPTA (0.5 eq, 0.001 mmol) were dissolved in another reaction vessel and preconditioned. The two mixtures were poured together, and the reaction was stopped after 10 min by direct preparative HPLC (20-40% B over 45 min). After the first HPLC purification the product was demetallated from any residual copper by incubation of NOTA (15 eq, 0.03 mmol) for 1 h at 60 °C at pH 2.4. The crude was finally purified again via preparative HPLC (20-40% B over 45 min) yielding compound C18 as colorless solid (0.0007 mmol, 42%, tR= 4.4 min, m / z = 1082.52 [M+4H]4+, 866.43 [M+5H]5+).

[0451]

[0452] C19

[0453] C7 (1 eq, 0.005 mmol) and C9 (3.3 eq, 0.0165 mmol) were dissolved in 1.5 mL tLOZ / BuOH (1 / 2, v / v). Copper acetate (5 eq, 0.025 mmol), sodium ascorbate (60 eq, 0.3 mmol) and THPTA (0.5 eq, 0.0025 mmol) were dissolved in another reaction vessel and preconditioned. The two mixtures were poured together, and the reaction was stopped after 10 min by direct preparative HPLC (20-40% B over 45 min). After the first HPLC purification the product was demetallated from any residual copper by incubation of NOTA (15 eq, 0.075 mmol) for 1 h at 60 °C at pH 2.4. The crude was finally purified again via preparative HPLC (20-40% B over 45 min) yielding compound C19 as colorless solid (0.002 mmol, 40%, tR= 5.4 min, m / z = 1740.38 [M+3H]3+, 1306.00 [M+4H]4+, 1044.45 [M+5H]5+, 870.47 [M+6H]6+).

[0454]

[0455] C28

[0456] CIO (1 eq, 0.01 mmol) and sulfo-Cy5-NHS ester (1.2 eq, 0.012 mmol) were dissolved in 1 mL of DMSO. DIPEA (4 eq, 0.04 mmol) was added and the reaction stirred for 2 h at room temperature. The crude was purified via preparative HPLC (20-70% B over 60 min) and compound C28 was obtained as blue solid (8 mg, 47%, tR= 5.2 min, m / z = 1673.80 [M+H]+, 837.03 [M+2H]2+).

[0457]

[0458] Example 2: In-vivo testing

[0459] Experimental procedures

[0460] The determination of the general in-vivo and tumor targeting properties was done following the standard protocols described in the pertinent literature (Quigley NG, et al., Eur J Nucl Med Mol Imaging 2022;49: 1136, doi: 10.1007 / s00259-021-05559-x), utilizing SCID mice bearing H2009 (avP6- expressing human lung adenocarcinoma cell line) subcutaneous xenografts on their right shoulders. These animal models were generated as described in Quigley NG, et al., ChemBioChem 2020; 19:2836, doi: 10.1002 / cbic.202000200.68Ga radiolabeling was done by mixing 2 nmol of the respective peptide- chelator conjugate with IM sodium acetate buffer (50 pL) and 500 pL of68Ge / 68Ga generator eluate (0. IN HC1). After heating to 95 °C for 10 min, 150 pL of sodium acetate buffer was added, resulting in a suitable pH for in-vivo administration (6.5).

[0461] For ex-vivo biodistribution, radiotracer solutions were diluted after labeling with saline to a total volume of 2 mL, and the animals (3 per investigated compound) injected with 100 pL (2-3 MBq) of the diluted solution. The mice were sacrificed after 90 min, a blood sample was taken, organs of interest were dissected and weighed, and the contained activity in each specimen was measured in a gamma counter. Injected activity per gram tissue (%IA / g) was calculated from the organ weights and counted activities.

[0462] For PET imaging, approx. 200 pL (8-10 MBq) of this solution was injected to the mice. PET data was recorded after 30 min and 90 min, acquisition time 15 min, reconstructed using an OSEM3D algorithm, and selected uptakes quantified via region-of-interest (ROI) analysis. 2 mice were imaged with68Ga- Trivehexin,68Ga-C17, and68Ga-C18 on consecutive days. Results

[0463] Ex-vivo biodistribution data were determined68Ga-C17 and68Ga-C18 for a time point of 90 min post injection (p.i .), and compared to the published data for the structurally related, clinically used compound68Ga-Trivehexin (Quigley NG, et al., Eur J Nucl Med Mol Imaging 2022;49: 1136, doi: 10.1007 / s00259- 021-05559-x). Figure 1 shows that tumor uptakes of68Ga-C17 and68Ga-C18 were comparable to68Ga- Trivehexin. Both68Ga-C17 and68Ga-C18 showed markedly lower activity levels in the blood and in the kidneys than68Ga-Trivehexin (Figure 1). As a result, substantially higher tumor-to-blood and tumor- to-kidney ratios were found for68Ga-C17 and68Ga-C18 as compared to68Ga-Trivehexin (Figure 2).

[0464] In accordance with ex-vivo biodistribution data (Figures 1 and 2), PET images acquired 30 min after injection of68Ga-Trivehexin,68Ga-C17, and68Ga-C18 to the same H2009-tumor bearing mouse (intraindividual comparison) showed a lower background signal intensity (reference region: heart) for68Ga-C17 and68Ga-C18, as compared to68Ga-Trivehexin (Figure 3A). Moreover, the kidney retention of68Ga-C17 and68Ga-C18 was also reduced (Figure 3B). PET images acquired 90 min p.i. for68Ga- Trivehexin and68Ga-C18 corroborated a higher image quality obtained with68Ga-C18, namely, a comparable tumor uptake, but lower blood pool retention (Figure 4A) and lower kidney retention (Figure 4B). These results are reflected by region-of-interest (ROI) analysis of the PET data (Figure 5). The PET-based tumor-to-kidney ratios of68Ga-C17 and68Ga-C18 were exceeding those of68Ga-Trivehexin at both investigated time points (Figure 6). Tumor-to-blood ratios of68Ga-C17 and68Ga-C18 were markedly higher compared to68Ga-Trivehexin at 90 min p.i. (Figure 6).

[0465] Figure 7 shows the improvement of the contrast of PET images acquired with68Ga-C17 and68Ga-C18 in relation to PET images acquired using68Ga-Trivehexin. The bars show tumor / blood and tumor / kidney ratios for68Ga-C17 and68Ga-C18 divided by tumor / blood and tumor / kidney ratios, respectively, for68Ga-Trivehexin, which were calculated as follows (example shows calculation of the enhancement factor Tumor / Blood,68Ga-C17):

[0466] (TumOr / Blood)68Ga-C17, 30 mm

[0467] Enhancement Factor (68Ga-C17, 30 min) = -

[0468] (Tumor / BloodjesGa -Trivehexin, 30min

[0469] Figure 7 illustrates that the PET-based tumor / blood and tumor / kidney ratios of68Ga-C17 and68Ga-C18 were higher than those of68Ga-Trivehexin at all investigated time points. Contrast enhancement factors ranged from 1.3 to 2.6 (tumor / blood) and from 1.5 to 2.4 (tumor / kidney). Example 3: Further in vivo tests

[0470] I. Experimental Procedures

[0471] Using compounds of Example 1 and further compounds obtained with procedures analogous to the procedures of Example 1, the following compounds were subjected to further in vivo tests.

[0472] Test compounds

[0473] Table 11

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] Reference compounds

[0488] The conjugates C100 and C0102 ("Tyr2" and "Trivehexin", respectively; see Quigley et al, Eur J Nucl Med Mol Imaging 2022, 49, 1136, DOI: 10.1007 / s00259-021-05559-x), and C0101 are covered by prior art (WO 2021 / 180969 A). These compounds were included into the experiments for comparison purposes.

[0489] Table 12

[0490] Synthetic procedures

[0491] Representative synthesis protocols for key compounds are provided below. The protocol for synthesis of C30 is representative for synthesis of the related structures C31, C32, C33, and C34. The protocol for synthesis of C40 is representative for synthesis of the related structures C41, C42, C43, and C44. The protocol for synthesis of C54 is representative for synthesis of the related structures C50, C51, C52, and C53. The protocol for synthesis of C60 is representative for synthesis of the related structures C55, C61, C62, and C63.

[0492] Synthesis of C29

[0493] Synthesis was started with reaction of Cl-trt resin (1 g) and Fmoc-Gly-OH (2 mmol). Loading capacity was not determined in detailed and expected to be 0.8 mmol (1 eq). In the next steps the following amino acids were coupled to yield the linear target peptide: Fmoc-(Pbf)Arg-OH, Fmoc-Pal-OH, Fmoc- NMeK(Ns)-OH, Fmoc-D-Pro-OH, Fmoc-7-N(Boc)- W-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc- (tBu)Asp-OH. Coupling and deprotection cycles were performed as described above in general SPPS section.

