Modified GRPR antagonist peptides for cancer imaging and therapy

Abstract

The present invention relates to a compound that binds to an endogenous receptor, comprising: (i) an oligopeptide comprising a dipeptide, wherein Trp is the C-terminal amino acid of the dipeptide, wherein Trp is replaced with an alpha amino acid, Xaa2, thereby increasing the stability in serum or plasma of the peptide bond connecting Xaa2 and the N-terminal adjacent amino acid compared to the peptide bond connecting Trp and the N-terminal adjacent amino acid in an otherwise identical compound; and (ii) a moiety capable of generating therapeutically effective radiation, covalently attached to the oligopeptide.

Description

[Technical field]

[0001] Prostate cancer (PCa), one of the most common malignant diseases in men in the West, remains a medical challenge due to poor survival rates at advanced stages. It has been shown that the earlier the diagnosis, the higher the success rate of treatment, and new therapeutic approaches are needed. In the last decades, there has been an increasing interest in cancer diagnosis and treatment by nuclear medicine, based on radioactive tracers that accumulate at high speed almost exclusively at the tumor site.

[0002] Prostate-specific membrane antigen (PSMA) tracers are often used for internal radiotherapy and imaging of PCa because of their excellent properties, such as overexpression in prostate cancer and low expression in healthy tissues, rapid clearance rate, and high incidence (92% of all prostate cancers). However, PSMA has the disadvantages of being easily taken up by the kidneys and salivary glands, and low expression in the early stages of the disease.

[0003] As an interesting alternative, the gastrin releasing peptide receptor (GRPR) also shows good expression in PCa (up to 100% in early stages and 60% in late stages), is overexpressed in malignant tissues, and shows high expression in only one healthy tissue (pancreas). This gives it an advantage compared to PSMA in the case of renal metastases, where it cannot be adequately detected using PSMA tracer due to high renal uptake. Furthermore, damage to the salivary glands and kidneys due to high accumulation of PSMA tracer seems to be a concern in treatment with high doses.

[0004] It has been found that GRPR shows high expression in early stages of PCa, whereas PSMA overexpression is more commonly observed in later stages of the disease. Moreover, GRPR overexpression is also found in breast cancers rich in estrogen receptors (ER), allowing the use of the same tracer for different cancers and genders. Therefore, GRPR tracers are a useful tool for the replacement of patients with low PSMA expression and for the diagnosis of metastases in the kidney area. Also, incidental treatment of prostate cancer (early stage) would benefit from the use of GRPR tracers instead of PSMA tracers due to their high incidence and fewer side effects (salivary gland damage). Moreover, since GRPR is overexpressed in prostate and breast cancers, GRPR antagonists may be used regardless of gender.

[0005] To date, both agonists and antagonists of GRPR have been and are still being used in clinical settings. The development of antagonists is underway, as agonists exhibit painful side effects after application to patients, while antagonists have poor pharmacokinetics due to significantly slower washout from non-tumor tissues. There are obviously fewer GRPR derivatives in clinical use compared to PSMA ligands. However, because only 92% of all PCa tumors express PSMA, and GRPR is also overexpressed in approximately 85% of all estrogen receptor (ER)-rich breast cancers, it is likely that they may offer clinical benefits.

[0006] The general structure of a GRPR antagonist molecule includes a binding unit based on the C-terminal part of natural bombesin or gastrin releasing peptide (GRP) with sub-nanomolar affinity. A linker between the pharmacological moiety and the N-terminal chelator is not necessarily required, as there are tracers that show good performance even without the linker unit, but there are many reports showing beneficial effects in terms of pharmacokinetics.

[0007] Among the GRPR antagonists, the derivative RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2) is the most commonly used agent for selective GRPR imaging and therapy. It is 68 Ga(88.9%β + , E β+,max = 1.89 MeV, t 1 / 2 = 68 minutes) for internal radiation therapy 177 Lu(78.6%β - , E β,max =0.498MeV, t 1 / 2 = 6.7 days) and is currently considered the gold standard for GRPR antagonists, as it can be applied to PCa and ER-rich breast cancer.

[0008] 68 Ga-RM2, 177 Both Lu-RM2 and Lu-RM3 show favorable pharmacokinetics in humans, with high accumulation in tumors, rapid clearance from non-tumor tissues, and long retention in tumors, resulting in high contrast and good therapeutic effects, respectively.

[0009] Nevertheless, certain bombesin analogs are metabolically unstable in animals, limiting their necessary accumulation in tumor tissue.

[0010] On the other hand, it must be mentioned that more stable GRPR derivatives have a slower washout from the GRPR-rich pancreas and the potential for pancreatitis must be considered before their use in human therapy.

[0011] In other malignant indications, many more markers and targets have emerged, including the neuromedin B receptor (bombesin 1 receptor, NMBR), bombesin receptor subtype 3 (BRS-3) and cholecystokinin 2 receptor (CCK-2R). Summary of the Invention [Problem to be solved by the invention]

[0012] It is therefore believed that the technical problem underlying the present invention is to provide improved radiopharmaceuticals and radiodiagnostic agents, including improved pharmacokinetic properties, in particular in the field of cancer.

[0013] This technical problem is solved by the problem disclosed below. [Means for solving the problem]

[0014] In a first aspect, the present invention provides a compound that binds to an endogenous receptor, comprising: (i) an oligopeptide comprising a dipeptide, wherein Trp is the C-terminal amino acid of said dipeptide, said Trp being the α-amino acid Xaa 2 This results in Xaa 2 and (ii) a moiety capable of generating therapeutically effective radiation, said moiety being covalently attached to said oligopeptide, wherein the stability in serum or plasma (preferably mammalian serum or plasma) of the peptide bond linking Trp to the N-terminal adjacent amino acid is increased compared to the peptide bond in an otherwise identical compound linking Trp to the N-terminal adjacent amino acid.

[0015] A receptor is a molecule capable of specifically binding its cognate ligand. The term "cognate ligand" designates a genus of molecules and includes natural ligands and the compounds of the present invention. A receptor is preferably a polypeptide or protein. It may comprise multiple subunits that may be non-covalently or covalently linked to each other. Preferably, said receptor is a transmembrane or membrane-bound protein. Preferably, the ligand binding site is located outside the cell.

[0016] The term "endogenous" refers to the occurrence of the receptor in a human or animal body, an animal, including a mammal, including a rodent. Preferred receptors are the subject of preferred embodiments disclosed further below.

[0017] The compound of the first embodiment comprises or consists of two parts. The first part is a targeting part. It comprises or consists of the oligopeptide disclosed above. The second part is a part that conveys the intended therapeutic effect, which in the case of the compound according to the first embodiment is radiation. Thus, it is understood that the treatment includes the destruction of the target tissue, since the target tissue is generally or comprises hyperproliferative tissue, such as malignant tissue.

[0018] As will become more apparent below, in other embodiments of the invention, the second portion serves diagnostic purposes.

[0019] In its broadest definition, the second moiety is not particularly limited other than that it must be capable of generating therapeutically effective radiation. In accordance with the present invention, this ability is conveyed by a radionuclide. Such a radionuclide may be present in the compound or, alternatively, the compound may comprise a moiety, which in turn is capable of carrying a radionuclide.

[0020] The term "oligopeptide" has its technically established meaning. It is a linear sequence of amino acids linked together by backbone peptide bonds. In terms of length, 5 to 20 amino acids are preferred. This includes oligopeptides having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 amino acids. Preferred are 6, 7, 8, 9 or 10 amino acids. Particularly preferred are 9 or 10 amino acids, most preferred are 9 amino acids. The term "oligopeptide" implies peptidicity, but the term also encompasses compounds that are not exclusively predominantly peptidic in nature. Preferably, assuming that said oligopeptide has N amino acids, at least (N-1) / 2 bonds linking said amino acids are peptide bonds. For example, N-1, N-2 or N-3 bonds linking said amino acids are peptide bonds.

[0021] Similar considerations apply mutatis mutandis to the building blocks of an oligopeptide, i.e. at least N / 2 building blocks are amino acids, e.g. N, N-1, N-2 or N-3 building blocks are amino acids.

[0022] The term "amino acid" designates a molecule having a carboxyl group and an amino group. Preferred amino acids are α-amino acids, including proteinogenic amino acids, although other amino acids such as β-, γ- or δ-amino acids may also be used. In particular, in the C-terminal region of the molecule, γ-amino acids may be employed, see further preferred embodiments below.

[0023] Overall, naturally occurring, preferably proteinogenic α-amino acids are preferred.However, as described in more detail below, for the purpose of imparting certain technical effects, one or more positions, generally less than half of the positions of an oligonucleotide, are non-naturally occurring amino acids or moieties.These are also referred to herein as modified amino acids or modified moieties.Such modifications may affect stereochemistry, for example, by using D-amino acids instead of naturally occurring L-counterparts, and / or modifications in terms of structure and composition.

[0024] A given amino acid is understood to be linked to an adjacent moiety via a backbone peptide bond, unless that amino acid is located at the end of the molecule, such that in such a case, there will be no free carboxylic acids and no primary amines.

[0025] Of particular interest among said oligopeptides are dipeptide units. The position of the dipeptide unit within said oligopeptide is not particularly limited. However, it is preferred that said dipeptide unit is located within the N-terminal half of the oligopeptide.

[0026] In said dipeptide, the C-terminal amino acid is a tryptophan derivative. In many cases, the naturally occurring ligand of the endogenous receptor mentioned is also peptidic in nature and has a tryptophan at the corresponding position, which is the position that aligns in the sequence alignment of the naturally occurring ligand with the compound of the first aspect.

[0027] According to the present invention, such tryptophan is modified. As will be further clarified below, preferred modifications are those that maintain the indole ring. Furthermore, the amino and carboxy functions are retained. In this sense, the meaning of the term "derivative" is accordingly limited, and the derivative must be an aromatic amino acid, preferably having a two-membered ring, more preferably an indole ring. Furthermore, according to the present invention, the tryptophan derivative is an α-amino acid.

[0028] According to the present invention, the modification of tryptophan is carried out by the synthesis of tryptophan derivatives (Xaa 2 It helps to increase the stability in serum or plasma of the peptide bond connecting the N-terminus of the ribozyme (also called the ribozyme 3 amino acid) to the adjacent amino acid at the N-terminus.

[0029] As used herein, the terms "increasing the stability of peptide bonds in serum or plasma" and "reducing cleavage of peptide bonds in serum or plasma" are used equivalently.

[0030] The stability in serum or plasma is preferably the stability in mammalian serum or plasma.Particularly preferred, in view of preferred use, the stability in serum or plasma is the stability in human serum or plasma.For testing and development purposes, the preferred serum or plasma is rodent serum or plasma, such as mouse serum or plasma.To determine the stability in serum or plasma, the compound of the present invention is, for example, incubated at 37°C for 3 days (for example, 72±2 hours).

[0031] Assays for determining stability in serum or plasma are well established in the art and include in vitro and in vivo assays. Exemplary or preferred assays are part of the Examples included herein. A reference compound is used to determine whether stability is increased. A reference compound for evaluating the compounds of the first aspect is one in which the only difference between the compound under study and the reference compound is at position Xaa. 2 In the reference compound, said position is a tryptophan.

[0032] Increased stability is understood to mean a statistically significant increased stability and / or at least a 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 50-fold or at least 100-fold increase in stability. The preferred parameter for determining the stated increase is the serum / plasma half-life. The preferred parameter for determining the stated increase is the amount of unchanged radiolabeled compound after 72±2 hours of incubation in human / mouse serum or plasma.

[0033] In an alternative approach, the cognate ligand of each of the endogenous receptors, or an established therapeutic agent that binds to the same receptor (such as RM2 when GRPR is the receptor, see also below), may be used as a reference compound.

