Modified grpr antagonist peptides for imaging and therapy of cancer

Abstract

To provide improved radiopharmaceuticals and radiodiagnostics, in particular in the field of cancer, including improvements in pharmacokinetic properties.SOLUTION: The present invention relates to a compound binding to an endogenous receptor, the compound comprising (i) an oligopeptide comprising a dipeptide with Trp being the C-terminal amino acid of the dipeptide, wherein the Trp is replaced with an α-amino acid Xaa2, whereby the stability in serum or plasma of the peptide bond connecting Xaa2 to the N-terminally adjacent amino acid is increased as compared to the peptide bond connecting Trp to the N-terminally adjacent amino acid in an otherwise identical compound; and (ii) a moiety capable of generating therapeutically effective radiation, the moiety being covalently bound to the oligopeptide.SELECTED DRAWING: Figure 12

Description

Technical Field

[0001] (No corresponding part in the original text)

Background Art

[0002] Prostate cancer (PCa), one of the malignant diseases that are more common in men in Europe and the United States, still poses a medical treatment challenge because the survival rate deteriorates as the disease progresses. It has been found that the earlier the diagnosis, the higher the success rate of treatment, and new treatment methods are needed. In the past few decades, there has been an increasing interest in nuclear medicine-based cancer diagnosis and treatment using radioactive tracers that accumulate rapidly almost only in tumor sites.

[0003] Prostate-specific membrane antigen (PSMA) tracers exhibit excellent properties such as overexpression in prostate cancer, low expression in healthy tissues, fast clearance rate, and high incidence (92% of all prostate cancers), and are commonly used for internal radiotherapy and imaging of PCa. However, PSMA has the drawbacks of being easily taken up by the kidneys and salivary glands, and having low expression in the early stage of the disease.

[0004] As an interesting alternative, gastrin-releasing peptide receptor (GRPR) also shows good expression in PCa (up to 100% in the early stage and 60% in the late stage), is overexpressed in malignant tissues, and shows high expression only in one healthy tissue (the pancreas). This is advantageous compared to PSMA in cases where uptake in the kidneys is high during kidney metastasis and thus it cannot be detected appropriately even when using a PSMA tracer. Furthermore, damage to the salivary glands and kidneys due to high-concentration accumulation of PSMA tracers seems to be a concern in high-dose treatments.

[0005] GRPR shows high expression in the early stages of PCa, while overexpression of PSMA is more frequently observed in the later stages of the disease. Furthermore, overexpression of GRPR has also been recognized in estrogen receptor (ER)-rich breast cancer, making it possible to use the same tracer for different cancers and genders. Therefore, GRPR tracers can serve as an alternative for patients with low PSMA expression and are useful tools for diagnosing metastases in the renal region. Additionally, for the incidental treatment of prostate cancer (early stage), using GRPR tracers instead of PSMA tracers is beneficial because of their high expression rate and few side effects (salivary gland disorders). Moreover, since GRPR is overexpressed in prostate and breast cancers, GRPR antagonists may have the potential to be used regardless of gender.

[0006] To date, both agonists and antagonists of GRPR have been used and are still being used in clinical settings. Agonists show side effects accompanied by pain after application to patients, and the development of antagonists has advanced because of their poor pharmacokinetics due to significantly slow washout from non-tumor tissues. The GRPR derivatives used clinically are clearly fewer compared to PSMA ligands. However, since 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 considered to have clinical advantages.

[0007] The general required structure of antagonistic GRPR molecules includes a binding unit based on the C-terminal part of natural bombesin or gastrin-releasing peptide (GRP) with sub-nanomolar affinity. The linker part between the pharmacologically active part and the N-terminal chelator is not necessarily required because there are tracers that still show good performance, but there are also many reports showing beneficial effects in terms of pharmacokinetics by using the linker unit.

[0008] Among GRPR antagonists, the derivative RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is the most commonly used agent for selective GRPR imaging and therapy. 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.

[0009] 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.

[0010] Nevertheless, certain bombesin analogs are metabolically unstable in animals, limiting their necessary accumulation in tumor tissue.

[0011] 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.

[0012] 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]

[0013] From the above, the technical problem underlying the present invention is considered to be to provide improved radiopharmaceuticals and radiodiagnostic agents, including improvements in pharmacokinetic properties, particularly in the field of cancer.

[0014] This technical problem is solved by the problems disclosed below.