[0494] The linear peptide C29-1 was cleaved from resin using HFIP / DCM (tR= 11.49 min, m / z = 1762.25 [M+H]+, 881.36 [M+2H]2+), Fmoc-deprotected and cyclized for 24 h using DPPA and sodium hydrogen carbonate to yield the protected cyclic peptide C29-2 (tR=9.9 min, m / z = 1521.17 [M+H]+, 761.91 [M+2H]2+).

[0495] C29-2

[0496] Finally, the crude mixture was deprotected and purified via preparative HPLC (10-60% B over 45 min) to yield C29 as colorless solid (70 mg, 8%, tR= 6.1 min, m / z = 1112.89 [M+H]+, 557.33 [M+2H]2+).

[0497] Synthesis of C30

[0498] C2 (1 eq, 1 mmol), HATU (5.5 eq, 5.5 mmol) and DIPEA (8 eq, 8 mmol) were dissolved in anhydrous DMSO (20 mL) and preactivated. NH2-PEG8-Alkyne was added to the solution and the reaction was stirred for at least two hours. Afterwards, the reaction was quenched with water and directly purified using preparative HPLC (25-50% B over 45 min). The product fractions were freeze-dried and yielded C30-1 as colorless oil (140 mg, 9%, tR= 6.1 min, m / z = 971.14 [M+2H]2+, 647.72 [M+3H]3+).

[0499] C30-1 (1 eq, 0.09 mmol), PyAOP (6 eq, 0.56 mmol) and DIPEA (10 eq, 0.93 mmol) were dissolved in anhydrous DMSO (3 mL) and preactivated. l-(t-Butyloxycarbonyl-amino)-3,6-dioxa-8-octaneamine (4 eq, 0.37 mmol) was added and the reaction was stirred for at least one hour. Afterwards, the mixture was directly purified using preparative HPLC (25-50% B over 45 min) to yield BOC-C30-2. Subsequently, these product fractions were treated with an excess of TFA and then concentrated in vacuo over 60 min at 60 °C. During this period, the N-BOC deprotection is complete. Final purification step using preparative HPLC was carried out (25-50% B over 45 min) yielding C30-2 as colorless oil (110 mg, 57%, tR= 5.8 min, m / z = 1036.22 [M+2H]2+, 691.06 [M+3H]3+.

[0500] Afterwards, C30-2 (1 eq, 0.05 mmol), HATU (5 eq, 0.25 mmol) and DIPEA (8 eq, 0.4 mmol) were dissolved in anhydrous DMSO (3 mL) and preactivated. 17-(t-Butyloxycarbonyl-amino)-9-aza- 3,6,12,15-tetraoxa-10-on-heptadecanoic acid (3 eq, 0.15 mmol) was added and the reaction was stirred for at least one hour. Afterwards, the mixture was directly purified using preparative HPLC (25-50% B over 45 min) to yield BOC-C30-3. Subsequently, these product fractions were treated with an excess of TFA and then concentrated in vacuo over 60 min at 60 °C. During this period, the N-BOC deprotection is complete. Final purification step using preparative HPLC was carried out (25-50% B over 45 min) yielding C30-3 as colorless oil (42 mg, 33%, tR= 6.3 min, m / z = 1109.72 [M+2H]2+, 739.79 [M+3H]3+.

[0501] C30-3 (1 eq, 0.005 mmol) and C14 (3.5 eq, 0.017 mmol) were dissolved in 1.5 mL tLOZ / BuOH (1 / 2, v / v). Copper acetate (5 eq, 0.025 mmol), sodium ascorbate (60 eq, 0.3 mmol) and THPTA (0.5 eq, 0.0025 mmol) were dissolved in another reaction vessel and preconditioned. The two mixtures were poured together, and the reaction was stopped after 10 min by direct preparative HPLC (10-40% B over 45 min). After the first HPLC purification the product was demetallated from any residual copper by incubation ofNOTA (15 eq, 0.075 mmol) for 1 h at 60 °C at pH 2.4. The crude was finally purified again via preparative HPLC (10-40% B over 45 min) yielding compound C30-4 as colorless solid (0.0012 mmol, 25%, tR= 4.8 min, m / z = 1361.27 [M+4H]4+, 1088.87 [M+5H]5+, 907.44 [M+6H]6+).

[0502] C30-4 (1 eq, 0.0012 mmol) was dissolved in 1 mL DMSO. (4-(4-iodophenyl)butanoyl)glycine NHS ester (1.2 eq, 0.0012 mmol) and DIPEA (4 eq, 0.0048 mmol) were added and reaction was kept for 2 h at room temperature. The crude mixture was directly purified using preparative HPLC (20-50% B over 45 min), yielding target compound C30 as colorless solid (0.0006 mmol, 50%, tR= 5.9 min, m / z = 1443.54 [M+4H]4+, 1154.44 [M+5H]5+, 962.14 [M+6H]6). Synthesis of C40

[0503] Cl (1 eq, 1 mmol), HATU (6 eq, 6 mmol) and DIPEA (8 eq, 8 mmol) were dissolved in anhydrous DMSO (5 mL) and preactivated. Propargyl -PEG4-NH2 (4 eq, 3.2 mmol) was added and the reaction was stirred for at least two hours. Afterwards, the mixture was directly purified using preparative HPLC (10- 60% B over 60 min) to yield C40-1 as colorless oil (510 mg, 42%, tR= 6.4 min, m / z = 1220.12 [M+H]+, 610.76 [M+2H]2+.

[0504] C40-1 (1 eq, 0.004 mmol) and C14 (3.5 eq, 0.016 mmol) were dissolved in 1.5 mL H2O / / B11OH 1 / 2 (V / V). Copper acetate (5 eq, 0.02 mmol), sodium ascorbate (60 eq, 0.24 mmol) and THPTA (0.5 eq, 0.002 mmol) were dissolved in another reaction vessel and preconditioned. The two mixtures were poured together, and the reaction was stopped after 10 min by direct preparative HPLC (10-40% B over 45 min). After the first HPLC purification the product was demetallated from any residual copper by incubation ofNOTA (15 eq, 0.075 mmol) for 1 h at 60 °C at pH 2.4. The crude was finally purified again via preparative HPLC (10-40% B over 45 min) yielding compound C40 as colorless solid (5 mg, 28%, tR= 4.6 min, m / z = 1481.65 [M+3H]3+, 1111.33 [M+4H]4+, 889.16 [M+5H]5+).

[0505] Synthesis of C45

[0506] C45 was synthesized following the same procedure as described for synthesis of C40, with the difference that instead of C40-1, TRAP(alkyne)3 (see Baranyai Z, et al., Dalton Trans., 2015;44: 11137— 11146) was used as substrate. Furthermore, instead of C14, the cyclic peptide C29 was used.

[0507] Synthesis of C54

[0508] C29 (1 eq, 0.014 mmol) and sulfo-Cy5 -alkyne (1 eq, 0.014 mmol) were dissolved in 2 mL of water / tBuOH 1 / 1 (V / V). Copper acetate (5 eq, 0.07 mmol), sodium ascorbate (60 eq, 0.84 mmol) and THPTA (0.5 eq, 0.007 mmol) were premixed in 2 mL of water / tBuOH 1 / 1 (V / V). The catalyst mix was added to the reactants, and the reaction was manually shaken for 10 min at room temperature. The crude was purified via preparative HPLC (10-90% B over 60 min) and compound C54 was obtained as blue solid (10 mg, 42%, tR= 5.3 min, m / z = 1755.47 [M+H]+, 878.03 [M+2H]2).

[0509] Synthesis of C60

[0510] C60-1 was synthesized according to literature known procedure (Zierke MA, et al., EJNMMI Radiopharm Chem. 2024;9:41).

[0511] C60-1

[0512] C29 (1 eq, 0.019 mmol) and C60-1 (1 eq, 0.0055 mmol) were dissolved in 2 mL of watcr / lBiiOH 1 / 1 (V / V). Copper acetate (5 eq, 0.028 mmol), sodium ascorbate (60 eq, 0.33 mmol) and THPTA (0.5 eq, 0.0028 mmol) were premixed in 2 mL of watcr / / BiiOH 1 / 1 (V / V). The catalyst mix was added to the reactants, and the reaction was manually shaken for 10 min at room temperature. The crude was purified via preparative HPLC (20-50% B over 45 min) and the still N-BOC protected compound C60-2 (tR= 5.9 min, m / z = 1837.62 [M+2H]2+, 1224.82 [M+3H]3+, 919.43 [M+4H]4+) was obtained as colorless oil, subsequently deprotected by incubation of TFA excess for one hour to yield C60-3 as colorless solid (10 mg, 53%, tR= 5.5 min, m / z = 1786.92 [M+2H]2+, 1192.01 [M+3H]3+, 894.41 [M+4H]4+).