[0034] The compounds according to the first aspect exhibit improved pharmacokinetic properties. The reference compound for comparison is defined above and is a compound which deviates from the compound according to the first aspect under consideration only in that unmodified tryptophan is present in said reference compound at the position where the compound according to the first aspect has a Trp derivative. Alternatively, the enhancement is in comparison with the respective natural ligand and / or with a technically established therapeutic agent targeting the same receptor. Insofar as the compounds according to the first aspect which are GRPR ligands are considered, a preferred technically established compound is RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 , where the abbreviations for the chelating agents, as well as the non-proteinogenic amino acids, are further explained below.

[0035] The natural ligands of the preferred receptors according to the invention, said preferred receptors being the subject of preferred embodiments further disclosed below, are as follows: neuromedin B in the case of the neuromedin B receptor, gastrin releasing peptide in the case of the gastrin releasing peptide receptor, and gastrin in the case of the cholecystokinin 2 receptor.

[0036] It will be appreciated that in a therapeutic context, high tumor uptake and / or tumor retention is desirable, evidence of which is provided in the Examples contained herein.

[0037] The technical means for achieving high tumor uptake and retention is shown above, which is to stabilise the peptide bonds within the dipeptide units contained in the compounds according to the first aspect.

[0038] In a preferred embodiment of the compound of the first aspect, the N-terminal flanking amino acid in the dipeptide is L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln.

[0039] In a further preferred embodiment, the endogenous receptor is a peptide receptor overexpressed in cancer diseases, such as neuromedin B receptor (bombesin 1 receptor, NMBR), gastrin releasing peptide receptor (bombesin 2 receptor, GRPR), bombesin receptor subtype 3 (BRS-3) or cholecystokinin 2 receptor (CCK-2R), and further preferably (a) the binding has a K of 50 nM or less, 15 nM or less, 5 nM or less or 1 nM or less. D and / or (b) the compound is a GRPR antagonist, preferably having an IC 50 is 50 nM or less, 15 nM or less, 5 nM or less, or 1 nM or less.

[0040] In a second aspect related to the first aspect, the present invention provides a compound of formula (I) SY-Xaa 1 -Xaa 2 -L-Ala-L-Val-Xaa 5 -L-His-T(I) During the ceremony, S is a moiety capable of generating therapeutically active radiation; Y is an optional linker, Xaa 1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) Xaa 1 -Xaa 2 The stability of the peptide bond in serum or plasma is 1 is Gln and Xaa 2 is an α-amino acid that is increased compared to that in an otherwise identical compound, Xaa 2 is Trp or Xaa 1 -Xaa 2 The stability of the peptide bond in serum or plasma is 1 is Gln and Xaa 2 is an α-amino acid that is increased compared to that in an otherwise identical compound, However, at the same time, Xaa 1is not any one of L-Gln, D-Gln, L-His, D-His and Gly, but Xaa 2 must not be Trp, Xaa 5 is Gly, N-Me-Gly, D-Ala, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly; T is an optional terminal group. A compound is provided.

[0041] The compounds of the second aspect are tailored to a specific endogenous receptor, the GRPR, and therefore contain some characteristics inherited from the natural cognate ligand, gastrin releasing peptide (GRP).

[0042] According to a second embodiment, the moiety capable of generating therapeutically active radiation is located at the N-terminus. The core of the compound of the second embodiment is an oligopeptide having six amino acids, and the dipeptide defining the peptide bond to be stabilized according to the invention is located at positions 1 and 2 of the core oligopeptide.

[0043] The optional linker Y may be absent or present and, if present, may be a means for incorporating further amino acids into the compound of the second aspect.

[0044] Additionally, the optional terminal group T may, but need not, be a means for extending the peptide portion of the compound of the second aspect.

[0045] The reference compound to determine whether stability in serum or plasma is increased is Xaa 1 is Gln and Xaa 2 is Trp. As described above in relation to the compounds of the first aspect, alternative reference compounds may be employed, including natural ligands that bind to GRPR, such as RM2, and pharmaceutical agents established in the art.

[0046] In a preferred embodiment of the compounds of the first and second aspects, Xaa 2 is (a) Trp modified to include (i) a C1-C4 optionally substituted alkyl moiety attached to the α-carbon, wherein the substituents are selected from halogen and hydroxyl, and / or (ii) substituents attached to the indole ring, wherein the substituents are selected from N-(2,2,2-trifluoromethyl), N-methyl, N-acetyl, 5-fluoro, 5-bromo, 5-iodo, 5-chloro, 5-hydroxy, 5-methoxy, 5-methyl, 6-chloro, 7-chloro, and 7-aza; (b) 1,2,3,4-tetrahydronorharman-3-carboxylic acid (L-Tpi).

[0047] This preferred embodiment relates to specific structural measures to achieve increased stability of the backbone peptide bond of the dipeptide moiety present in the compounds of the first and second aspect (Xaa in the case of the compounds of the second aspect). 1 -Xaa 2 is specified).

[0048] Particularly preferred among these structural criteria are those defined in part (a)(i) of this preferred embodiment.

[0049] In a more preferred embodiment thereof, the optionally substituted alkyl moiety is -CH 3 , -CH 2 CH 3 , and C.H. n Hal 3-n where n is 0, 1 or 2 and Hal is F, Cl, Br and / or I, e.g. -CF 3 is preferably selected from -CH 3 It is. Most preferably, Xaa 2 is α-methyltryptophan.

[0050] Preferred embodiments of the first and second aspects are derivatives of the compounds of Tables 1A and / or B. As an explanation of the term "derivatives" of the compounds of Tables 1A and B, Tables 1A and B are further provided below.

[0051] Particularly preferred embodiments of the compounds of the first and second aspects are compounds of formula (IIIa and IIIb), further disclosed below.

[0052] A third aspect of the present invention is a compound of formula (II) SY-Xaa 3 -Xaa 4 -L-Ala-L-Val-Xaa 5 -L-His-T(II) During the ceremony, S is a moiety capable of producing a detectable signal, Y is an optional linker, Xaa 3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) Xaa 3 -Xaa 4 The stability of the peptide bond in serum or plasma is 3 is Gln and Xaa 4 is an α-amino acid that is decreased compared to that in an otherwise identical compound, Xaa 4 is Trp or Xaa 3 -Xaa 4 The stability of the peptide bond in serum or plasma is 3 is Gln and Xaa 4 is an α-amino acid that is decreased compared to that in an otherwise identical compound, Xaa 3 -Xaa 4 Position Xaa, which reduces the stability of the peptide bond in serum or plasma 4 The α-amino acids are not proteinogenic amino acids, However, at the same time, Xaa 3is not any one of L-Gln, D-Gln, L-His, D-His and Gly, but Xaa 4 must not be Trp, Xaa 5 is Gly, N-Me-Gly, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly; T is an optional terminal group. Concerning compounds.

[0053] The compound of formula (II) shows structural similarity to the compound of formula (I) according to the second embodiment, but is distinguished from it in that the peptide bond of the dipeptide moiety contained in the oligopeptide is less stable in serum or plasma.

[0054] This provides a different but related technical effect. As is well established in the art, radiolabeled compounds are useful not only for therapeutic but also for diagnostic purposes. In diagnostic settings, more rapid degradation is desired. This is because the metabolic activity in tumors is generally lower than that of surrounding normal tissues, and as a result, more rapid degradation is accompanied by a higher tumor / background ratio, which allows for more sensitive, more detailed and / or more accurate detection of tumors and metastases.

[0055] 2 positions Xaa 3 and Xaa 4 is at position Xaa of the compound of the second embodiment 1 and Xaa 2 It will be understood that they correspond to and are aligned with each other and are simply shown separately for clarity. When it comes to a concrete structural implementation, on the one hand, Xaa 1 and Xaa 2 , on the other hand, Xaa 3 and Xaa 4 will generally be distinguished. This will become clearer in the context of preferred embodiments of the third aspect, further disclosed below.

[0056] For the purpose of determining the decreased stability, what has been explained above in relation to the compounds of the first and second aspects applies mutatis mutandis. Thus, in vitro and in vivo serum or plasma assays may be used. The preferred readout is the serum / plasma half-life. The more preferred readout is the amount of unchanged radiolabeled compound after 72±2 hours of incubation in human / mouse plasma. The reference compound for the purpose of determining the decreased stability is, as described above, a compound having a 5'-amino acid at position Xaa 3 and Xaa 4 Also included are compounds which differ from the compound of formula (II) only in that are Gln and Trp, respectively.

[0057] As established in the art, three-letter codes are commonly used to designate amino acids. If the first letter is capitalized, the L-form is intended, whereas if the first letter is lowercase, the D-form is intended. For example, Trp refers to L-tryptophan and trp refers to D-tryptophan. Also, explicit indications of stereochemistry are used herein (L-Trp, D-Trp, etc.).

[0058] The surrogate reference compounds are the respective natural ligand, GRP if the receptor is GRPR, or RM2, which is an antagonist.

[0059] In a preferred embodiment of the compound of formula (II), Xaa 3 is Hse and / or Xaa 4 is Bta (3-benzothienylalanine).

[0060] In preferred embodiments of the compound of the second aspect, S is selected from a radioactive moiety and a moiety capable of carrying a radionuclide.

[0061] In preferred embodiments of the compound of the third aspect, S is selected from a fluorescent moiety, a radioactive moiety and a moiety capable of carrying a radionuclide.

[0062] The previous two preferred embodiments relate to preferred embodiments of the moiety S, depending on whether a therapeutic or a diagnostic compound is being considered.

[0063] To the extent that use is made of a moiety capable of carrying a radionuclide, said moiety is preferably a metal ion chelator, preferably bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl- ... (C)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-pentane Diacid (DOTAGA), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphat) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7, 10-Tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H. 2macropa), 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 6-carboxy-1,4,8,11-tetraazaundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl} -1,4,8,11-Tetraazaundecane (N4'), 1,4,7,10-Tetraazacyclododecane-1,4.7-triacetic acid (DO3A), S-acetylmercaptoacetyltricerin (MAS3), mercaptoacetyltriglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA), 3,6,9,15-tetraazabicyclo[9.3.1]Pentadeca-1(15),11,13-triene-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentaazatricyclo[15,3,2,1]trieicosa-1(21),17,19-triene-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanatobenzyl)oxy-methyl]propylene-1,3-dinitrilotetraacetic acid (TAME-Hex), 4-((4-(3-bis(2-(3-hydroxy- 1-Methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazepane-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methy 1,4,7,10-Tetrakis[methylene(2-carboxyethyl)phosphinic acid] (TRAP) and its functional derivatives, such as NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid] (DOTPI), 6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridyl) dipicolinic acid (H2bispa2), 1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N'',N'''',N''''''-hexaacetic acid (HEHA), 1,2-[{6-(carboxy)-pyridin-2-yl}-methylamino]ethane (H. 2 dedpa), N,N'-bis{6-carboxy-2-pyridylmethyl}-ethylenediamine-N,N'-diacetic acid (H 4octapa), 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane (sar) and its functional derivatives, {4-[2-(biscarboxymethylamino)-ethyl]-7-carbamoylmethyl}-1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (sar) and its functional derivatives, carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NETA), N,N',N'',tris(2-mercaptoethyl)1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanatobenzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N'-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N'-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (H 2 azapa), N,N'-[[6-(carboxy)pyridin-2-yl]methyl]diethylenetriamine-N,N',N''-triacetic acid (H 5 decapa), N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA), and N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane (H 6 phospa), more preferably DOTA or DOTAGA, and preferably a radioactive cation is attached to said chelating agent, said radioactive cation being preferably 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu,66 Ga、 68 Ga、 67 Ga、 89 Zr、 90 Y、 86 Y、 94m Tc、 99m Tc、 97 Ru、 105 Rh、 109 Pd、 111 Ag、 110m In、 111 In、 113m In、 114m In、 117m Sn、 121 Sn、 127 Te、 140 La、 142 La、 142 Pr、 143 Pr、 147 Nd、 149 Gd、 149 Pm、 151 Pm、 149 Tb、 152 Tb、 155 Tb、 153 Sm、 156 Eu、 157 Gd、 161 Tb、 164 Tb、 161 Ho、 166 Ho、 157 Dy、 166 Dy、 165 Dy、 160 Er、 165 Er、 169 Er、 171 Er、 166 Yb、 169 Yb、 175 Yb、 167 Tm、 172 Tm、 177 Lu、 186 Re、 188 Re、 188 W、 191 Pt、 195m Pt、 194 Ir、 197 Hg、 198 Au、 199 Au、 212 Pb、 203 Pb、 211 At、 212Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th, or 18 F-[AlF] 2+ Like 18 The cationic molecule is selected from the group consisting of F-containing cationic molecules.