Means for Solving the Problems

[0015] In a first aspect, the present invention relates to a compound that binds to an endogenous receptor, the compound comprising: (i) an oligopeptide comprising a dipeptide in which Trp is the C-terminal amino acid of the dipeptide, wherein the Trp is substituted with an α-amino acid Xaa2, whereby the stability of the peptide bond linking Xaa2 and the N-terminal adjacent amino acid in serum or plasma (preferably mammalian serum or plasma) is increased compared to the peptide bond in the same compound in other respects that links Trp and the N-terminal adjacent amino acid; and (ii) a moiety capable of generating a therapeutically effective radiation, the moiety being covalently bound to the oligopeptide.

[0016] A receptor is a molecule that can specifically bind its cognate ligand. The term "cognate ligand" designates the genus of the molecule and includes natural ligands and the compounds of the present invention. The receptor is preferably a polypeptide or protein. It may comprise a plurality of subunits that may be linked non-covalently or covalently to each other. Preferably, the receptor is a transmembrane protein or a membrane-bound protein. Preferably, the ligand-binding site is located extracellularly.

[0017] The term "endogenous" means the occurrence of a receptor in a human or animal body, an animal including a mammal, a mammal including a rodent. Preferred receptors are the subject of the preferred embodiments further disclosed below.

[0018] The compound of the first aspect comprises or consists of two parts. The first part is the targeting part. It comprises or consists of the oligopeptide disclosed above. The second part is the part that conveys the intended therapeutic effect, which is radiation in the case of a compound according to the first aspect. Thus, generally, since the target tissue is a hyperproliferative tissue such as a malignant tissue or includes them, it is understood that the treatment includes the destruction of the target tissue.

[0019] As will be further clarified below, in other aspects of the invention, the second part serves for diagnostic purposes.

[0020] In its broadest definition, the second part is not particularly limited except that it must have the ability to generate therapeutically effective radiation. According to 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 part which, in turn, is capable of carrying the radionuclide.

[0021] The term "oligopeptide" has its technically established meaning. It is a linear sequence of amino acids linked to each other 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, and most preferred is 9 amino acids. The term "oligopeptide" implies peptidic nature, but this term also encompasses compounds that are not essentially exclusively and predominantly peptidic. Preferably, assuming that the oligopeptide has N amino acids, at least (N - 1) / 2 of the bonds linking the amino acids are peptide bonds. For example, N - 1, N - 2 or N - 3 of the bonds linking the amino acids are peptide bonds.

[0022] Similar considerations also apply to the building blocks of the oligopeptide. That is, at least N / 2 of the building blocks are amino acids. For example, N, N-1, N-2, or N-3 building blocks are amino acids.

[0023] 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 also the following preferred embodiments.

[0024] Overall, naturally occurring, preferably proteinogenic α-amino acids are preferred. That being said, for the purpose of imparting certain technical effects, as will be further detailed below, at one or more positions, generally less than half of the positions of the 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 their naturally occurring L-counterparts, and / or by modifications regarding structure and composition.

[0025] Unless an amino acid is located at the end of the molecule, a given amino acid is understood to be linked to an adjacent site via a backbone peptide bond, such that in such cases, there will be no free carboxylic acid and primary amine.

[0026] Among the above oligopeptides, the dipeptide unit is particularly relevant. The position of the dipeptide unit within the oligopeptide is not particularly limited. However, it is preferred that the dipeptide unit is located within the N-terminal half of the oligopeptide.

[0027] Within said dipeptide, the C-terminal amino acid is a tryptophan derivative. In many cases, the naturally occurring ligands of the endogenous receptors mentioned are also essentially peptidic and have tryptophan at the corresponding position. The corresponding position is the position that aligns in the alignment of the sequences of the naturally occurring ligand and the compound of the first aspect.

[0028] According to the present invention, such tryptophan is modified. As will be further clarified below, the preferred modification is one that maintains the indole ring. Further, the amino functional group and the carboxy functional group are retained. In that sense, the meaning of the term "derivative" is accordingly limited, and the derivative must be an aromatic amino acid, preferably having a bicyclic ring, more preferably an indole ring. Further, according to the present invention, the tryptophan derivative is an α-amino acid.

[0029] According to the present invention, the modification of tryptophan serves to increase the stability of the peptide bond that links the tryptophan derivative (also called Xaa2) to the amino acid adjacent to the N-terminus in serum or plasma.

[0030] In this specification, the terms "increase in the stability of the peptide bond in serum or plasma" and "decrease in the cleavage of the peptide bond in serum or plasma" are used equivalently.