[0513]

[0514] C60-3 (1 eq, 0.006 mmol), 2,2-Dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-oic TFP ester (3 eq, 0.018 mmol) and DIPEA (10 eq, 0.06 mmol) were dissolved in DMSO and the reaction was stirred for four hours at room temperature. Afterwards, the raw mix was purified using preparative HPLC (25-50% B over 45 min) and the still N-BOC protected compound C60-4 (tR = 6.2 min, m / z = 1910.07 [M+2H]2+, 1273.89 [M+3H]3+, 955.78 [M+4H]4+) was obtained as colorless oil, subsequently deprotected by incubation of TFA excess for one hour to yield C60-5 as colorless solid (4 mg, 19%, tR = 5.8 min, m / z = 1859.74 [M+2H]2+, 1239.99 [M+3H]3+, 930.22 [M+4H]4+).

[0515]

[0516] C60-5 (1 eq, 0.002 mmol), NODAGA-tris-tBu-NHS-ester (1.5 eq, 0.003 mmol), HATU (1.5 eq, 0.003 mmol) and DIPEA (4 eq, 0.008 mmol) were dissolved in DMSO and the reaction was stirred for 10 min at room temperature. Afterwards, the raw mix was purified using preparative HPLC (30-70% B over 45 min) and the still / Bn protected compound C60-6 (tR = 6.9 min, m / z = 1415.82 [M+3H]3+, 1061.53 [M+4H]4+) was obtained as colorless oil, subsequently deprotected by incubation of TFA excess for one hour to yield C60 as colorless solid (2 mg, 25%, tR = 5.8 min, m / z = 1359.44 [M+3H]3+, 1019.42 [M+4H]4+).

[0517] Formulations

[0518] Table 13

[0519] 2. Administration

[0520] The following conjugate compounds of the above table were administered to animals in accordance with the following details:

[0521] Table 14

[0522] Ol: SCID mouse bearing an avP6-integrin expressing subcutaneous xenograft of the human lung adenocarcinoma cell line H2009 (ATCC, CRL-5911) on the left shoulder. 3. Activity testing

[0523] Activity testing was done relying on one or more of the following procedures.

[0524] Integrin affinity testing

[0525] Determination of the avP6-integrin affinities was carried out as decribed in: Kapp TG, Rechenmacher F, Neubauer S, Maltsev OV, Cavalcanti-Adam EA, Zarka R, Reuning U, Notni J, Wester HJ, Mas- Moruno C, Spatz J, Geiger B, Kessler H. A Comprehensive Evaluation of the Activity and Selectivity Profde of Ligands for RGD -binding Integrins. Sci Rep. 2017;7:39805.

[0526] Ex-vivo biodistribution

[0527] Ex-vivo biodistribution, referring to the procedure of dissecting an euthanatized laboratory animal after a given time point after administration, followed by determination of the radioactivity contained in the specimens (typically whole organs or tissue samples) using a radioactivity counter, was performed as described in Stangl S, et al., Eur J Nucl Med Mol Imaging. 2024;51 :3191.

[0528] PET imaging

[0529] PET imaging of laboratory animals, typically mice, was performed as described in Stangl S, et al., Eur J Nucl Med Mol Imaging. 2024;51 :3191.

[0530] Cellular Uptake Assays

[0531] Cellular binding assays were carried out in analogy to a previously reported protocol [Quigley NG, et al., Eur J Nucl Med Mol Imaging. 2022;49: 1136] . The177Lu labeled compound was added to suspensions of 100,000 H2009 (avP6-integrin expressing) or PANCI (avP6-integrin negative, DSMZ, growth medium: DMEM with 10% FBS) cells in a final concentration of 0.3 nM (50 MBq / nmol) in complete culture medium and incubated for 1 h at 37°C. For blockade of avP6-integrin binding, 250 nMnatGa-Trivehexin [Eur J Nucl Med Mol Imaging. 2022;49: 1136] was added in addition to the radioligand. After incubation, cells were separated from the supernatant by centrifugation, washed with buffer, centrifuged off, and the activity contained in the cell pellets determined via a Wizard2gamma counter (PerkinElmer). In the plots, "Control" refers to the experiment without addition of blocking substance, "Blockade" refers to the experiment with addition of blocking agentnatGa-Trivehexin.

[0532] Data processing

[0533] Data were processed and visualized using GraphPad Prism 10.4.0, and statistical calculations and data fitting was done as implemented in this software package. II. Results

[0534] Integrin affinity and selectivity

[0535] Lower IC50 values correspond to a lower concentration of the respective ligand necessary to achieve 50% target binding and hence, to higher activity. Correspondingly, higher IC50 values correspond to a higher concentration of the respective ligand necessary to achieve 50% target binding and hence, to lower activity.

[0536] A high activity for avP6-integrin is considered a benefit in terms of the invention. Hence, IC50 values for avP6-integrin should be as low as possible.

[0537] Herein, the term selectivity refers to the concept of preferential binding to a particular integrin subtype. The activity for other integrin subtypes, such as avP8- and a5 pi -integrin, should be as low as possible in relation to the activity towards avP6-integrin. To achieve this, avP8- and a5pi-integrin affinities of test compounds should not be evaluated in direct relation to the reference compound. Rather, the avP6- integrin selectivity quotients should be compared, which are defined herein as the quotients obtained by division of the IC50 for avP8- or a5pi -integrin, respectively, by the IC50 for avP6-integrin determined for the same compound. A higher selectivity quotient is considered a benefit in terms of the invention.

[0538] In the tables below, affinity and selectivity values that constitute an improvement over prior art are highlighted in bold face.

[0539] Table 15: Integrin activites for cyclic peptides. All IC50 are given in nanomolar (nM).

[0540] Compound ICso [nM] avP6 selectivity quotients avP6 avP8 a5pi avP8 a5pi

[0541] C100

[0542] 0.32 22 62 67 192

[0543] C14

[0544] 0.23 21 389 92 1690

[0545] C15

[0546] 0.18 16 51 89 283

[0547] C16

[0548] 0.38 31 190 81 499 Cl l

[0549] 0.13 2.8 59 21 438

[0550] C29

[0551] 0.07 3.1 46 43 632

[0552] Table 16: Integrin activites for peptide conjugates. The affinities were determined for the Lu111complexes of the listed compounds. All IC50 are given in nanomolar (nM).

[0553] Compound IC50 [nM] av[36 selectivity quotients av[36 av[38 a5[31 av[38 a5[31

[0554] C101

[0555] 0.031 19 15 602 494

[0556] C30

[0557] 0.022 22 259 988 4700

[0558] C31

[0559] 0.018 5 60 292 3380

[0560] C32

[0561] 0.019 27 90 1399 11800

[0562] C33

[0563] 0.016 11 49 703 3100

[0564] C34

[0565] 0.004 1.7 60 430 14800

[0566] Evaluation of177l_u labeled compounds

[0567] Tumor and kidney uptakes of177Lu labeled compounds C101, C30, C31, C32, C33, and C34 were determined 24 h post injection (p.i.) in H2009 tumor bearing mice by ex-vivo biodistribution. Data are shown in Figure 8(A) and (B) as averages ± standard deviation (sample size: n=4). A higher tumor uptake was observed for all tested compounds of the invention (C30, C31, C32, C33, C34) in relation to prior art (Cl 01). Furthermore, said compounds of the invention showed lower kidney uptake in relation to prior art, as shown below. As this invention aims at lower kidney uptakes with, at the same time, similar or even higher tumor uptakes, all tested compounds (C30, C31, C32, C33, C34) are considered superior to the reference (CO 101).

[0568] Tumor-to-kidney ratios, calculated from dividing tumor uptakes by kidney uptakes, were consistently higher for compounds C30, C31, C32, C33, and C34, in relation to C101, as shown in Figure 8(C). Since this invention aims at higher tumor-to-kidney ratios, all tested compounds (C30, C31, C32, C33, C34) are considered superior to the reference CO 101.

[0569] Evaluation of68Ga labeled compounds

[0570] Compounds C40, C41, C42, C43, C44

[0571] PET imaging was performed using approx. 10 MBq of the68Ga labeled compounds Cl 02, C40, C41, C42, C43, and C44, 30 min post injection (p.i.), with a recording time of 15 min. PET images (maximum intensity projections, coronal position) are shown below. T = tumor. K = kidney. Bl = urinary bladder content. Note that the activity accumulation in the urinary bladder may be subject of substantial variation, depending on whether the animal had urinated before the PET scan or not. The PET images are shown in Figure 9(A).