[0064] For therapeutic compounds, preferred nuclides are: 177 Examples of preferred nuclides for diagnostic compounds are: 68 It's Ga.

[0065] In a preferred embodiment of the compounds of the second and third aspects, the linker Y is present and (a) comprises 1, 2, 3, 4, 5 or 6 positive and / or negative charges; (b) comprises or consists of 1, 2, 3, 4, 5 or 6 amino acids, preferably D-amino acids among said amino acids, more preferably D-α-amino acids; (c) PEG n wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; and / or (d) comprising a moiety capable of producing a detectable signal.

[0066] Suitable moieties capable of generating a detectable signal according to item (d) of the above preferred embodiment may be moieties that are fluorescent or that contain or can carry a radionuclide. An example of the latter is a silicon fluoride acceptor moiety (SiFA), which is 18 F labeling. To the extent that compounds of the invention containing such SiFA moieties further contain a chelating agent (such as DOTA or DOTAGA), such compounds contain two radionuclides and therefore can be used for both diagnostics and therapy.

[0067] In a preferred embodiment, the SiFA moiety has a structure represented by formula (VI): [ka] During the ceremony, t-Bu represents a tert-butyl group; The dashed line indicates the bond connecting the moiety to the remainder of the compound.

[0068] The preferred attachment site of the SiFA moiety in the linker Y is the side chain of 2,3-diaminopropionic acid, said side chain being -CH 2 -NH 2 and the terminal amino group of the side chain preferably forms an amide bond with the carboxyl group bonded to the free valence of the SiFA moiety in formula (VI).

[0069] Linkers Y having a fluorinated silicon acceptor moiety are preferred linkers Y for compounds of all embodiments of the present invention.

[0070] In a further preferred embodiment, said linker Y is selected from the group consisting of (a) D-Glu-Urea-D-Glu, (b) one or two 2,3-diaminopropionic acid moieties, optionally substituted with a moiety capable of generating a detectable signal, (c) D- / L-aspartic acid, D- / L-ornithine, 4-amino-1-carboxymethyl-piperidine (Pip), D- / L-2,3-diaminopropionic acid, D- / L-serine, D- / L-citrulline moieties, L-cysteic acid (Ala(SO 3 H)), 1, 2, 3, 4, 5 or 6 consecutive amino acids comprising or consisting of one or more amino acids selected from aminovaleric acid (Ava), 4-aminobenzoic acid (PABA) and D-Phe, and / or (d) p-aminomethylaniline-diglycolic acid (abbreviated as pABza-DIG or AMA-DGA), and / or diglycolate (abbreviated as DIG or DGA).

[0071] Particularly preferred is when Y is Pip-phe.

[0072] The D-Glu-Urea-D-Glu moiety according to item (a) of this preferred embodiment is believed to be a means for rendering the compound more hydrophilic.

[0073] In further preferred embodiments of the compounds of the second and third aspects, i.e. both the therapeutically active agent and the diagnostically active agent, the terminal group T is present and is selected from the group consisting of (a) a statin (Sta or (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), 2,6-dimethylheptane, Leu or β-thienyl-L-alanine (Thi), and / or (b) Leu, norleucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methyl-butane, wherein the amidoamine group of said Leu is ethyl (NH-ethyl) or NH 2 (NH-NH 2 ), and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH 2 N)Pro-NH 2 ), with the proviso that when T is or ends in an amino acid, the carboxylic acid of said amino acid is amidated.

[0074] Particularly preferred is where T is Sta-Leu-NH 2 It is to be.

[0075] With regard to the preferred choices of moieties Y and T, in general no distinction is made between therapeutic and diagnostic compounds of the invention.

[0076] As already mentioned further above, in a preferred embodiment of the compounds of all aspects of the invention, said serum or plasma is human serum or plasma, i.e. of particular importance is the increased or decreased stability in human serum or plasma, respectively.

[0077] Table 1A below shows the sequences of known GRPR binders. 1 and in the case of the compound of formula (II), 3The hexapeptide sequence beginning with Xaa and ending with L-His corresponds to positions 7 through 12 in the table below. As can be seen, the GRPR binders generally shown in this table have a hexapeptide sequence at position 8 (which is Xaa 2 and Xaa 4 7 (corresponding to positions Xaa 1 , Xaa 3 and 8, respectively) are highly conserved. As is evident from the table below, the art has not recognized that the peptide bond linking positions 7 and 8 (as numbered in the table) is a target site for fine tuning the pharmacokinetic properties.

[0078] Tables 1B and 1C show the sequences of ligands acting on modified GRPR and the effect of introducing either an α-Me-Trp or Bta moiety at position 8 or an Hse moiety at position 7 into different GRPR targeting compounds. As in Table 1A, in the case of compounds of formula (I), Xaa 1 and in the case of the compound of formula (II), 3 The hexapeptide sequence beginning with and ending with L-His corresponds to positions 7 to 12.

[0079] Problems arising from the metabolic degradation of GRPR-targeting linear peptides have been suggested to be due to neutral endopeptidases (NEPs, EC 3.4.24.11), which are known to cleave linear peptides at the N-terminal side of hydrophobic amino acids (e.g., tryptophan). Thus, these peptides are likely to be cleaved at the dipeptidic Gln residues present in almost all GRPR-acting compounds. 7 -Trp 8 The cleavage is predicted to occur at the motif (Table 1A). To demonstrate that the introduction of α-Me-Trp or Hse at the above positions increases the metabolic stability in human serum or plasma, different GRPR targeting ligands were synthesized and the above modifications were introduced. For almost all of the evaluated GRPR targeting peptides shown in Table 1B, Trp 8 α-Me-Trp 8 or Gln 7 Hse 7 When replaced with, each Gln7 -Trp 8 The metabolic stability of the derivatives was increased compared to those containing α-Me-Trp (Table 1C). For most of these derivatives, the addition of α-Me-Trp did not dramatically reduce the affinity of GRPR. However, the Gln 7 Hse 7 Substitution with Hse clearly reduced the affinity of GRPR for most ligands, but a stabilizing effect of the Hse moiety was also observed.

[0080] Similarly, Bta was introduced at the above positions to demonstrate reduced metabolic stability in human serum or plasma. For most of the evaluated GRPR acting compounds shown in Table 1B, Trp 8 Bta 8 When replaced with, each Gln 7 -Trp 8 In fact, metabolic stability was decreased compared to derivatives containing Bta (Table 1C). GRPR affinity was not dramatically affected by the addition of Bta in most of the derivatives shown in Table 1B.

[0081] Therefore, for GRPR targeting ligands, Gln 7 -Trp 8 It is concluded that it is not important which amino acids are located on the N- and C-terminal sides of the dipeptide. 8 The introduction of α-Me-Trp reduces metabolic stability. 8 Or Hse 7 The introduction of these modifications (α-Me-Trp) increases the metabolic stability in human serum or plasma. 8 , Bta 8 , Hse 7 ) enables broad application of GRPR target compounds in general.

[0082] [Table 1-1]

[0083] [Table 1-2]

[0084] [Table 2-1]

[0085] [Table 2-2]

[0086] [Table 3]

[0087] Preferred compounds of the invention include derivatives of the compounds shown in Tables 1A and 1B, which preferably differ from the compounds of Tables 1A and 1B only in that positions 7 and / or 8 (numbering in the tables) are modified according to the invention.

[0088] As an example, preferred compounds according to the first and second aspects of the invention can be obtained by substituting α-methyltryptophan for tryptophan in any of the compounds of Table 1A.

[0089] Similarly, at position 7 of the compounds of Table 1A, Gln (or, where applicable, His or gln) may be substituted with Hse, and at position 8 of the compounds of Table 1A, Trp may be substituted with Bta, thereby obtaining preferred compounds according to the third aspect of the invention.

[0090] Xaa 1 From Xaa 4 applies mutatis mutandis to any of the modifications at these four positions disclosed herein above, whether in relation to the compounds of the first, second or third aspects.

[0091] In a fourth aspect, which is also a preferred embodiment of the first and second aspects, the present invention provides compounds of formula (IIIa) or (IIIb): [ka]

[0092] In a fifth aspect, which is also a preferred aspect of the third aspect, the present invention provides a compound of formula (IV) or (V): [ka]

[0093] In a sixth aspect, the present invention provides a compound according to any one of the preceding claims for use in medicine.

[0094] In a seventh aspect, the present invention provides a pharmaceutical composition comprising or consisting of a compound of the first, second or fourth aspects.

[0095] In an eighth aspect, the present invention provides a diagnostic composition comprising or consisting of a compound of the third or fifth aspects.

[0096] In a further, less preferred aspect, the present invention provides a diagnostic composition comprising or consisting of a compound of the first, second or fourth aspect, and in a further, less preferred aspect, a pharmaceutical composition comprising or consisting of a compound of the third or fifth aspect.

[0097] In the pharmaceutical and diagnostic compositions of the invention, the compound may be the only active agent, and in the pharmaceutical compositions of the invention, more than one compound of the first, second or fourth aspect may be utilized, and in the diagnostic compositions of the invention, more than one compound of the third or fifth aspect may be utilized.

[0098] Also envisaged, although less preferred, are pharmaceutical and diagnostic compositions of the invention in which, in addition to one or more compounds of the invention, further pharma- ceutical or diagnostically active agents are present.

[0099] The pharmaceutical or diagnostic compositions may further comprise pharma- ceutically or diagnostically acceptable carriers, excipients and / or diluents. Examples of suitable carriers, excipients and / or diluents are well known in the art and include phosphate buffered saline, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, etc. Compositions comprising such carriers can be formulated by well-known conventional methods. These pharmaceutical and diagnostic compositions can be administered to the subject in an appropriate dose. The administration of suitable compositions can be performed by different methods, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intrabronchial administration, with intravenous administration being preferred. In particular, it is preferred that said administration is performed by injection. The compositions may also be administered directly to the target site, for example, by biolistic delivery to an external or internal target site. The administration regimen is determined by the attending physician and clinical factors. As is well known in the medical art, the dosage for any one patient will depend on many factors, including the patient's size, body surface area, age, the particular compound being administered, sex, time and route of administration, general condition, and other drugs being administered concomitantly.

[0100] Radiolabels of the present invention (e.g., 177 A preferred dosage of the compound (Lu) is 1-100 GBq, 2-60 GBq, 2-50 GBq, 2-10 GBq, or 3-6 GBq.

[0101] A preferred medical indication according to the present invention is a hyperproliferative disease, more preferably a malignant disease.

[0102] Thus, in a ninth aspect, the present invention provides a pharmaceutical composition of the seventh aspect or a compound of any one of the first, second or fourth aspects for use in a method of treating cancer, wherein the cancer is (a) characterised by overexpression of said receptor, and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumours, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, squamous cell carcinoma of the head and neck, neuro / glioblastoma, colorectal cancer and, in the context of CCK-2R, medullary thyroid carcinoma (MTC).