[0031] The stability in serum or plasma is preferably the stability in mammalian serum or plasma. Particularly preferred, from the perspective of preferred uses, the stability in serum or plasma is the stability in human serum or plasma. For the purposes of testing and development, the preferred serum or plasma is the serum or plasma of a rodent such as mouse serum or plasma. To determine the stability in serum or plasma, the compounds of the present invention are incubated, for example, at 37 °C for 3 days (e.g., 72 ± 2 hours).

[0032] 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 for the purpose of determining whether stability is increased. The reference compound for evaluating the compound of the first aspect is selected such that the only difference between the compound under consideration and the reference compound is at position Xaa2. In the reference compound, the position is tryptophan.

[0033] An increase in stability is understood to mean a statistically significantly increased stability and / or a stability increase of at least 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. A preferred parameter for determining the mentioned increase is the serum / plasma half-life. A preferred parameter for determining the mentioned increase is the amount of unchanged radiolabeled compound after incubation for 72 ± 2 hours in human / mouse serum or plasma.

[0034] 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 the reference compound.

[0035] The compounds according to the first aspect exhibit improved pharmacokinetic properties. The reference compound for comparison is defined above and differs from the compounds according to the first aspect only in that, at the position where the compounds according to the first aspect have a Trp derivative, unmodified tryptophan is present in the reference compound. Alternatively, the enhancement is in comparison to the respective natural ligand and / or a technically established therapeutic agent targeting the same receptor. Among the compounds of the first aspect that are GRPR ligands, a preferred technically established compound is RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, where the abbreviations of the chelating agent and the non-proteinogenic amino acids are further explained below).

[0036] The natural ligands of the preferred receptors according to the invention, said preferred receptors being the subject of the preferred embodiments further disclosed below, are as follows: in the case of the neuromedin B receptor, neuromedin B; in the case of the gastrin-releasing peptide receptor, gastrin-releasing peptide; in the case of the cholecystokinin 2 receptor, gastrin.

[0037] In the context of therapy, high tumor uptake and / or retention is understood to be desirable. Evidence in this regard is shown in the examples included herein.

[0038] The technical means for achieving high tumor uptake and retention are as shown above and consist of stabilizing the peptide bond within the dipeptide unit contained in the compounds according to the first aspect.

[0039] In a preferred embodiment of the compounds of the first aspect, the N-terminal adjacent amino acid in the dipeptide is L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln.

[0040] In a more 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 D of 50 nM or less, 15 nM or less, 5 nM or less or 1 nM or less, and / or (b) the compound is a GRPR antagonist, preferably with an IC 50 of 50 nM or less, 15 nM or less, 5 nM or less or 1 nM or less.

[0041] In a second aspect related to the first aspect, the present invention is a compound of formula (I), S-Y-Xaa1-Xaa2-L-Ala-L-Val-Xaa5-L-His-T(I) wherein, S is a moiety capable of generating therapeutically active radiation, Y is any linker, Xaa1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) an α-amino acid in which the stability of the Xaa1-Xaa2 peptide bond in serum or plasma is increased compared to the case of the same compound in other respects where Xaa1 is Gln and Xaa2 is Trp, Xaa2 is Trp or an α-amino acid in which the stability of the Xaa1-Xaa2 peptide bond in serum or plasma is increased compared to the case of the same compound in other respects where Xaa1 is Gln and Xaa2 is Trp, provided that simultaneously, Xaa1 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, and Xaa2 is not Trp, Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is any terminal group. A compound is provided.

[0042] The compounds of the second aspect are tailored to a specific endogenous receptor, which is GRPR, and thus include some features inherited from the natural cognate ligand, which is gastrin-releasing peptide (GRP).

[0043] According to the second aspect, the moiety capable of generating therapeutically active radiation is located at the N-terminus. The core of the compounds of the second aspect is an oligopeptide having six amino acids, and the dipeptide that defines the peptide bond to be stabilized according to the present invention is located at positions 1 and 2 of the core oligopeptide.

[0044] Any linker Y may or may not be present, and insofar as it is present, it may be a means for incorporating additional amino acids into the compounds of the second aspect.

[0045] Also, any terminal group T may be a means for extending the peptide portion of the compounds of the second aspect, but this is not necessarily the case.

[0046] The reference compound for determining whether stability in serum or plasma is increased is a compound that deviates from the compound of formula (I) under consideration in that Xaa1 is Gln and Xaa2 is Trp. As described above in connection with the compounds of the first aspect, alternative reference compounds may be employed, and such alternative reference compounds include natural ligands that bind to GRPR, such as RM2, and technically established pharmaceuticals.