[0572] Region-of-interest (ROI) based quantification data of PET images are shown in Figure 9(B)-(D). ROIs were drawn encompassing the entire organ of choice. Blood uptake was approximated by defining a ROI over the heart content.

[0573] A similar or slightly higher tumor uptake was observed for all tested compounds of the invention in relation to prior art (C 102) . Furthermore, said compounds of the invention showed a lower blood uptake and kidney uptake in relation to prior art. As a consequence, tumor-to-blood ratios and tumor-to-kidney ratios were consistently higher for compounds C40, C41, C42, C43, and C44, in relation to Cl 02, as shown in Figure 9(E) and (F). Since this invention aims at higher tumor-to-blood and higher tumor-to- kidney ratios, all tested compounds (C40, C41, C42, C43, C44) are considered superior to the reference C102.

[0574] Compound C45

[0575] PET imaging was performed using approx. 10 MBq of the68Ga labeled compounds Cl 02 and C45. The same animal was used for imaging with both radiolabeled compounds, with a time period of 24 h between tracer injections. The animal was scanned 3 times after each injection, at time points of 30 min, 90 min, and 180 min post injection (p.i.), each scan with a recording time of 15 min. PET images (maximum intensity projections, coronal position) are shown in Figure 10(A). T = tumor. K = kidney.

[0576] Bl = urinary bladder content

[0577] At all time points, tumor-to-blood ratios and tumor-to-kidney ratios, as shown in Figure 10(B) and (C) respectively, were higher for compound C45 in relation to Cl 02, as shown below. Since this invention aims at higher tumor-to-blood and tumor-to-kidney ratios, the tested compound C45 is considered superior to the reference Cl 02.

[0578] Evaluation of fluorescent conjugates

[0579] Fluorescent conjugates C28, C50, C51, C52, C53, C54, and C55 were incubated for 1 h with avP6- integrin expressing BHY cells grown in 6-well plates at 10 pM concentration. DAPI was used for staining of cell nuclei. Fluorescence microscopy was done applying an excitation wavelength of 647 nM matched to the sulfoCy5 fluorophor comprised in the tested compounds. The fluorescence microscopy images shown in Figure 11 confirm cellular internalization of the test compounds.

[0580] References

[0581] 1. Breuss JM, Gillett N, Lu L, Sheppard D, Pytela R. Restricted distribution of integrin P6 mRNA in primate epithelial tissues. J Histochem Cytochem. 1993 :41 ; 1521— 7.

[0582] 2. Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor P in human disease. N Engl J Med. 2000;34: 1350-8.

[0583] 3. Dong X, Zhao B, lacob RE, Zhu J, Koksal AC, Lu C, et al. Force interacts with macromolecular structure in activation of TGF-p. Nature. 2017;542:55-9.

[0584] 4. Ha T. Growth factor rattled out of its cage. Nature. 2017;542:40-1.

[0585] 5. Brown NF, Marshall JF. Integrin-Mediated TGFp Activation Modulates the Tumour Microenvironment. Cancers. 2019;l 1: 1221.

[0586] 6. Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, et al. A Mutant- p53 / Smad Complex Opposes p63 to Empower TGFp-Induced Metastasis. Cell. 2009;137:87- 98.

[0587] 7. Ahmed S, Bradshaw AD, Geta S, Dewan MZ, Xu R. The TGFp / Smad4 signalling pathway in pancreatic carcinogenesis and its clinical significance. J Clin Med. 2017;6:5-15.

[0588] 8. Worthington JJ, Klementowicz JE, Travis MA. TGFP: a sleeping giant awoken by integrins. Trends Biochem Sci. 2011;36:47-54.

[0589] 9. Koopman Van Aarsen LA, Leone DR, Ho S, Dolinski BM, McCoon PE, LePage DJ, et al. Antibody-Mediated Blockade of Integrin avP6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-P-Regulated Mechanism. Cancer Res. 2008;68:561-70.

[0590] 10. Niu J, Li Z. The roles of integrin avP6 in cancer. Cancer Lett. 2017;403: 128el37. Horan GS, Wood S, Ona V, Li DJ, Lukashev ME, Weinreb PH et al. Partial inhibition of integrin avP6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med. 2008;177:56-65. Steiger K, Schlitter AM, Weichert W, Esposito I, Wester HJ, Notni J. Perspective of avP6- Integrin Imaging for Clinical Management of Pancreatic Carcinoma and Its Precursor Lesions. Mol Imaging. 2017; 16: 1536012117709384. Meecham A, Cutmore LC, Protopapa P, Rigby LG, Marshall JF. Ligand-bound integrin avP6 internalisation and trafficking. Front Cell Dev Biol. 2022 Aug 24; 10:920303. doi: 10.3389 / fcell.2022.920303. Kraft S, Diefenbach B, Mehta R, Jonczyk A, Luckenbach GA, Goodman SL. Definition of an unexpected ligand recognition motif for avP6 integrin. J Biol Chem. 1999;274: 1979-85. Hausner SL, DiCara D. Marik J, Marshall JF, Sutcliffe JF. Use of a peptide derived from foot- and-mouth disease virus for the noninvasive imaging of human cancer: generation and evaluation of 4-[18F]fluorobenzoyl A20FMDV2 for in vivo imaging of integrin avP6 expression with positron emission tomography. Cancer Res. 2007;67:7833-40. Li, S, Mcguire, MJ, Lin M, et al. Synthesis and characterization of a high-affinity avP6-specific ligand for in vitro and in vivo applications. Mol Cancer Ther. 2009;8: 1239-49. Kimura RH, Teed R, Hackel BJ, et al. Pharmacokinetically stabilized cystine knot peptides that bind alpha-v-beta-6 integrin with single-digit nanomolar affinities for detection of pancreatic cancer. Clin Cancer Res. 2012;18:839-49. John AE, Luckett JC, Tatler AL, et al. Preclinical SPECT / CT imaging of avP6 integrins for molecular stratification of idiopathic pulmonary fibrosis. J Nucl Med. 2013;54:2146-52. Liu Z, Liu H, Ma T, et al. Integrin avP6-Targeted SPECT Imaging for Pancreatic Cancer Detection. J Nucl Med. 2014;55:989-94. Zhu X, Li J, Hong Y, et al. 99mTc-labeled cystine knot peptide targeting integrin avP6 for tumor SPECT imaging. Mol Pharm. 2014;11: 1208-17. Hausner SH, Abbey CK, Bold RJ, et al. Targeted in vivo imaging of integrin avP6 with an improved radiotracer and its relevance in a pancreatic tumor model. Cancer Res. 2009;69:5843- 50. Singh AN, McGuire MJ, Li S, et al. Dimerization of a phage-display selected peptide for imaging of avP6- integrin: two approaches to the multivalent effect. Theranostics. 2014;4:745- 60. Hausner SH, Bauer N, Sutcliffe JL. In vitro and in vivo evaluation of the effects of aluminum [18F]fluoride radiolabeling on an integrin avP6-specific peptide. Nucl Med Biol. 2014;41:43- 50. Hausner SH, Bauer N, Hu LY, Knight LM, Sutcliffe JL. The Effect of Bi-Terminal PEGylation of an Integrin avP6-Targeted 18F-Peptide on Pharmacokinetics and Tumor Uptake. J Nucl Med. 2015;56:784-90. Hausner SH, Carpenter RD, Bauer N, Sutcliffe JL. Evaluation of an integrin avP6-specific peptide labeled with [18F]fluorine by copper-free, strain-promoted click chemistry. Nucl Med Biol. 2013;233:233-9. Altmann A, Sauter M, Roesch S, Mier W, Warta R, Debus J, et al. Identification of a Novel ITGavP6-Binding Peptide Using Protein Separation and Phage Display. Clin Cancer Res. 2017;23:4170-80. Roesch S, Lindner T, Sauter M, Loktev A, Flechsig P, Muller M, et al. Comparison of the RGD Motif-Containing avP6 Integrin-Binding Peptides SFLAP3 and SFITGv6 for Diagnostic Application in HNSCC. J Nucl Med. 2018;59: 1679-85. Muller M, Altmann A, Sauter M, Lindner T, Jager D, Rathke H, et al. Preclinical evaluation of peptide-based radiotracers for integrin avP6-positive pancreatic carcinoma. Nuklearmedizin. 2019;58:309-18. Flechsig P, Lindner T, Loktev A, Roesch S, Mier W, Sauter M, et al. PET / CT Imaging of NSCLC with a avP6 Integrin-Targeting Peptide. Mol Imaging Biol. 2019;21 :973-83. Hausner SH, Bold RJ, Cheuy LY, Chew HK, Daly ME, Davis RA, et al. Preclinical Development and First-in-Human Imaging of the Integrin avP6 with [18F]avP6-Binding Peptide in Metastatic Carcinoma. Clin Cancer Res. 2019;25: 1206-15. Kimura RH, Wang L, Shen B, Huo L, Tummers W, Filipp FV, et al. Evaluation of integrin avP6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. Nat Commun. 2019;10,4673. Lukey PT, Coello C, Gunn R, Parker C, Wilson FJ, Saleem A, et al. Clinical quantification of the integrin avP6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study). Eur J Nucl Med Mol Imaging. 2020;47:967-79. Maher TM, Simpson JK, Porter JC, Wilson FJ, Chan R, Eames R, et al. A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled avP6 integrin inhibitor. Respirat Res. 2020;21:75. Meecham A, Marshall J. Harnessing the power of foot-and-mouth-disease virus for targeting integrin alpha-v beta-6 forthe therapy of cancer. Expert Opin Drug Discov. 2021 Jul;16(7):737- 744. doi: 10.1080 / 17460441.2021.1878143. Maltsev OV, Marelli UK, Kapp TG, Di Leva FS, Di Maro S, Nieberler M, Reuning U, Schwaiger M, Novellino E, Marinelli L, Kessler H. Stable Peptides Instead of Stapled Peptides: Highly Potent avP6-Selective Integrin Ligands. Angew Chem Int Ed Engl. 2016 Jan 22;55(4): 1535-9. doi: 10.1002 / anie.201508709 Notni J, Hermann P, Havlickova J, Kotek J, Kublcek V, Plutnar J, Loktionova N, Riss PJ, Rosch F, Lukes I. A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric 68Ga tracers for positron emission tomography. Chemistry. 2010 Jun 25; 16(24): 7174-85. doi: 10.1002 / chem.200903281 Notni J, Reich D, Maltsev OV, Kapp TG, Steiger K, Hoffmann F, Esposito I, Weichert W,