[0103] Similarly, the present invention provides in a tenth aspect a diagnostic composition of the eighth aspect or a compound of the third or fifth aspect for use in a method of diagnosing cancer, wherein the cancer is (a) characterised by overexpression of said receptor, and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumours, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, squamous cell carcinoma of the head and neck, neuro / glioblastoma, colorectal cancer and, in the range of CCK-2R, medullary thyroid carcinoma (MTC).

[0104] In an eleventh aspect, the present invention provides an in vitro method of diagnosing cancer, wherein the cancer is (a) characterized by overexpression of said receptor, and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumours, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head and neck squamous cell carcinoma, neuro / glioblastoma, colorectal cancer and, in the case of CCK-2R, medullary thyroid carcinoma (MTC), said method comprising contacting a sample obtained from a subject with a diagnostic composition of the eighth aspect or a compound of the third or fifth aspect.

[0105] With regard to the embodiments characterized in this specification, and in particular in the claims, it is intended that each embodiment recited in a dependent claim be combined with each embodiment of each claim (independent or dependent) on which the dependent claim depends. For example, given independent claim 1 reciting three options A, B and C, dependent claim 2 reciting three options D, E and F, and claim 3 reciting three options G, H and I dependent on claims 1 and 2, it will be understood that the specification, unless expressly stated otherwise, expressly discloses embodiments corresponding to the combinations A,D,G;A,D,H;A,D,I;A,E,G;A,E,H;A,E,I;A,F,G;A,F,H;A,F,I;B,D,G;B,D,H;B,D,I;B,E,G;B,E,H;B,E,I;B,F,G;B,F,H;B,F,I;C,D,G;C,D,H;C,D,I;C,E,G;C,E,H;C,E,I;C,F,G;C,F,H;C,F,I.

[0106] Similarly, even if an independent and / or dependent claim does not recite an alternative, it is understood that if a dependent claim refers to more than one preceding claim, any combination of the subject matter covered thereby is considered to be explicitly disclosed. For example, in the case of independent claim 1, dependent claim 2 referring to claim 1, and dependent claim 3 referring to both claims 2 and 1, the combination of the subject matter of claims 3 and 1 is clearly and unambiguously disclosed as is the combination of the subject matter of claims 3, 2 and 1. If there is a further dependent claim 4 referring to any one of claims 1 to 3, the combinations of the subject matter of claims 4 and 1, claims 4, 2 and 1, claims 4, 3 and 1, and claims 4, 3, 2 and 1 are clearly and unambiguously disclosed.

[0107] The present invention includes the following items. 1. A compound that binds to an endogenous receptor, (i) an oligopeptide comprising a dipeptide, in which Trp is the C-terminal amino acid of the dipeptide, 2 This results in Xaa 2and the N-terminal adjacent amino acid has increased stability in serum or plasma compared to a peptide bond in an otherwise identical compound linking Trp and the N-terminal adjacent amino acid, (ii) a moiety capable of generating therapeutically effective radiation, said moiety being covalently attached to said oligopeptide; The compound comprising: 2. The compound according to item 1, wherein the N-terminal adjacent amino acid in the dipeptide is L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln. 3. The endogenous receptor is a peptide receptor overexpressed in cancer diseases, such as neuromedin B receptor (bombesin 1 receptor, NMBR), gastrin releasing peptide receptor (bombesin 2 receptor, GRPR), bombesin receptor subtype 3 (BRS-3) or cholecystokinin 2 receptor (CCK-2R), and more preferably (a) the binding has a K of 15 nM or less; D and / or (b) the compound is a GRPR antagonist, preferably IC 50 is 15 nM or less, The compound according to item 1 or 2. 4. A compound of formula (I), SY-Xaa 1 -Xaa 2 -L-Ala-L-Val-Xaa 5 -L-His-T(I) During the ceremony, S is a moiety capable of generating therapeutically active radiation; Y is an optional linker, Xaa 1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln; or (ii) Xaa 1 -Xaa 2 The stability of the peptide bond in serum or plasma is 1 is Gln and Xaa 2is an α-amino acid that is increased compared to that in an otherwise identical compound, Xaa 2 is Trp or Xaa 1 -Xaa 2 The stability of the peptide bond in serum or plasma is 1 is Gln and Xaa 2 is an α-amino acid that is increased compared to that in an otherwise identical compound, However, at the same time, Xaa 1 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, but Xaa 2 must not be Trp, Xaa 5 is Gly, N-Me-Gly, D-Ala, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly; T is an optional terminal group. compound. 5. Xaa 2 teeth, (a)(i) a C1-C4 optionally substituted alkyl moiety attached to the α-carbon, the substituents being selected from halogen and hydroxyl; and / or (ii) a substituent attached to the indole ring, the substituent being selected from N-(2,2,2-trifluoromethyl), N-methyl, N-acetyl, 5-fluoro, 5-bromo, 5-iodo, 5-chloro, 5-hydroxy, 5-methoxy, 5-methyl, 6-chloro, 7-chloro, and 7-aza; Trp modified to include (b) 1,2,3,4-Tetrahydronorharman-3-carboxylic acid (L-Tpi) 5. The compound according to any one of items 1 to 4, wherein 6. The optionally substituted alkyl moiety is -CH 3 , -CH 2 CH 3 , and C.H. n Hal 3-nwhere n is 0, 1 or 2 and Hal is F, Cl, Br and / or I, e.g. -CF 3 is preferably selected from -CH 3 Item 6. The compound according to item 5, wherein 7. Xaa 2 7. The compound according to any one of items 1 to 6, wherein is α-Me-Trp. 8. A compound of formula (II), SY-Xaa 3 -Xaa 4 -L-Ala-L-Val-Xaa 5 -L-His-T(II) During the ceremony, S is a moiety capable of producing a detectable signal, Y is an optional linker, Xaa 3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln; or (ii) Xaa 3 -Xaa 4 The stability of the peptide bond in serum or plasma is 3 is Gln and Xaa 4 is an α-amino acid that is decreased compared to that in an otherwise identical compound, Xaa 4 is Trp or Xaa 3 -Xaa 4 The stability of the peptide bond in serum or plasma is 3 is Gln and Xaa 4 is an α-amino acid that is increased compared to that in an otherwise identical compound, Xaa 3 -Xaa 4 Position Xaa, which reduces the stability of the peptide bond in serum or plasma 4 The alpha amino acids are not proteinogenic amino acids, However, at the same time, Xaa 3 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, but Xaa4 must not be Trp, Xaa 5 is Gly, N-Me-Gly, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly; T is an optional terminal group. compound. 9. Xaa 3 is Hse and / or Xaa 4 The compound according to item 8, wherein is Bta. 10. The compound according to any one of items 4 to 7, wherein S is selected from a radioactive moiety and a moiety capable of carrying a radionuclide. 11. The compound according to item 8 or 9, wherein S is selected from a fluorescent moiety, a radioactive moiety and a moiety capable of carrying a radionuclide. 12. The moiety capable of carrying a radionuclide is a metal ion chelator, preferably bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoic acid, 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA ), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphat) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraacetic acid lazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H. 2macropa), 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 6-carboxy-1,4,8,11-tetraazaundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl} -1,4,8,11-Tetraazaundecane (N4'), 1,4,7,10-Tetraazacyclododecane-1,4.7-triacetic acid (DO3A), S-acetylmercaptoacetyltricerin (MAS3), mercaptoacetyltriglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA), 3,6,9,15-tetraazabicyclo[9.3.1]Pentadeca-1(15),11,13-triene-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentaazatricyclo[15,3,2,1]trieicosa-1(21),17,19-triene-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanatobenzyl)oxy-methyl]propylene-1,3-dinitrilotetraacetic acid (TAME-Hex), 4-((4-(3-bis(2-(3-hydroxy- 1-Methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazepane-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methy 1,4,7-Triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid] (DOTPI), 6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridyl)amino)phenyl)-1,4,7,10-tetrakis(2-carboxyethyl)phosphinic acid) (TRAP) and its functional derivatives, such as NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid] (DOTPI), dipicolinic acid (H2bispa2), 1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N'',N'''',N''''''-hexaacetic acid (HEHA), 1,2-[{6-(carboxy)-pyridin-2-yl}-methylamino]ethane (H. 2 dedpa), N,N'-bis{6-carboxy-2-pyridylmethyl}-ethylenediamine-N,N'-diacetic acid (H 4octapa), 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane (sar) and its functional derivatives, {4-[2-(biscarboxymethylamino)-ethyl]-7-carbamoylmethyl}-1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (sar) and its functional derivatives, carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NETA), N,N',N'',tris(2-mercaptoethyl)1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanatobenzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N'-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N'-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (H 2 azapa), N,N'-[[6-(carboxy)pyridin-2-yl]methyl]diethylenetriamine-N,N',N''-triacetic acid (H 5 decapa), N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA), and N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane (H 6 phospa), more preferably DOTA or DOTAGA, Preferably, a radioactive cation is attached to said chelating agent; The radioactive cation is preferably 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu,67 Cu、 66 Ga、 68 Ga、 67 Ga、 89 Zr、 90 Y、 86 Y、 94m Tc、 99m Tc、 97 Ru、 105 Rh、 109 Pd、 111 Ag、 110m In、 111 In、 113m In、 114m In、 117m Sn、 121 Sn、 127 For, 140 The、 142 The、 142 Pr、 143 Pr、 147 Nd、 149 Gd、 149 Pm、 151 Pm、 149 Tb、 152 Tb、 155 Tb、 153 Sm、 156 Eu、 157 Gd、 161 Tb、 164 Tb、 161 Ho、 166 Ho、 157 Dy、 166 Dy、 165 Dy、 160 Er、 165 Er、 169 Er、 171 Er、 166 Yb、 169 Yb、 175 Yb、 167 Tm、 172 Tm、 177 Lu、 186 Re, 188 Re, 188 W、 191 Pt、 195m Pt、 194 Is、 197 Hg、 198 I、 199 I、 212 Pb、 203 Pb、 211At, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th, or 18 F-[AlF] 2+ Like 18 The cationic molecule is selected from the group consisting of F-containing cationic molecules. 13. Y exists, (a) containing 1, 2, 3, 4, 5 or 6 positive and / or negative charges; (b) comprising or consisting of 1, 2, 3, 4, 5 or 6 amino acids, preferably D-amino acids among said amino acids, more preferably D-α amino acids; (c)PEG n and / or comprising or consisting of: (d) containing a moiety capable of producing a detectable signal; 13. The compound according to any one of items 4 to 12. 14. The linker Y is (a) D-Glu-Urea-D-Glu, (b) one or two 2,3-diaminopropionic acid moieties, optionally substituted with a moiety capable of producing a detectable signal; (c) D- / L-aspartic acid, D- / L-ornithine, 4-amino-1-carboxymethyl-piperidine (Pip), D- / L-2,3-diaminopropionic acid, D- / L-serine, D- / L-citrulline moiety, L-cysteic acid (Ala(SO 3 H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA) and D-Phe, and / or (d) p-aminomethylaniline-diglycolic acid (pABza-DIG, AMA-DGA) and / or diglycolate (DIG, DGA); 14. The compound according to item 13, comprising or consisting of: 15.T exists, (a) statins (Sta or (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), 2,6-dimethylheptane, Leu or β-thienyl-L-alanine (Thi), (b) Leu, norleucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methyl-butane, where the amidoamine group of the Leu is ethyl (NH-ethyl) or NH 2 (NH-NH 2 ), and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH 2 N)Pro-NH 2 ), comprising or consisting of with the proviso that when T is or ends in an amino acid, the carboxylic acid of said amino acid is amidated. 15. A compound according to any one of items 4 to 14. 16. The compound according to any one of items 1 to 15, wherein the serum or plasma is human serum or plasma. 17. A compound of formula (IIIa) or (IIIb). [ka] 18. A compound of formula (IV) or (V). [ka] 19. A compound according to any one of items 1 to 18 for use in medicine. 20. A pharmaceutical composition comprising or consisting of a compound according to any one of items 1 to 7 or 10 to 17, to the extent that items 10 to 16 refer back to any one of items 1 to 7. 21. A diagnostic composition comprising or consisting of a compound according to any one of items 8, 9, 10 to 16 or 18, to the extent that items 10 to 16 refer back to items 8 or 9. 22. The pharmaceutical composition of item 20 or, to the extent that items 10 to 16 refer back to any one of items 1 to 7, the compound of any one of items 1 to 7 or 10 to 17 for use in a method for treating cancer, wherein the cancer is (a) characterized by overexpression of said receptor, and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, squamous cell carcinoma of the head and neck, glioblastoma, colorectal cancer, and, in the case where the receptor is CCK-2R, medullary thyroid carcinoma (MTC). 23. The diagnostic composition of item 21 or, to the extent that items 10 to 16 refer back to items 8 or 9, the compound of any one of items 8, 9, 10 to 16 or 18 for use in a method for diagnosing cancer, wherein the cancer is (a) characterized by overexpression of said receptor, and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, squamous cell carcinoma of the head and neck, glioblastoma, colorectal cancer, and, in the case where the receptor is CCK-2R, medullary thyroid carcinoma (MTC). 24. An in vitro method for diagnosing cancer, comprising: (a) characterized by overexpression of said receptor, and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head and neck squamous cell carcinoma, neuro / glioblastoma, colorectal cancer, and, in the case of CCK-2R, medullary thyroid carcinoma (MTC); The method comprises contacting the diagnostic composition of item 20 or, to the extent that items 10 to 16 refer back to items 8 or 9, a compound according to any one of items 8, 9, 10 to 16 or 18 with a sample obtained from a subject. [Brief description of the drawings]