[0591] Kessler H, Wester HJ. In Vivo PET Imaging of the Cancer Integrin avP6 Using 68Ga-Labeled Cyclic RGD Nonapeptides. J Nucl Med. 2017 Apr;58(4):671-677. doi:

[0592] 10.2967 / jnumed.l 16.182824 Farber SF, Wurzer A, Reichart F, Beck R, Kessler H, Wester HJ, Notni J. Therapeutic Radiopharmaceuticals Targeting Integrin avP6. ACS Omega. 2018 Feb 28;3(2):2428-2436. doi: 10.1021 / acsomega.8b00035 Quigley NG, Czech N, Sendt W, Notni J. PET / CT imaging of pancreatic carcinoma targeting the "cancer integrin" avP6. Eur J Nucl Med Mol Imaging. 2021 Nov;48(12):4107-4108. doi: 10.1007 / s00259-021-05443-8 Quigley NG, Steiger K, Hoberiick S, Czech N, Zierke MA, Kossatz S, Pretze M, Richter F, Weichert W, Pox C, Kotzerke J, Notni J. PET / CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" avP6 with Ga-68-Trivehexin. Eur J Nucl Med Mol Imaging. 2022 Mar;49(4): 1136-1147. doi: 10.1007 / s00259-021-05559-x Das SS, Ahlawat S, Thakral P, Malik D, Simecek J, Cb V, Koley M, Gupta J, Sen I. Potential Efficacy of 68Ga-Trivehexin PET / CT and Immunohistochemical Validation of avP6 Integrin Expression in Patients With Head and Neck Squamous Cell Carcinoma and Pancreatic Ductal Adenocarcinoma. Clin Nucl Med. 2024 May 15. doi: 10.1097 / RLU.0000000000005278 Rehm J, Winzer R, Notni J, Hempel S, Distler M, Folprecht G, Kotzerke J. Concomitant metastatic head-and-neck cancer and pancreatic cancer assessed by avP6-integrin PET / CT using 68Ga-Trivehexin: incidental detection of a brain metastasis. Eur J Nucl Med Mol Imaging. 2024 May 21. doi: 10.1007 / s00259-024-06750-6 de Roode KE, Joosten L, Behe M. Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of Radioligands. Pharmaceuticals. 2024:256. doi: 10.3390 / phl7020256 Sabet A, Ezziddin K, Pape UF, Ahmadzadehfar H, Mayer K, Poppel T, Guhlke S, Biersack HJ, Ezziddin S. Long-term hematotoxicity after peptide receptor radionuclide therapy with177Lu- octreotate. J Nucl Med. 2013;54: 1857-61. doi: 10.2967 / jnumed. l 12.119347.

Claims

Claims1. Cyclic peptide, which is characterized by the following sequence 1 : cyclo-(A1-Arg-A2-Asp-A3-A4-A5-D-Pro-A6) (sequence 1), wherein A1,A2,A3,A4,A5,and A6represent amino acids selected from the following lists of meanings:A1: Alanine, Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Tryptophane, Tyrosine, and anon- canonical amino acid.A2: Serine, Glycine, and Threonine,A3: Leucine, Isoleucine, Norleucine, Valine, and Phenylalanine,A4: Glycine, and Alanine,A5: Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Lysine, Tyrosine, Tryptophane, Arginine, and a non-canonical amino acid.A6: Proline, Pro-Rx3, A'-Mc-amino acid such as A'-Mc-Lys. A'-Mc-Lys(Ac). A'-Mc-L s-Rx4, A'-Mc-Lyy. A'-Mc-Lyy-R'4. A-Me-Gln, A'-Mc-GIn-R4. A'-Mc-Gyy. A'-Mc-Gyy-Rx4. and A'-Mc-ALa-Rx4. with the proviso that at least one of the amino acids A1and A5in Sequence l is a non-canonical amino acid, provided that the non-canonical amino acid is not 3-iodo-Tyr; and wherein A'-Mc-Gyy represents an amino acid residue derived from A'-Mc-GIn. but having an alkylene chain of 1, 3, 4, 5, 6, 7, 8, 9 or 10 methylene groups in the sidechain; wherein A'-Mc-Lyy represents an amino acid residue derived from A'-Mc-Lys. but having an alkylene chain of 1, 2, 3, 5, 6, 7, 8, 9 or 10 methylene groups in the sidechain; wherein Rx3is selected from -NH2, -OH, -NH-Ac, -NH-L4-R4; wherein Rx4is a spacer group of the formula -L4-R4, wherein L4 is selected from the group consisting of covalent bond, -C(O)-, -(CH2)n-O-, and -C(O)-O-, with 11 being 1 or 2, and wherein R4 is an alkylene-based group ABG carrying a functional group FG1; and pharmaceutically acceptable salts thereof.

2. The cyclic peptide and pharmaceutically acceptable salts thereof according to claim 1, wherein A2is Glycine, A3is Leucine and A4is Alanine.

3. The cyclic peptide and pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein the cyclic peptide is characterized by formula 10:Formula 10 wherein in Formula 10,XArepresents a group selected from Formula A and Formula B, or represents a functional group chosen such that the resulting amino acid in the cyclopeptide is Alanine, Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Tryptophane, Tyrosine;XBrepresents a group selected from Formula A and Formula B, or represents a functional group chosen such that the resulting amino acid in the cyclopeptide is Leucine, Isoleucine, Norleucine, Valine, Phenylalanine, Lysine, Tyrosine, Tryptophane, or Arginine; with the proviso that at least one of the groups XAand XBis selected from Formula A and Formula B with the following structures:Formula AFormula B wherein in Formula A and Formula B, § denotes the methylene group to which XAor XBis attached, and whereinX1is -C(H)=, and X2, X3, X4, and X5are all -C=, X6, X7, X8, and X9are independently selected from H, -OH, F, Br, and I, wherein at least two of X6, X7, X8, and X9are H, and wherein -C= denotes an aromatic ring carbon atom; and wherein optionally one of X1, X2-X6, X3-X7, X4-X8, and X5-X9is replaced by an aromatic nitrogen atom (~N=);X10represents a group selected from -H, -CH3, and -CH2-COOH;X11, X12, X13, and X14are collectively selected such that they adopt one of the configurations listed in the following Table, wherein -C(H)= denotes an aromatic ring carbon atom with a hydrogen, -C= denotes an aromatic ring carbon atom without a hydrogen, and -N= denotes an aromatic ring nitrogen atom:whereinXcin Formula 10 represents a functional group which is chosen such that the resulting amino acid in the cyclopeptide is Proline, Pro-Rx3, A'-Mc-amino acid such as A'-Mc-Lys. A'-Mc-Lys(Ac). A'-Mc-Lys-Rx4, A'-Mc-Lyy. X-Me-Lyy-Rx4, X-Me-Gln, A'-Mc-GIn-R4. X-Mc-Gyy. X-Mc-Gyy-Rx4. X-Mc-Ala-Rx4. wherein Rx3and Rx4are as specified in claim 1.

4. The cyclic peptide and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, wherein at least one of the groups XAand XBis selected such that the resulting amino acid is characterized by a structure selected from the following group consisting of Formulae (la) to (Ik) and (2a) to (2d):wherein * denotes the point of attachment of the N-terminal adjacent amino acid via a peptide bond and # denotes the point of attachment of the C-terminal adjacent amino acid via a peptide bond, and wherein, optionally, at least one of the groups XAand XBis in one embodiment selected such that the resulting amino acid is characterized by a structure selected from the following group consisting of Formulae (la) to (Id), (2a) to (2d), wherein the meanings of * and # are as specified above.

5. The cyclic peptide and pharmaceutically acceptable salts thereof according to claims 3 or 4, wherein Xcin Formula 10 represents a functional group such that the resulting amino acid is characterized by a structure '-Mc-Lys or A'-Mc-Ala-Rx4. wherein Rx4is represented by the formula -L4-R4, wherein L4 is a covalent bond, and wherein R4 is an alkylene based group carrying a functional group, which R4 is selected from the group consisting of-(CH2)n-C=CH and -(CFFjn-Ns with n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein R4 is preferably an alkylene based group carrying a functional group -(CFFjn-Ns with n = 2, 3, or 4, more preferably R4 is -(CFFjn-Ns with n = 3.

6. The cyclic peptide and pharmaceutically acceptable salts thereof according to any one of claims 1 to5, wherein the peptide is selected from the group consisting ofwherein Xchas the same meaning as specified in claim 3 or claim 5.

7. The cyclic peptide and pharmaceutically acceptable salts thereof according to any one of claims 1 to6, wherein the peptide is selected from the group consisting of8. A conjugate compound of the following Formula I:E((L)q-Cp)n*(OS)os(I)wherein each Cp represents a cyclopeptide according to any one of claims 1 to 7, L represents alinker, q is 0 or 1, n* is an integer selected from 1 to 6, and E represents an effector moiety, OSrepresents an optional substituent, os is an integer selected from 0 to 5, wherein n* and os are selectedsuch that n*+os=6 or less, or a pharmaceutically acceptable salt thereof.

9. The conjugate of claim 8, which is characterized by one of the following formulae (Ia), (Ia’), (Ia”), (Ia’’’), (Ia*), (Ia**), (Ib), (Ib’), (Ib”), (Ib*), (Ic), (Ic’), (Ic”), (Ic*), (Id), (Ie) and (If): Aa(Cg)((L)qCp)n*(Ia) Aa’(Cg)((L)qCp)n* (Ia’) (Cg)((L)qCp)n* (Ia”) (Cg)((L)qCp)n*Ss (Ia’’’) Aa(Cg)((L)qCp)n*Ss (Ia*) Aa’(Cg)((L)qCp)n*Ss (Ia**)Aa(Cg)((L)qCp)n’(LAa’) (Ib)(Cg)((L)qCp)n’(LAa’) (Ib’)(Cg)((L)qCp)n’(LAa’)Ss’(Ib”) Aa(Cg)((L)qCp)n’(LAa’)Ss’ (Ib*) Aa’(Cm)((L)qCp)n* (Ic) (Cm)((L)qCp)n* (Ic’) (Cm)((L)qCp)n*Ss(Ic”) Aa’(Cm)((L)qCp)n*Ss(Ic*) (Cm)((L)qCp)n*(L(Aa’)p’(Cp)m)o(Id) (Cm)((L)qCp)(n*-1)(LCp(Aa’)p’)o’ (Ie) Cp((L)qAa’)p’(If) 150wherein Aa represents an atom or atomic group that is capable of being bonded via chelation,Aa’ represents an active atom or active atomic group that is capable of being bonded via covalent bonding,Cp represents a cyclopeptide according to any one of claims 1 to 7,Cg represents a chelating group,Cm represents a central moiety,L represents a linker,S represents a spacer, m is 0 or 1, n* is an integer selected from 1 to 6, n’ is an integer selected from 1 to 5 and preferably 1, 2 or 3, o is an integer selected from 1 to 5, o’ is an integer selected from 1 to 6, p’ is 1 or 2, q is 0 or 1, s is an integer selected from 1 to 5, wherein n* and s are selected such that n*+s = 6 or less, s’ is an integer selected from 1 to 4, wherein n’ and s’ selected such that n’+s’+l = 6 or less, or a pharmaceutically acceptable salt thereof.

10. The conjugate of claim 8 or 9, wherein the conjugate is characterized by one of the following formulae (laa), (laa’), (Ibb), (Ibb’), (Ibb”), (Ibb’”), (Icc), (Icc’), (Idd), (Idd’), (lee), (lee’), (Iff), (lai), (lai ’), (Ibl), (Ibl’), (Ib2), (Ib2’), (Ifl) and (Ifl’):Pm(Cg)((L)qCp)n* (laa)Aa(Cg)((L)qCp)n ((L)qPm) (Ibb)(Cg)((L)qCp)n ((L)qPm) (Ibb')Pm(Cm)((L)qCp)n*(Icc) (Cm)((L)qCp)n*(L(Aa’)p’(Cp)m)o1(L(Pm)p’(Cp)m)o2(Idd) (Cm)((L)qCp)(n*-1)((L(Cp)m)(Aa’)p1(Pm)p2)o’ (Iee) Cp(Aa’)p1((L)qPm)p2 (Iff) Pm(Cg)((L)qCp)n*Ss (Iaa’) Aa(Cg)((L)qCp)n’((L)qPm)Ss (Ibb”) (Cg)((L)qCp)n’((L)qPm)Ss(Ibb’’’) Pm(Cm)((L)qCp)n*Ss(Icc’) (Cm)((L)qCp)n*(L(Aa’)p’(Cp)m)o1(L(Pm)p’(Cp)m)o2Ss (Idd’) (Cm)((L)qCp)(n*-1)((L(Cp)m)(Aa’)p1(Pm)p2)o’Ss (Iee’) Aa(Cg)(LCp)3 (Ia1) (Cg)(LCp)3 (Ia1’) (Cg)(LCp)4 (Ia1’’) Aa(Cg)((L)qCp)n’((L)qAa’)n”(Ib1) (Cg)((L)qCp)n’((L)qAa’)n”(Ib1’) Aa(Cg)(LCp)n’(LAa’)n”(Ib2) (Cg)(LCp)n’(LAa’)n” (Ib2’)Cp(Aa’) (If1)Cp(Pm) (If1’)wherein Pm represents a pharmacokinetic modifier, Aa, Aa’, L, Cg, Cp, Cm, m, n*, n’, o, o’, p’ and q are as specified in claim 8 or 9, o1 and o2 are selected such that o2 is at least 1 and o1+o2=o, and p1 and p2 are selected such that p2 is at least 1 and p1+p2=p’; 152in formula (lai) and (Tai ’) Cg is preferably a trivalent chelating group, preferably at least one of the linkers L contains a PEG group with 3 to 10 repeating units, more preferably 4 to 8 repeating units, preferably, the cyclopeptide Cp is of Formula 10 and / or the chelating group Cg is a TRAP group; in formula (lb 1) and (lb 1 ’) Cg is preferably a trivalent or tetravalent chelating group, wherein, if Cg is trivalent, n’ is 2 or 3 and n” is 0 or 1, such that n’+n”=3 or less, preferably q is 1, n’ is 2 and n” is 1, Cp is a cyclopeptide of Formula 10 and / or the chelating group Cg is a TRAP group; if Cg in formula (lb 1) and (Ibl ’) is tetravalent, n’ is 1 to 4 and n” is 0 to 3, such that n’+n”=4 or less, preferably Cp is a cyclopeptide of Formula 10, q is 1, n’ is 3 and n” is 1; more preferably Cg is DOTPI, q is 1, at least one L and preferably each L contains PEG groups of a length of 3 to 10, preferably 4 to 8 repeating units, n’ is 3 and n” is 1; in formula (Ib2) and (Ib2 ’), Cg is preferably a tetravelant chelating group, n’ is 2 or 3 and n” is 1 or 2 such that n’+n”=4 or less, each of the linkers L carrying the cyclopeptides Cp contains a polyethylene glycol PEG with 3 to 10, preferably 4 to 8, repeating units, and the linker L carrying Aa’ is a cleavable or non-cleavable linker, preferably also containing a PEG with 3 to 10, more preferably 4 to 8, repeating units; in formula (Ifl), preferably the cyclopeptide is a cyclopeptide of Formula 10 and / or the active atom or atomic group Aa’ is a cytostatic agent or a siRNA, or a fluorophore; in formula (Ifl ’), preferably the cyclopeptide is a cyclopeptide of Formula 10; in formulae (laa’) and (Icc’), n* and s are selected such that n*+s = 6 or less, preferably n*+s = 3 or 4; in formulae (Ibb”) and (Ibb’”), n’ and s are selected such that n’+s = 5 or less, preferably n’+s = 2 or 3; and in formula (Idd’), n*, ol, o2 and s are selected such that n*+ol+o2+s = 6 or less, preferably n*+ol+o2+s = 3 or 4; and in formula (lee’), n*, o’ and s are selected such that n*+o’+s = 7 or less, preferably n*+o’+s = 4 or 5; or a pharmaceutically acceptable salt thereof.