[0108] [Figure 1]Analysis of [177Lu]RM2 (tR = 15.3 min, 20 → 35% in 20 min) in human plasma after 72 ± 2 h incubation at 37 °C. The chromatogram shows two important metabolites (tR = 2.9 min, 54% and tR = 8.5 min, 9%) as well as remaining unchanged tracer (tR = 15.3 min, 36%). [Diagram 2] Analysis of [177Lu]DOTA-[Hse7]MJ9 (tR = 16.1 min, 20 → 35% in 20 min) in human plasma after 72 ± 2 h incubation at 37 °C. The chromatogram shows two important metabolites (tR = 3.4 min, 30% and tR = 8.6 min, 8%) as well as remaining unchanged tracer (tR = 15.3 min, 56%). [Diagram 3] Analysis of [177Lu]DOTA-[Bta8]MJ9 (tR = 17.9 min, 20 → 35% in 20 min) in human plasma after 72 ± 2 h incubation at 37 °C. The chromatogram shows two metabolites (tR = 3.1 min, 79% and tR = 12.3 min, 8%) and the remaining unchanged tracer (tR = 17.9 min, 12%). [Figure 4] Analysis of [177Lu]AMTG (tR = 17.0 min, 20 → 35% in 20 min) in human plasma after 72 ± 2 h incubation at 37 °C. The chromatogram shows two metabolites (tR = 1.7 min, 2% and tR = 8.0 min, 5%) and the remaining unchanged tracer (tR = 17.0 min, 92%). [Diagram 5] Analysis of [177Lu]RM2 (tR = 15.5 min, 20 → 35% in 20 min) in mouse plasma after 6 ± 0.5 h incubation at 37 °C. The chromatogram shows three metabolites (tR = 3.1 min, 2%, tR = 8.2 min, 2% and tR = 17.3 min, 4%) and the remaining unchanged tracer (tR = 17.0 min, 92%). [Figure 6]Analysis of [177Lu]AMTG (tR = 17.0 min, 20 → 35% in 20 min) in mouse plasma after 6 ± 0.5 h incubation at 37 °C. The chromatogram shows three metabolites (tR = 2.6 min, 2%, tR = 13.7 min, 2% and tR = 18.8 min, 5%) and the remaining unchanged tracer (tR = 17.0 min, 89%). [Figure 7] Analysis of [177Lu]RM2 (tR = 15.5 min, 20 → 35% in 20 min) in mouse plasma after 72 ± 2 h incubation at 37 °C. The chromatogram shows several minor metabolites and residual unchanged tracer (tR = 15.5 min, 67%). [Figure 8] Analysis of [177Lu]AMTG (tR = 17.0 min, 20 → 35% in 20 min) in mouse plasma after 72 ± 2 h incubation at 37 °C. The chromatogram shows several metabolites and remaining unchanged tracer (tR = 17.0 min, 59%). [Figure 9] Figure 1 shows the biodistribution (in %ID / g) of [177Lu]RM2 (white), [177Lu]DOTA-[Hse7]MJ9 (black) and [177Lu]DOTA-[Bta8]MJ9 (hatched) in selected organs at 1 hour pi in PC-3 tumor-bearing CB17-SCID mice (100 pmol each). Data are presented as mean ± SD (n=4). [Figure 10] Figure 1 shows tumor / background ratios in selected organs of [177Lu]RM2 (white), [177Lu]DOTA-[Hse7]MJ9 (black) and [177Lu]DOTA-[Bta8]MJ9 (hatched) in PC-3 tumor-bearing CB17-SCID mice at 1 hour pi. Data are presented as mean ± SD (n=4). [Figure 11]Biodistribution (in %ID / g) of [177Lu]RM2 (white), [177Lu]NeoBOMB1 (grey), [177Lu]DOTA-[Hse7]MJ9 (black), [177Lu]DOTA-[Bta8]MJ9 (hatched lines), [177Lu]AMTG (dots) and [177Lu]AMTG2 (squares) in selected organs at 24 hours pi in PC-3 tumor-bearing CB17-SCID mice (100 pmol each). Data are presented as mean ± SD (n=4). [Figure 12] Tumor / background ratios in selected organs of [177Lu]RM2 (white), [177Lu]NeoBOMB1 (grey), [177Lu]DOTA-[Hse7]MJ9 (black), [177Lu]DOTA-[Bta8]MJ9 (hatched lines), [177Lu]AMTG (dots) and [177Lu]AMTG2 (squares) at 24 hours pi in PC-3 tumor-bearing CB17-SCID mice. Data are presented as mean ± SD (n=4). [Figure 13] Biodistribution (in %ID / g) of [99mTc]N4-asp-MJ9 (grey, hatched lines), [99mTc]N4-asp-[Bta8]MJ9 (grey, dots), [99mTc]N4-[Hse7]MJ9 (grey, bricks) and [99mTc]N4-[α-Me-Trp8]MJ9 (grey, squares) in selected organs at 1 hour pi in PC-3 tumor-bearing CB17-SCID mice (100 pmol each). Data are presented as mean ± SD (n=4). [Figure 14] FIG. 1 shows biodistribution (n=1) (in %ID / g) of [99mTc]N4-asp-MJ9 (grey, hatched lines), [99mTc]N4-asp-[Bta8]MJ9 (grey, dots), [99mTc]N4-[Hse7]MJ9 (grey, bricks) and [99mTc]N4-[α-Me-Trp8]MJ9 (grey, squares) in selected organs of PC-3 tumor-bearing CB17-SCID mice (100 pmol each) at 4 hours pi. [Figure 15]Tumor / background ratios in selected organs of [99mTc]N4-asp-MJ9 (grey, hatched lines), [99mTc]N4-asp-[Bta8]MJ9 (grey, dots), [99mTc]N4-[Hse7]MJ9 (grey, bricks) and [99mTc]N4-[α-Me-Trp8]MJ9 (grey, squares) at 1 hour pi in PC-3 tumor-bearing CB17-SCID mice. Data are presented as mean ± SD (n=4). [Figure 16] FIG. 1 shows tumor / background ratios (n=1) in selected organs of [99mTc]N4-asp-MJ9 (grey, hatched lines), [99mTc]N4-asp-[Bta8]MJ9 (grey, dots), [99mTc]N4-[Hse7]MJ9 (grey, bricks) and [99mTc]N4-[α-Me-Trp8]MJ9 (grey, squares) in PC-3 tumor-bearing CB17-SCID mice at 1 hour pi. [Figure 17] Maximum intensity projections (dorsal) of [99mTc]N4-asp-MJ9, [99mTc]N4-asp-[Bta8]MJ9, [99mTc]N4-[Hse7]MJ9 and [99mTc]N4-[α-Me-Trp8]MJ9 in PC-3 tumor-bearing CB17-SCID mice (200 pmol each) at 1 hour pi (top) and 4 hours pi (bottom). PC-3 tumors are indicated by white arrows. [Figure 18] Biodistribution (in %ID / g) of [177Lu]GT50 (dark grey, hatched lines), [177Lu]GT51 (dark grey, dots), [177Lu]GT52 (dark grey, bricks), and [177Lu]GT53 (dark grey, squares) in selected organs at 24 hours pi in PC-3 tumor-bearing CB17-SCID mice (100 pmol each). Data are presented as mean ± SD (n=4). [Figure 19] FIG. 1 shows maximum intensity projections (dorsal) of [177Lu]RM2 (top) and [177Lu]AMTG (bottom) at 1, 4, 8, 24 and 28 hours pi in PC-3 tumor-bearing CB17-SCID mice (100 pmol each). PC-3 tumors are indicated by white arrows. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0109] The examples illustrate the invention. Example 1 Materials and Methods (general) Fmoc-(9-fluorenylmethoxycarbonyl-) and all other protected amino acid analogs are purchased from Bachem (Bubendorf, Switzerland), Sigma-Aldrich (Munich, Germany) or Iris Biotech (Marktredwitz, Germany). H-Rink amide ChemMatrix® resin (35-100 mesh particle size, 0.4-0.6 mmol / g loading) is purchased from Sigma-Aldrich (Munich, Germany). Chematech (Dijon, France) provides the chelating agent DOTA ( t Bu) 3 and DOTAGA( t Bu) 4 Deliver the following.

[0110] Necessary solvents and other organic reagents are purchased from either Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich (Munich, Germany) or VWR (Darmstadt, Germany). Solid-phase synthesis of peptides is performed manually using a Scilogex MX-RL-E Analog Rotisserie Tube Rotator (Scilogex, Rocky Hill, CT, USA).

[0111] Analytical and preparative reversed-phase high pressure chromatography (RP-HPLC) are performed with a Shimadzu gradient system (Shimadzu Deutschland GmbH, Neufahrn, Germany) equipped with an SPD-20A UV / Vis detector (220 nm, 254 nm). Different gradients of acetonitrile (0.1% TFA) in water (0.1% TFA) were used as eluents for all HPLC runs.

[0112] For analytical measurements, a Nucleosil 100 C18 (125 × 4.6 mm, 5 μm particle size) column (CS GmbH, Langerwehe, Germany) is used with a flow rate of 1 mL / min. The specific gradient and the corresponding retention time t R Both and the capacity factor K' are referred to in the text.

[0113] Preparative HPLC purification is performed using a Multospher 100 RP 18 (250×10 mm, 5 μm particle size) column (CS GmbH, Langerwehe, Germany) at a constant flow rate of 5 mL / min.

[0114] Analytical and preparative radioactive RP-HPLC are performed using a Nucleosil 100 C18 (5 μm, 125×4.0 mm) column (CS GmbH, Langerwehe, Germany).

[0115] Electrospray ionization mass spectrometry for the characterization of materials is an expression L Acquisition is performed on a CMS mass spectrometer (Advion Ltd., Harlow, UK). Radioactivity is detected by coupling the UV photometer outlet to a NaI(Tl) well-type scintillation counter from EG&G Ortec (Munich, Germany).

[0116] Radioactive probes are 2 The IC was measured using a 2480 Automatic γ-Counter (Perkin Elmer, Waltham, MA, USA).50 Values ​​were determined using GraphPad Prism 6 (GraphPad Software Inc., San Diego, CA, USA).

[0117] For radio-TLC a Scan-RAM™ Scanner with Laura™ software (LabLogic Systems Ltd., Broomhill, Sheffield, United Kingdom) is used.

[0118] Example 2 Synthesis Protocol Solid-phase peptide synthesis by the Fmoc strategy On-resin peptide formation Each side-chain protected Fmoc-AA-OH (1.5 eq.) is dissolved in NMP and preactivated with TBTU (1.5 eq.), HOAt (1.5 eq.) and DIPEA (4.5 eq.). After 10 min activation, this solution is added to the resin-bound free amine peptide and shaken at room temperature for 1.5 h. The resin is then washed with NMP and, after Fmoc deprotection, the next amino acid is coupled in the same manner.

[0119] On-resin Fmoc deprotection The resin-bound Fmoc peptide is treated with 20% piperidine (v / v) in NMP for 5 min, followed by 15 min, after which the resin is washed extensively with NMP.

[0120] On-resin Dde deprotection Dde-deprotection is carried out by adding a solution of imidazole (75 equiv.), hydroxylamine hydrochloride (100 equiv.) in NMP (7 mL) and DCM (3 mL) at room temperature for 3 h. After deprotection, the resin is washed with NMP.

[0121] DOTA( t Bu) 3 Or DOTAGA( t Bu) 4 Conjugations of The protected chelating agent DOTA( tBu) 3 Or DOTAGA( t Bu) 4 (1.5 eq.) is dissolved in NMP and preactivated with TBTU (1.5 eq.), HOAt (1.5 eq.) and DIPEA (4.5 eq.). After activation for 10 min, this solution is added to the resin-bound N-terminally deprotected peptide and shaken at room temperature for 3 h. The resin is then washed with NMP and DCM.

[0122] Peptide cleavage from the resin with further deprotection of the acid-labile protecting groups The fully protected resin-bound peptide is washed with DCM and then dissolved in a mixture of TFA / TIPS / DCM (v / v / v; 95 / 2.5 / 2.5) and shaken for 30 min. The solution is filtered and the resin is treated in the same way for another 30 min. Both filtrates are combined and concentrated under a stream of nitrogen. The residue is dissolved in MeOH and precipitated with diethyl ether, after which the liquid is decanted and the remaining solid is dried.

[0123] residual t Bu / Boc deprotection Residual after peptide cleavage from resin t Removal of the Bu / Boc protecting groups (see above) is carried out by dissolving the crude product in TFA and stirring at room temperature for 6 hours. After removal of the TFA under a stream of nitrogen, the crude unprotected product is obtained.

[0124] Example 3 Materials and Methods (Labeling Experiments) Non-radioactive complex formation [ nat Ga]Gallium complex formation Purified chelator-containing ligand (Tracepur H 2 10 in O -3 M, 1.00 equivalents) and [ nat Ga]Ga(NO 3 ) 3 6H 2 O(Tracepur H 2 10 mM in HO, 1.50 equivalents) in Tracepur water to a final concentration of 10 -4Dilute to 100 mM and heat to 70° C. for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0125] [ nat Lu] Lutetium complex formation Purified chelator-containing ligand (Tracepur H 2 10 in O -3 M, 1.00 equivalents) and [ nat Lu]LuCl 3 (Tracepur H 2 20 mM in HO, 2.50 equivalents) in Tracepur water to a final concentration of 10 -4 Dilute to 0.1M and heat to 95° C. for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0126] radioactive label [ 125 I]Iodine labeling I C 50 Reference ligand for the study ([D-3-[ 125 I]I-Tyr 6 ]MJ9) is prepared according to a previously published procedure. Briefly, 0.2 mg of [D-Tyr 6 ]MJ9 is dissolved in 20 μL of Tracepur water and 280 μL of TRIS buffer (25 mM TRIS HCl, 0.4 M NaCl, pH = 7.9). After adding the solution to a vial containing 150 μg Iodo-Gen® (1,3,4,6-tetrachloro-3α,6α-diphenylglycolyl, surface-bound), 5.0 μL (16 MBq) [ 125 Add [I]NaI (74 TBq / mmol, 3.1 GBq / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany). Incubate the reaction solution at room temperature for 15 min and analyze by RP-HPLC (20 → 35% in 20 min): R = 18.9 min, K' = 10.46.

[0127] [ 177 Lu] Lutetium labeling [ 177Labeling with [Lu] lutetium is performed using a procedure developed in-house. Therefore, purified chelator-containing ligand (Tracepur H 2 10 in O -3 M, 1 μL), sodium acetate buffer (1 M, pH = 5.50, 10 μL) and approximately 10–30 MBq [ 177 Lu]LuCl 3 The solution (0.04M in HCl) is diluted to a total volume of 90 μL with HCl (0.04M) and heated to 95°C for 10 min. Sodium ascorbate (0.1M, 10 μL) is added immediately after labeling to prevent radiolysis. 177 The incorporation of [Lu] lutetium is determined by radio-TLC (ITLC-SG chromatography paper, mobile phase: 0.1 M trisodium citrate). The radiochemical purity of the labeled compounds is determined by radio-RP-HPLC.

[0128] [ 99m Tc]Technetium labeling [ 99m Labeling with [Tc]technetium is accomplished using a procedure developed in-house. Thus, purified chelator-containing ligand (Tracepur H 2 10 in O -3 M, 5 μL), NaHPO 4 Buffer (0.05M, pH=11.5, 25μL), sodium citrate buffer (0.1M, 3μL), SnCl 2 solution (1 g / L in sodium ascorbate solution (3 g / L), 5 μL), and approximately 50–150 MBq [ 99m TcO 4 ] - Heat the solution to 95°C for 10 minutes. 99m The incorporation of [Tc]technetium is determined by radio-TLC (ITLC-SG chromatography paper, mobile phase: isotonic NaCl). The radiochemical purity of the labeled compounds is determined by radio-RP-HPLC.

[0129] Example 4 Materials and Methods (in vitro experiments) n-Octanol-PBS partition coefficient, logD 7.4 Approximately 1 MBq of labeled tracer was dissolved in 1 mL of a 1:1 mixture (v / v) of phosphate-buffered saline (PBS, pH = 7.4) and n-octanol in an Eppendorf tube. After vigorously mixing the suspension for 3 min at room temperature, the vial was centrifuged at 9000 rpm for 5 min (Biofuge 15, Heraus Sepatech, Osterode, Germany) and 200 μL aliquots of both layers were measured in a γ-counter. This experiment was repeated at least four times.

[0130] I C 50 Decision GRPR-positive PC-3 cells were cultured in Dublecco's modified Eagle's medium / Nutrition Mixture F-12 with Glutamax-I (1:1) (Invitrigon) supplemented with 10% fetal bovine serum and incubated at 37 °C for 24 h at 5% CO. 2 The cells were maintained at 37°C in a humidified atmosphere. GRPR affinity (IC 50 For the determination of ), cells are harvested 24 ± 2 h before the experiment and seeded into 24-well plates (1.5 × 10 in 1 mL / well). 5 contains 100 cells).

[0131] After removing the medium, the cells were washed once with 500 μL of HBSS (Hank's balanced salt solution, Biochrom, Berlin, Germany, supplemented with 1% bovine serum albumin (BSA)) and equilibrated in 200 μL of HBSS (1% BSA) for 9 min at room temperature. Then, the cells were incubated with either HBSS (1% BSA) as a control or increasing concentrations of the respective ligand (10 -10 M~10 -4 Add 25 μL of a solution containing [D-3-[ 125 I]I-Tyr 6 ]Add 25 μL of MJ9 (2.0 nM).

[0132] All experiments are performed in triplicate for each concentration. After 2 h incubation at room temperature, the experiment is terminated by removing the medium and rinsing successively with 300 μL HBSS. The medium from both steps is combined into one fraction, which represents the amount of free radiolabeled reference. The cells are then lysed with 300 μL 1 M NaOH for at least 15 min and merged with 300 μL NaOH from the next washing step. Quantification of bound and free radiolabeled reference is performed in a γ-counter. IC for each ligand 50 This decision was repeated twice.

[0133] internalization For internalization studies, PC-3 cells are harvested 24 ± 2 h before the experiment and seeded in 24-well plates (1.5 × 10 5 After removing the medium, the cells were washed once with 500 μL DMEM / F-12 (5% BSA) and equilibrated in 200 μL DMEM / F-12 (5% BSA) at 37°C for at least 15 minutes. Each well was then resuspended in 25 μL DMEM / F-12 (5% BSA) or 25 μL [ nat Lu]RM2(10 -3 M) and block. Then, 25 μL of 125 I / 177 Lu-labeled GRPR ligand (10 nM) is added and the cells are incubated at 37° C. for 60 min.

[0134] The experiment is terminated by placing the 24-well plate on ice for 1 min and successively removing the medium. Each well is rinsed with 300 μL ice-cold PBS and the fractions from these first two steps are combined and expressed as the amount of free radiolabeled reference. Surface-bound activity is removed by incubating with 300 μL ice-cold acidic washing solution (0.02 M NaOAc, pH = 5.0) for 10 min at room temperature and rinsing again with 300 μL ice-cold PBS. Internalized activity is determined by incubation with 300 μL NaOH (1 M) and combined with the fractions from the subsequent washing step with 300 μL NaOH (1 M).

[0135] Each experiment (control and blocked) is performed in 6 replicates. Free, surface-bound and internalized activity are quantified in a γ-counter. Data are corrected for nonspecific internalization.

[0136] plasma research The in vitro metabolic stability was determined by applying the procedure published by Linder et al. with minor modifications. Immediately after labeling, human (200 μL) or mouse (100 μL) plasma was added and the mixture was incubated at 37 °C for 72 ± 2 h (or 6 ± 0.5 h). Proteins were precipitated by treatment with ice-cold EtOH (150 μL [human], 100 μL [mouse]) and ice-cold MeCN (450 μL [human], 300 μL [mouse]) and centrifugation at 13000 rpm for 20 min. The supernatant was decanted and further analyzed by radioactive RP-HPLC.

[0137] Example 5 Materials and Methods (in vitro experiments) All animal experiments followed the general German animal protection regulations (German Animal Protection Act as amended on 2018.05.18, Art. 141Gv.29.3.2017I626, approval number ROB-55.2-2532.Vet_02-18-109) and the institutional guidelines for the care and use of animals. To establish tumor xenografts, PC-3 cells (5 × 10 per 200 µL) were cultured in 1000 x 100 cells / mL for 1 h. 6 Cells) were suspended in a 1:1 mixture (v / v) of Dulbecco's Modified Eagle Medium / Ham's F-12 (DMEM / F-12) containing Glutamax-I (1:1) and Cultrex® Basement Membrane Matrix Type 3 (Trevigen Inc., Gaithersburg, MD, USA) and inoculated subcutaneously into the right shoulder of 6- to 10-week-old female CB17-SCID mice (Charles River Laboratories International Inc., Sulzfeld, Germany). Mice were cultured with 100% lysed ... 3 They were used in the experiment 2 to 3 weeks after inoculation.

[0138] Biodistribution Approximately 1–5 MBq (100–200 pmol) of radiolabeled GRPR antagonist was injected into the tail vein of PC-3 tumor-bearing mice and sacrificed at 1, 4, or 24 h p.i. (n=4). Selected organs were harvested, weighed, and assayed in a γ-counter (Perkin Elmer, Waltham, MA, USA).