11. The conjugate of claim 8, 9 or 10, wherein Aa is represented by a metal ion selected from La3+,Al3+, Cr' . Cu2+, Zn2+, Th3+, and mixtures thereof, preferably a metal ion selected from the group consisting of Ga3+, Gd3+, Cu2+, Sc3+, Y3+, and Lu3+and mixtures thereof, or wherein Aa is aradioisotope selected from43Sc,44Sc,46Sc,47Sc,55Co, "mTc,203Pb,66Ga,67Ga,68Ga,72As, ”’ln,113mIn,114mIn,97Ru,62Zn,61Cu,62Cu,64Cu,52Fe,52mMn,51Cr,186Re,188Re,77As,86Y,90Y,67Cu,169Er,117mSn,121Sn,127Te,134Ce,142Pr,143Pr,198Au,199Au,149Tb,152Tb,155Tb,161Tb,109Pd,165Dy,149Pm,151Pm,153Sm,157Gd,166HO,172Tm,169Yb,175Yb,177Lu,105Rh, ”’Ag,88Zr,89Zr,212Pb,212Bi,213Bi,225Ac,227Th and mixtures thereof, preferably8Ga,44Sc, "mTc,11’in,64Cu,89Zr,90Y,177Lu,212Pb,225Ac, and mixtures thereof or wherein Aa is an atomic group of the formula [18FM](ch l)+, wherein M is a nonradioactive metal selected from the elements of the groups 2, 3, 4, and 13 of the periodic system, and from lanthanides, preferably selected from Ca2+, Sc3+, Y3+, Ti4+, Zr4+, Ga3+, and Al3+, most preferably [18FA1]2+, with ch representing the charge of M.

12. The conjugate of claim 8, 9 or 10, wherein Aa’ is represented by(i) a non-metal radioisotope which is selected from ”C,13N,150,18F,1231,1241,1251,131I, or211At, preferably18F or211At; or(ii) a chromophore of a fluorescence or non-fluorescent dye; or(iii) a contrast agent for magnetic resonance imaging (MRI); or(iv) an atom or atomic group suitable for enhancement of imaging by X-ray based technology such as iodine or an iodine -containing atomic group; or(v) an agent suitable for ribonucleic acid (RNA) interference (RNAi) such as a siRNA molecule; or(vi) a therapeutic agent such as an anti-cancer agent selected from alkylating agents, anti-metabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors and other anti-tumor drugs. More specifically, the following can be mentioned: platinum based compounds, antibiotics with anti-cancer activity, anthracyclines, anthracenediones, alkylating agents, antimetabolites, Antimitotic agents, taxanes, taxoids, microtubule inhibitors, Vinca alkaloids, folate antagonists, topoisomerase I inhibitors (Topi inhibitors), topoisomerase II inhibitors (TopIl inhibitors), etoposide, etoposide phosphate and teniposide, antiestrogens, antiandrogens, aromatase inhibitors, GnRh analogs, inhibitors of 5 a- reductase, bisphosphonates, a metabolic inhibitor, preferably a mTOR inhibitor; an epigenetic inhibitor, preferably a DNMT inhibitor; an anthracy cline antibiotic; a camptothecan; an anthracy cline; histone deacetylase (HDAC) inhibitors, proteasome inhibitors, JAK2 inhibitors, tyrosine kinase inhibitors (TKIs), PI3K inhibitors, Protein kinase inhibitors, Inhibitors of serine / threonine kinases, inhibitors of intracellular signaling, inhibitors of Ras / Raf signaling, MEK inhibitors, AKT inhibitors, inhibitors of survival signaling proteins, cyclin dependent kinase inhibitors, therapeutic monoclonal antibodies, TRAIL pathway agonists, anti-angiogenic agents, metalloproteinase inhibitors, cathepsin inhibitors, inhibitors of urokinase plasminogen activator receptor function, immunoconjugates, antibody drug conjugates, antibody fragments, bispecfic antibodies, bispecific T cell engagers (BiTEs). Said anticancer drug is preferably selected from the group consisting of 5 -fluorouracil, cisplatin, irinotecan, hydrochloride, epirubicin, paclitaxel, docetaxel, camptothecin, exatecan, deruxtecan, doxorubicin, rapamycin, 5 -azacytidine, doxorubicin, the primary active metabolite of irinotecan SN-38, govitecan, topotecan, amsacrin, UFT, capecitabine, CPT-II, oxaliplatin,cyclophosphamide, methotrexate, aminopterin, permetrexed, navelbine, epirubicin, mitoxantrone, raloxifen, mitomycin, carboplatinum, gemcitabine, etoposide, topotecan, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), vedotin, mertansine (DM1), emtansine, soravtansine, calicheamicins, ozogamicin, maytansinoides, maytansin, a-amanitin, mafotodin, exotoxin a, pasudotox, pyrrolobenzodiazepines, tesirine, sarotalocan, siRNA therapeutics, such as patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, fitusiran, QPI-1002, olpasiran, ARO-APOC3, Tivansiran, MIR19, revusiran, fazirsiran, cemdisiran, thapsigargin, or an agent for treating fibrosis.

13. The conjugate of any one of claims 8 to 12, wherein L is represented by a group selected from the following formulae (III) to (Illg”):*-L4-(ABG)-(CFG)r(ABG)- (III)*-C(O)-(ABG)-(CFG)r(ABG)- (Illa)*-C(O)-(CH2)k-(CFG)r(CH2)k- (Ilf)*-C(O)-(CH2)k-(taz)r(CH2)k- (III")*-C(O)-(ABG)-(CFG)r(ABG)-(CFG)r(ABG)- (Illa)*-C(O)-(CH2)k-(CFG)r(CH2)k-(CFG)r(CH2)k- (Illa')*-C(O)-(CH2)k-(taz)r(CH2)k-(CFG)r(CH2)k- (Illa")*-C(O)-(ABG)-NH-CO-(ABG)- (lllb)*-C(O)-(CH2)k-NH-CO-(CH2)k- (lllb')*-C(O)-(ABG)-CO-NH-(ABG)- (lllc)*-C(O)-(CH2)k-CO-NH-(CH2)k- (lllc')*-C(O)-(ABG)-(CFG)r(ABG)-CO-NH-(ABG)- (Hid)*-C(O)-(CH2)k-(CFG)i-(CH2)k-CO-NH-(CH2)i<- (Hid')*-C(O)-(CH2)k-(taz)r(CH2)k-CO-NH-(CH2)k- (Hid")*-C(O)-(ABG)-(CFG)r(ABG)-NH-CO-(ABG)- (Hie)*-C(O)-(CH2)k-(CFG)i-(CH2)k-NH-CO-(CH2)k- (Hie')*-C(O)-(CH2)k-(taz)r(CH2)k-NH-CO-(CH2)k- (Hie")*-C(O)-(ABG)k-CO-NH-(ABG)-(CFG)i-(ABG)k- (lllf)*-C(O)-(CH2)k-CO-NH-(CH2)k-(CFG)i-(CH2)i<- (lllf')*-C(O)-(CH2)k-CO-NH-(CH2)k-(taz)r(CH2)k- (lllf")*-C(O)-(ABG)-NH-CO-(ABG)-(CFG)r(ABG) - (Illg)*-C(O)-(CH2)k-NH-CO-(CH2)k-(CFG)i-(CH2)i<- (Illg')*-C(O)-(CH2)k-NH-CO-(CH2)k-(taz)r(CH2)k- (Illg") wherein taz represents a triazole ring with all three nitrogen atoms being adjacent to each other, 1 may be 0 or 1, each ABG represents a group independently selected from (CH2)k, -(CH2)pr-(O-CH2CH2)p- and -(CH2CH2-O)p-(CH2)pr- with k being an integer independently selected from 0 to 20, preferably 1 to 10, p being an integer independently selected from 1 to 20, preferably 3 to 10, more preferably 4 to 8, and pl’ being independently selected from 0, 1 or 2, wherein, if one or both of (CH2)k, -(CH2)PI - (O-CH2CH2)P- and -(CH2CH2-O)P-(CH2)PI - is present, L may have any of the configurations (III’- PEG1) to (IIIg”-PEG26) as specified in the description ; the asterisk (*) marks the point of attachment of the cyclopeptide.