[0139] μSPECT / CT imaging Imaging research with MILabs VECTor 4 The studies were performed on a small animal SPECT / PET / OI / CT device (MILabs, Utrecht, the Netherlands). Data were reconstructed using MILabs Rec software (version 10.02) and a pixel-based Similarity-Regulated Ordered Subsets Expectation Maximization (SROSEM) algorithm, followed by data analysis using PMOD4.0 software (PMOD TECHNOLOGIES LLC, Zurich, Switzerland). For SPECT studies, mice were anesthetized with isoflurane and injected with 2–4 MBq (100–200 pmol) of radiolabeled tracer in the tail vein. Still images were recorded at 1 h and 28 h pi with an acquisition time of 45–60 min using a HE-GP-RM collimator and stepwise multiplanar bed movement.

[0140] Example 6 result GRPR reference ligand [ka]

[0141] Exemplary Synthetic Competitive GRPR Ligands of the Invention [ka]

[0142] HPLC [ natGa]RM2 (10→90% MeCN in 15 min):t R =6.7 minutes, K'=3.47. Calculated monoisotopic mass (C 78 H 115 GaN 20 O 19 ): 1704.8, detection: m / z = 1706.6 [M+H] + , 854.1[M+2H] 2+ . [ nat Ga]DOTA-[Hse 7 ]MJ9 (10→90% MeCN in 15 min):t R =6.8 minutes, K'=3.53. Calculated monoisotopic mass (C 77 H 114 GaN 19 O 19 ): 1677.8, detection: m / z = 1679.3 [M+H] + , 840.4[M+2H] 2+ . [ nat Ga]DOTA-[Bta 8 ]MJ9 (10→90% MeCN in 15 min):t R =7.0 min, K'=3.67. Calculated monoisotopic mass (C 78 H 114 GaN 19 O 19 S): 1721.7, detection: m / z = 1723.7 [M + H] + , 862.3[M+2H] 2+ . [ nat Ga]AMTG (10→90% MeCN in 15 min):t R =6.9 minutes, K'=3.60. Calculated monoisotopic mass (C 79 H 117 GaN 20 O 19 ): 1718.8, detection: m / z = 1720.0 [M+H] + , 860.6[M+2H] 2+ . [ natGa]AMTG2 (10→90% MeCN in 15 min):t R =6.9 minutes, K'=3.31. Calculated monoisotopic mass (C 82 H 121 GaN 20 O 21 ): 1790.8, detection: m / z = 896.3 [M+2H] 2+ , 1792.6[M+H] + . [ nat Lu]RM2 (10→90% MeCN in 15 min):t R =6.6 minutes, K'=3.40. Calculated monoisotopic mass (C 78 H 115 LuN 20 O 19 ): 1810.8, detection: m / z = 1812.2 [M+H] + , 906.8[M+2H] 2+ . [ nat Lu]DOTA-[Hse 7 ]MJ9 (10→90% MeCN in 15 min):t R =6.8 minutes, K'=3.53. Calculated monoisotopic mass (C 77 H 114 LuN 19 O 19 ): 1783.8, detection: m / z = 1784.9 [M+H] + , 893.6[M+2H] 2+ . [ nat Lu]DOTA-[Bta 8 ]MJ9 (10→90% MeCN in 15 min):t R =7.0 min, K'=3.67. Calculated monoisotopic mass (C 78 H 114 LuN 19 O 19 S): 1827.8, detection: m / z = 1828.9 [M + H] + , 915.1[M+2H] 2+ . [ nat Lu]AMTG (10→90% MeCN in 15 min):tR =6.8 minutes, K'=3.53. Calculated monoisotopic mass (C 79 H 117 LuN 20 O 19 ): 1824.8, detection: m / z = 1826.3 [M+H] + , 913.6[M+2H] 2+ . [ nat Lu]AMTG2 (10→90% MeCN in 15 min):t R =7.0 min, K'=3.38. Calculated monoisotopic mass (C 82 H 121 LuN 20 O 21 ): 1896.8, detection: m / z = 949.5 [M+2H] 2+ , 1897.6[M+H] + . [ nat Lu]NeoBOMB1 (10→90% MeCN in 15 min):t R =9.6 minutes, K'=5.00. Calculated monoisotopic mass (C 77 H 107 LuN 18 O 18 ): 1746.7, detection: m / z = 874.5 [M+2H] 2+ , 1747.3[M+H] + .

[0143] Determination of hydrophilicity (n-octanol / l-PBS partition coefficient, logD 7.4 ) 177 The determined n-octanol / PBS partition coefficients (logD 7.4 ) are shown in Table 2. For all compounds, either DOTA or DOTAGA was used as the chelating agent. 177 Of the Lu-labeled GRPR ligands, the reference RM2 was found to be the most hydrophilic, while the 3-benzothienylalanine (Bta) modified derivative was found to be the most lipophilic.

[0144] [Table 4]

[0145] Determination of affinity of GRPR The synthesized compounds showed similar affinity, but the homoserine derivative showed a slightly lower affinity. nat The gallium complex ligand is nat The affinity of the non-radioactive standard [D-3-I-Tyr] lutetium complex was high, similar to that of the corresponding [D-3-I-Tyr] lutetium complex (Table 3). 6 ]MJ9 showed particularly high affinity and all IC 50 It was suggested that it would be suitable as a competitive radiolabeled reference for experiments.

[0146] [Table 5]

[0147] internalization To demonstrate the antagonistic activity of the modified statin GRPR ligands, we determined their internalization into PC-3 cells. 177 Lu-labeled compounds showed low internalization, as expected from antagonists (Table 4). 177 The internalization of [Lu]RM2 correlated well with the results of other published studies.

[0148] [Table 6]

[0149] plasma research The in vitro stability of synthetic GRPR ligands was measured in human plasma (Figures 1-4), while the stabilizing ligand [ 177 Lu]AMTG and references 177[Lu]RM2 was further analyzed in mouse plasma. Therefore, only 100 μL of mouse plasma was added to the tracer solution (final volume 200 μL) immediately after the end of labeling. According to Linder et al. (Bioconjugate Chem. 20, 1171-1178 (2009)), the experiment was terminated after 6 ± 0.5 h of incubation at 37 °C, due to the faster metabolism in mouse plasma than in human plasma (Figures 5 and 6). However, due to the smaller volume of the mouse mixture, it was additionally examined after 72 ± 2 h of incubation at 37 °C (Figures 7 and 8). Four 177 When comparing the Lu-labeled GRPR ligands in human plasma after incubation at 37°C for 72 ± 2 h (Figs. 1–4), significant differences in the amount of unchanged tracer were observed. 177 The in vitro stability of [Lu]RM2 (Fig. 1) was determined to be only 33.5 ± 2.7% during that time period, whereas [ 177 Lu]DOTA-[Hse 7 ]MJ9 (40.1±1.4%) and [ 177 Lu]AMTG (77.6 ± 10.1%) was higher after 72 ± 2 h incubation at 37 °C. The most lipophilic derivative, [ 177 Lu]DOTA-[Bta 8 ]MJ9 (19.0 ± 1.7%) was the least stable of these four compounds. 177 Lu]NeoBOMB1 exhibited 60.8 ± 1.2% unchanged tracer amount after the same time period.

[0150] Reference compound [ 177 Lu]RM2 (Figures 5 and 7) and the stabilized derivative [ 177 Lu]AMTG (Figures 6 and 8) was further investigated in mouse plasma to investigate possible differences between humans and animals. According to Linder et al., the metabolism in mouse plasma after about 6 hours is comparable to that in human plasma after about 3 days. Thus, the stability of these two ligands after 6 hours in mouse plasma was measured, and the unchanged [ 177Lu]AMTG (tR = 17.0 min, 89%, Fig. 6 and 92%, Fig. 4, respectively) were found to be in comparable amounts, whereas [ 177 Lu]RM2 unchanged ligand was significantly biased (tR = 15.5 min, 92%, Fig. 5 and 36%, Fig. 1, respectively).

[0151] When we examined these two tracers in mouse plasma after a longer time period (72 ± 2 h incubation at 37°C), [ 177 Lu]RM2 (Figure 7) is 177 Although it was cleaved by mouse endopeptidases to a greater extent than [Lu]AMTG (Fig. 8), the amount of unchanged tracer still appeared to be high (67% and 59%, respectively), suggesting that there may be large differences between human and animal plasma, especially for the reference compounds.

[0152] From these observations, stabilization 177 We show that [Lu]AMTG outperforms the reference ligand in vivo in humans, but not necessarily in mice.

[0153] Biodistribution and μSPECT / CT studies Reference compound [ 177 Lu]RM2 and diagnostic ligands[ 177 Lu]DOTA-[Hse 7 ]MJ9 and [ 177 Lu]DOTA-[Bta 8 The in vivo pharmacokinetics of MJ9 was examined in CB17-SCID mice at 1 and 24 h pi, whereas the therapeutic ligand 177 Lu]AMTG, 177 Lu]AMTG2 and the second reference [ 177 Lu]NeoBOMB1 was only examined (100 pmol each) at 24 hours pi. The data are compared to the references shown in Figures 9 to 12.

[0154] Both destabilized compounds show superior pharmacokinetic profiles compared to the reference ligand in mice at 1 hour pi (Figures 9 and 10). In all organs, the uptake of the diagnostic ligands was comparable to or lower than the reference, especially in the GRPR-positive pancreas, highlighting a fast washout from this organ likely due to high metabolism at the destabilized site. Interestingly, tumor uptake of both diagnostic ligands was superior to the reference compound (Figure 9), with [ 177 This led to the hypothesis that tumor enrichment at high levels, such as that achieved with [Lu]RM2, would be possible. Furthermore, because metabolism in tumors is less rapid than in non-tumor organs, no negative washout effect from tumors was observed at 1 h pi, despite destabilizing conjugation of the diagnostic derivative.

[0155] As shown by the tumor / background ratio (Figure 10), 177 Lu]DOTA-[Hse 7 ]MJ9 showed the best contrast between tumor and nontumor organs at 1 hour pi, while the reference was the poorest of these three.

[0156] Three ligands, [ 177 Lu]NeoBOMB1, stabilized[ 177 Lu]AMTG and [ 177 Lu]AMTG2 was examined 24 hours pi in CB17-SCID mice (Figures 11 and 12). The pharmacokinetic profile confirms the suggestion that destabilizing ligands are washed out faster from tumors after a longer time period. All four compared ligands were similarly retained in normal tissues, whereas in tumors, [ 177 Lu]RM2, [ 177 Lu]AMTG, 177 There was a significant difference in retention, as [Lu]AMTG2 was still present in large amounts and the destabilizing compound was in small amounts. 177 Lu]NeoBOMB1 also showed high tumor retention in the tumor, but also in the pancreas. Uptake into bone for all derivatives was not fully complexed with their respective chelators [177 Lu]LuCl 3 This can be explained by (Figure 11).

[0157] [ 177 Lu]RM2, [ 177 Lu]AMTG, 177 [Lu]AMTG2 showed higher tumor retention at 24 hours pi than the other derivatives in this series (Figure 11). Considering the tumor / background ratio after that time period, [ 177 Lu]AMTG and [177 Lu]AMTG2 showed superior tumor-to-blood and tumor-to-muscle ratios (Figure 12). 177 Both [Lu]NeoBOMB1 and [Lu]NeoBOMB1 showed tumor / background ratios lower than the reference. 177 Lu]RM2 and [ 177 Imaging studies of [Lu]AMTG show their in vivo distribution over time (Figure 19). Both conjugates showed good pharmacokinetics, with fast clearance from GRPR-positive tissues (pancreas, intestine) and high retention in the tumor, respectively. Background activity was [ 177 In the case of [Lu]AMTG, clearance from the pancreas was particularly slow, which was expected due to its high metabolic stability in vivo.

[0158] In conclusion, considering the results, both destabilized ligands outperformed the reference in mice at 1 hour pi, but were significantly inferior in mice at 24 hours pi, which suggests that 177 Lu]DOTA-[Bta 8 ]MJ9 was found to have the lowest metabolic stability in vitro, which correlates well with the observations in the plasma studies. As mentioned before, metabolism in non-tumor tissues is faster than in tumor tissues, leading to the well-known washout effect of GRPR antagonists. Gln 7 -Trp 8Further destabilization of the bond resulted in faster washout from the background but not from the tumor, providing excellent contrast compared to the reference at 1 h p.i. However, after longer time periods, significantly faster washout from the tumor was observed, with the more lipophilic [ 177 Lu]DOTA-[Bta 8 ] The hypothesis that the enzymatic degradation of MJ9 is increased was confirmed, and therefore it may be useful as a diagnostic agent.

[0159] Another destabilizing derivative [ 177 Lu]DOTA-[Hse 7 ]MJ9 showed only limited in vitro stability in human plasma, but its in vivo behavior in mice showed rapid clearance from nontumor tissues at 1 hour pi and minimal retention in tumors at 24 hours pi, suggesting little metabolic stability.

[0160] Stabilizing compounds [ 177 Considering the in vitro and in vivo results, [Lu]AMTG showed particularly good overall performance, with good affinity for GRPR-expressing PC-3 cells, moderate lipophilicity, the best metabolic stability in human plasma, and 177 AMTG has been confirmed to have pharmacokinetic properties equivalent to or superior to those of [Lu]RM2. Because of its high in vitro metabolic stability in human plasma, AMTG may have the potential to compete with or even surpass the current gold standard of GRPR-targeting ligands (RM2, NeoBOMB1) for targeted radiotherapy of GRPR-expressing malignancies in men.

[0161] Example 7 [ 99m Tc]N4-containing ligands Test Compounds [ka]

[0162] In vitro data The determined n-octanol-PBS partition coefficient (logD 7.4 ) and 99m Binding affinity (IC) of Tc-labeled compounds to GRPR 50 ) are shown in Table 5. For all compounds, N 4 (6-(carboxy))-1,4,4,11-tetraazaundecane) was used as the chelating agent.

[0163] [Table 7]

[0164] In this series, 99m Tc]N 4 -asp-MJ9 was found to be the most hydrophilic, while the other three compounds were found to be similar but more lipophilic. All conjugates had similar IC in the low nanomolar range. 50 However, homoserine and α-methyltryptophan derivatives had slightly reduced GRPR affinity compared to the other two ligands in this series.

[0165] In vivo data 99m The in vivo pharmacokinetics of Tc-labeled ligands (8), (9), (10), and (11) were studied in CB17-SCID mice at 1 h pi and 4 h pi (200 pmol each). 99m Tc]N 4 -asp-MJ9(8), [ 99m Tc]N 4 -asp-[Bta 8 ]MJ9 and [ 99m Tc]N 4 -[Hse 7 ]MJ9 showed excellent pharmacokinetics at 1 hour pi, with high tumor and low overall background accumulation (Figure 13). In GRPR-positive pancreas, [ 99m Tc]N 4 -asp-[Bta 8]MJ9 showed the lowest uptake, highlighting its rapid washout from this organ due to the high metabolic rate at the destabilized site. 99m Tc]N 4 -[Hse 7 ]MJ9 was found to have the highest tumor uptake and the second lowest pancreatic uptake in this series.[ 99m Tc]N 4 -[α-Me-Trp 8 ]MJ9 had the highest accumulation in the pancreas, presumably due to its improved metabolic stability due to the α-methyltryptophan modification, as already mentioned in the previous section. The tumor / background ratio at 1 h pi was mostly [ 99m Tc]N 4 -asp-MJ9 was advantageous (Figure 14). 177 Lu]DOTA-asp-[Bta 8 ]MJ9 and [ 177 Lu]DOTA-[Hse 7 ]MJ9 is [ 99m It was speculated that if the α-Tc complex showed similar hydrophilicity to N4-asp-MJ9, it would improve the tumor / background ratio.

[0166] Biodistribution studies 4 hours p.i. demonstrated that these 99m The in vivo time course of Tc-labeled ligand was revealed (Figure 15). 99m Tc]N 4 -[α-Me-Trp 8 ]MJ9 showed increased tumor accumulation compared to 1 h pi, whereas all other derivatives in the series showed decreased tumor values, further supporting the suggestion of improved metabolic stability by α-methyltryptophan modification. 99m In the case of [Tc]technetium, this is undesirable since for diagnostic reasons, high tumor uptake at 1 hour pi (not just 4 hours pi) and fast clearance from background organs is desired. Nevertheless, this modification is useful for therapeutic compounds, e.g. 177This is very useful for Lu-labeled ligands. Faster clearance from background organs is beneficial for diagnostic compounds, so [ 99m Tc]N 4 -asp-[Bta 8 ]MJ9 is ideal for use due to its enhanced metabolic instability, which is highlighted by the uptake values ​​in most organs at 4 hours pi. The tumor / background ratios at 4 hours pi are shown in Figure 16, with most organs showing [ 99m Tc]N 4 -asp-MJ9 and [ 99m Tc]N 4 -[Hse 7 ]MJ9 has been shown to be the best.

[0167] The excellent contrast at 1 hour pi enabled by the destabilizing modifications homoserine and 3-benzothienylalanine was further accentuated by μSPECT / CT imaging (Figure 17). 99m Tc]N 4 -asp-[Bta 8 ]MJ9 and [ 99m Tc]N 4 -[Hse 7 ]MJ9, despite its high lipophilicity, is a soluble form of unmodified [ 99m Tc]N 4 -The contrast is slightly enhanced compared to asp-MJ9. 99m Tc]N 4 -[α-Me-Trp 8 ]MJ9 has high metabolic stability and slow pancreatic and intestinal clearance, so it is expected to have inferior contrast to the other three derivatives, which is unfavorable for diagnosis.

[0168] Example 8 Bombesin-SiFA derivative Test Compounds

[0169] [Table 8]

[0170] In vitro data The determined n-octanol-PBS partition coefficient (logD 7.4 ) and the binding affinity (IC 50 ) are shown in Table 6. For all compounds, DOTAGA was used as the chelating agent.

[0171] [Table 9]

[0172] All four compounds in this series showed similar hydrophilicity. IC 50 The value is 177 Lu]GT50 and [ 177 Lu]GT52 is in the same range, [ 177 Lu]GT51 and [ 177 Lu] increased slightly in GT53.

[0173] Biodistribution studies All four compounds are 18 A SiFA moiety for F labeling; 68 Ga- or 177 It contains a chelating agent for Lu-labeling. 18 F][ nat Ga / nat Lu] ligand and [ 19 F][ 68 Ga / 177 This is a useful feature, as they are chemically indistinguishable regardless of which [Lu] ligand is applied, making radioactive hybrid-based ligands an ideal theranostic pair. 177 The biodistribution of Lu-labeled ligands GT50, GT51, GT52, and GT53 was assessed 24 hours p.i. (100 pmol each) in CB17-SCID mice. All derivatives showed low background retention overall, with the exception of liver and kidney (Figure 18). Tumor retention was [ 177 Lu]RM2, [ 177 Lu]AMTG and [ 177The radioactivity of the bombesin-SiFA conjugates was reduced compared to [Lu]AMTG2 (Figure 11). All bombesin-SiFA conjugates need to be optimized, especially considering the high retention in the kidney and somewhat higher retention in the liver. However, the ligands evaluated in this series proved the functionality of the radiohybrid-based concept.

Claims

1. A GRPR antagonist of formula (I): _________________________ １ ︁︁ ２ _______________________________! ５ ｨisa()) During the ceremony, S is a moiety capable of generating therapeutically active radiation; Y is an optional linker, Xaa １ is L-Gln, D-Gln, or L-His; Xaa ２ is α-Me-Trp, Xaa ５ is Gly, N-Me-Gly, D-Ala, or β-Ala; T is Sta-Leu-NH ２ , Leu-ψ(CH ２ N)-Pro-NH ２ , Leu-NHEt or NH-CH[CH ２ -CH(CH ３ ) ２ ] ２ where Sta is (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid. The GRPR antagonist.

2. Xaa １ The GRPR antagonist of claim 1, wherein is L-Gln.

3. Xaa ５ The GRPR antagonist of claim 1 , wherein is Gly.

4. A GRPR antagonist of formula (II): _________________________ ３ ︁︁ ４ _______________________________! ５ ___________________________________________________ During the ceremony, S is a moiety capable of producing a detectable signal; Y is an optional linker, Xaa ３ is L-Gln, D-Gln, or L-His; Xaa ４ is Bta, Xaa ５ is Gly, N-Me-Gly, or β-Ala; T is Sta-Leu-NH ２ , Leu-ψ(CH ２ N)-Pro-NH ２ , Leu-NHEt or NH-CH[CH ２ -CH(CH ３ ) ２ ] ２ where Sta is (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid. The GRPR antagonist.

5. A GRPR antagonist of formula (II): _________________________ ３ ︁︁ ４ _______________________________! ５ ___________________________________________________ During the ceremony, S is a moiety capable of producing a detectable signal; Y is an optional linker, Xaa ３ is Hse, Xaa ４ is Trp, Xaa ５ is Gly, N-Me-Gly, or β-Ala; T is Sta-Leu-NH ２ , Leu-ψ(CH ２ N)-Pro-NH ２ , Leu-NHEt or NH-CH[CH ２ -CH(CH ３ ) ２ ] ２ where Sta is (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid. The GRPR antagonist.

6. Xaa ３ The GRPR antagonist of claim 4, wherein is L-Gln.

7. Xaa ５ The GRPR antagonist of claim 4 or 5, wherein is Gly.

8. The GRPR antagonist of any one of claims 1 to 3, wherein S is selected from a radioactive moiety and a moiety capable of carrying a radionuclide.

9. The GRPR antagonist of any one of claims 4 to 7, wherein S is selected from a fluorescent moiety, a radioactive moiety and a moiety capable of carrying a radionuclide.

10. Y, (a) containing 1, 2, 3, 4, 5 or 6 positive and / or negative charges; (b) comprising or consisting of 1, 2, 3, 4, 5 or 6 amino acids; (c) PEG ｎ and / or comprising or consisting of: (d) comprising a moiety capable of producing a detectable signal; A GRPR antagonist according to any one of claims 1 to 9.

11. The GRPR antagonist of claim 10, wherein the amino acid in (b) is a D-amino acid.

12. The GRPR antagonist of claim 10, wherein the amino acid in (b) is a D-α-amino acid.

13. The linker Y is (i) D-Glu-urea-D-Glu, (ii) one or two 2,3-diaminopropionic acid moieties, optionally substituted with a moiety capable of producing a detectable signal; (iii) D- / L-aspartic acid, D- / L-ornithine, 4-amino-1-carboxymethyl-piperidine (Pip), D- / L-2,3-diaminopropionic acid, D- / L-serine, D- / L-citrulline moiety, L-cysteic acid (Ala(SO ３ H)), 1, 2, 3, 4, 5 or 6 consecutive amino acids comprising or consisting of one or more amino acids selected from aminovaleric acid (Ava), 4-aminobenzoic acid (PABA) and D-Phe, and / or (iv) p-aminomethylaniline-diglycolic acid (pABza-DIG, AMA-DGA), and / or diglycolate (DIG, DGA); Comprising or consisting of A GRPR antagonist according to any one of claims 10 to 12.

14. A pharmaceutical composition comprising or consisting of a GRPR antagonist according to any one of claims 1 to 3, 8 and 10 to 13.

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