14. The conjugate of any one of claims 8 to 13, wherein the cyclopeptide is a cyclopeptide of Formula 10 as specified in any of claims 3 to 7, wherein Xc-L is selected such that the resulting amino acid in the cyclopeptide with the adjacent linker L has the following structure:wherein * denotes the point of attachment of the N-terminal adjacent amino acid via a peptide bond and # denotes the point of attachment of the C-terminal adjacent amino acid via a peptide bond, and ABG is a group as specified in claim 13, and wherein the linker L may optionally contain further groups bonded to ABG.

15. The conjugate of any one of claims 8 to 14, wherein Cm is represented by an atomic group having 1 to 30 atoms selected from C, N, O, S and P, the remaining valences being saturated by hydrogen;wherein the Cm group is typically selected from aromatic groups such as phenyl, naphthyl, or Cm is derived from larger condensed aromatic groups containing 3 or 4 6-membered rings such as anthracene, phenanthrene, benzpyrene, etc.; or Cm is selected from non-aromatic cyclic groups including C5-7 carbocycles such as cyclopentane, cyclohexane, cycloheptane, condensed groups containing 2, 3 or 4 rings, each consisting of 5 to 7 ring members such as fully or partially hydrogenated forms of naphthalene, anthracene, phenanthrene, benzpyrene, or Cm is selected from bi- or tricyclic groups having 7 to 10 carbon atoms such as norbomene or adamantane, or Cm is selected from heterocyclic groups containing 1, 2, 3 or 4 condensed rings each having a ring size independently selected from 5, 6 or 7 ring members, which may be aromatic, partially or fully saturated and combinations thereof in case of condensed rings; or Cm is a single atom selected from C, N and P.

16. The conjugate of any one of claims 8 to 15, wherein the conjugate consists of or contains a structure characterized by one of the following formulas:or a pharmaceutically acceptable salt thereof.

17. Pharmaceutical composition comprising an agent selected from the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, together with one or more excipients.

18. Kit comprising an agent selected from the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, in a container.

19. The kit according to claim 18, wherein a radionuclide-free conjugate of any of claims 8 to 16, serving as a radiolabeling precursor compound, or pharmaceutically acceptable salt thereof is provided in one container and a radionuclide or atomic group comprising a radionuclide is provided in a separate container.

20. The cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, , the pharmaceutical composition according to claim 17, or the kit according to claim 18 or 19 for use in the treatment, imaging or diagnosis of a disease, wherein the disease is associated with increased expression level of avP6-integrin, preferably selected from cancer and fibrosis.

21. An article selected from(a) microbeads containing or carrying at their surface the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16;(b) nanocarriers containing or carrying at their surface the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16; and(c) medical devices coated with the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16.

22. Synthetic intermediate characterized by a structure or sequence selected from the following sequences and structures:HO-Gly-Arg(Pbf)-DOPA(ac2)-( 'Mc)-azidolysinc-D-Pro-DOPA(ac2)-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-I)-Pro-4-Pal-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-I)-Pro-7-AW-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-4-Pal-(AMc)Lys(Boc)-I)-Pro-7-AW(Boc)-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-7-AW-Ala-Lcii-Asp( / Bu)-FmocHO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-7-AW(Boc)-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-Tyr( / Bii)-(AMc)-azidolysinc-d-Pro-7-AW-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-Tyr( / Bii)-(AMc)-azidolysinc-d-Pro-7-AW(Boc)-Ala-Lcii-Asp( / Bii)-FmocHO-Gly-Arg(Pbf)-Phc-(AMc)-azidolysinc-D-Pro-4-Pal-Ala-Lcii-Asp( / Bu)-FmocHO-Gly-Arg(Pbf)-4-Pal-(AMc)-azidolysinc-D-Pro-Trp(Boc)-Ala-Lcii-Asp( / Bii)-FmocHO-Gly–Arg(Pbf)–DOPA(ac2)–(NMe)-azidolysine–D-Pro–DOPA(ac2)–Ala–Leu–Asp(tBu)-NH2 HO-Gly–Arg(Pbf)–4-Pal–(NMe)Lys(Boc)–D-Pro–4-Pal–Ala–Leu–Asp(tBu)-NH2 HO-Gly–Arg(Pbf)–4-Pal–(NMe)Lys(Boc)–D-Pro–7-AW–Ala–Leu–Asp(tBu)-NH2HO-Gly–Arg(Pbf)–4-Pal–(NMe)Lys(Boc)–D-Pro–7-AW(Boc)–Ala–Leu–Asp(tBu)-NH2HO-Gly–Arg(Pbf)–4-Pal–(NMe)-azidolysine–D-Pro–7-AW–Ala–Leu–Asp(tBu)-NH2 HO-Gly–Arg(Pbf)–4-Pal–(NMe)-azidolysine–D-Pro–7-AW(Boc)–Ala–Leu–Asp(tBu)-NH2HO-Gly–Arg(Pbf)–Tyr(tBu)–(NMe)-azidolysine–D-Pro–7-AW–Ala–Leu–Asp(tBu)-NH2HO-Gly–Arg(Pbf)–Tyr(tBu)–(NMe)-azidolysine–D-Pro–7-AW(Boc)–Ala–Leu–Asp(tBu)-NH2 HO-Gly–Arg(Pbf)–Phe–(NMe)-azidolysine–D-Pro–4-Pal–Ala–Leu–Asp(tBu)-NH2HO-Gly–Arg(Pbf)–4-Pal–(NMe)-azidolysine–D-Pro–Trp(Boc)–Ala–Leu–Asp(tBu)-NH21764-Pal has the meaning 4-pyridylalanine, 7 -AW has the meaning 7-aza-tryptophane, and D0PA(ac2) has the meaning l-DOPA-(acetonide), Pbf means 2,2,4,6,7-pentamethyldihydrobenzofuran-5 -sulfonyl group (Pbf) and Boe means tert-butyloxy carbonyl group.

23. Method of treating or diagnosing a disease, wherein the disease is associated with increased expression level of avP6-integrin, preferably selected from cancer and fibrosis, in a patient in need thereof, which comprises administering the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, the pharmaceutical composition according to claim 17, or the kit according to claim 18 or 19 to the patient.

24. Method of treating or diagnosing a disease according to claim 23, wherein the disease is selected from pancreatic adenocarcinoma, head-and-neck cancers, tonsillar carcinoma, urothelial carcinoma, esophageal squamous cell carcinoma, cervical carcinoma (i.e. related to the cervix uteri), endometrial carcinoma, breast cancer, triple-negative breast carcinoma, non-small cell lung cancer, gastric cancer, colorectal cancer, renal cancer, prostate cancer, thyroid cancer, testicular cancer, hepatocellular carcinoma, cholangiocellular carcinoma, or salivary gland adenoma.\T125. Method of diagnosing a disease according to claim 23, wherein the disease is hyperparathyroidism, preferably when associated with parathyroid gland adenoma.

26. Use of the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, the pharmaceutical composition according to claim 17, or the kit according to claim 18 or 19 for imaging, wherein the imaging modality is selected from positron emission tomography (PET), singlephoton emission computed tomography (SPECT), planar scintigraphy, X-ray imaging, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), multi -spectral opto-acoustic tomography (MSOT), fluorescence imaging, cherenkov imaging, autoradiography, or any combination of two or more of these methods, preferably PET / CT, PET / MRI, or SPECT / CT.

27. Use according to claim 26, wherein the imaging modality is PET / CT or PET / MRI.

28. Use of the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, the pharmaceutical composition according to claim 17, the kit according to claim 18 or 19 or the article of claim 21, for targeted therapy, wherein the therapeutic modality is selected from radioligand therapy, radionuclide therapy, radioembolization, targeted delivery, or photodynamic therapy.

29. Use of the cyclic peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, the conjugate or pharmaceutically acceptable salt thereof according to any one of claims 8 to 16, the pharmaceutical composition according to claim 17, the kit according to claim 18 or 19 or the article of claim 21, for fluorescence-guided surgery, radioguided surgery, a combination of fluorescence- and radioguided surgery, also in combination with robotic systems for surgery (surgery robots).

Images