[0047] In a preferred embodiment of the compounds of the first and second aspects, Xaa2 is (a) (i) an optionally substituted C1-C4 alkyl moiety bonded to the α-carbon, wherein the substituent is selected from halogen and hydroxyl, and / or (ii) a substituent bonded to the indole ring, wherein the substituent is 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, and Trp is modified to include a substituent selected from the group consisting of (b) 1,2,3,4-tetrahydronorharman-3-carboxylic acid (L-Tpi).

[0048] This preferred embodiment relates to specific structural means for achieving an increase in the stability of the backbone peptide bond of the dipeptide moiety present in the compounds of the first and second aspects (designated as Xaa1-Xaa2 in the case of the compounds of the second aspect).

[0049] Particularly preferred among these structural criteria are those defined in part (a)(i) of this preferred embodiment.

[0050] A more preferred embodiment thereof is that the optionally substituted alkyl moiety is -CH3, -CH2CH3, and CH n Hal 3-n (wherein n is 0, 1 or 2, and Hal is F, Cl, Br and / or I), for example selected from -CF3, preferably -CH3. Most preferably, Xaa2 is α-methyltryptophan.

[0051] 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 "derivative" of the compounds of Tables 1A and B, Tables 1A and B are further presented below.

[0052] Particularly preferred embodiments of the compounds of the first and second aspects are the compounds of formulas (IIIa and IIIb) further disclosed below.

[0053] A third aspect of the present invention is a compound of formula (II), S-Y-Xaa3-Xaa4-L-Ala-L-Val-Xaa5-L-His-T(II) wherein, S is a moiety capable of generating a detectable signal, Y is an optional linker, Xaa3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) an α-amino acid in which the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is reduced compared to the same compound in other respects where Xaa3 is Gln and Xaa4 is Trp, Xaa4 is Trp or an α-amino acid in which the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is reduced compared to the same compound in other respects where Xaa3 is Gln and Xaa4 is Trp, Said α-amino acid at position Xaa4, which reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma, is not a proteinogenic amino acid, provided that at the same time, respectively, Xaa3 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, and Xaa4 is not Trp, Xaa5 is Gly, N-Me-Gly, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an optional terminal group, relates to a compound.

[0054] The compounds of formula (II) show structural similarity to the compounds of formula (I) according to the second aspect, while being distinguished by the inferior stability of the peptide bond of the dipeptide moiety contained in the oligopeptide in serum or plasma.

[0055] This provides different but related technical effects. As is well established in the art, radiolabeled compounds are useful not only for therapy but also for diagnostic purposes. In the diagnostic setting, more rapid degradation is desired. This is because the metabolic activity in tumors is generally lower than that in the surrounding normal tissues, and as a result, more rapid degradation is associated with a higher tumor / background ratio, and such a high tumor / background ratio enables higher sensitivity, more detailed and / or more accurate detection of tumors and metastases.

[0056] It is understood that the two positions Xaa3 and Xaa4 correspond to, align with, and are simply distinguished for clarity from the positions Xaa1 and Xaa2 of the compound of the second aspect. In a specific structural implementation, Xaa1 and Xaa2 on the one hand and Xaa3 and Xaa4 on the other hand will generally be distinguished. This will become clearer in the context of the preferred embodiments of the third aspect disclosed further below.

[0057] For the purpose of determining the reduction in stability, what was described above in connection with the compounds of the first and second aspects applies mutatis mutandis. Thus, in vitro and in vivo serum or plasma assays may be used. A preferred readout is the serum / plasma half-life. A more preferred readout is the amount of unchanged radiolabeled compound after incubation for 72 ± 2 hours in human / mouse plasma. The reference compound for the purpose of determining reduced stability includes compounds that differ from the compound of formula (II) only in that the positions Xaa3 and Xaa4 are Gln and Trp, respectively, as described above.

[0058] As is established in the art, the three-letter code is generally used to specify amino acids. When the first letter is capitalized, the L-form is intended, while when the first letter is in lower case, the D-form is intended. For example, Trp refers to L-tryptophan and trp refers to D-tryptophan. Also, in this specification, explicit indications of stereochemistry are used (L-Trp, D-Trp, etc.).

[0059] The replacement reference compound is the respective natural ligand, which is GRP when the receptor is GRPR, or RM2, which is an antagonist.

[0060] In a preferred embodiment of the compound of formula (II), Xaa3 is Hse and / or Xaa4 is Bta (3-benzothienylalanine).

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

[0062] In a preferred embodiment 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.

[0063] The two previous preferred embodiments relate to the preferred embodiments of moiety S, depending on whether a therapeutic compound or a diagnostic compound is being considered.

[0064] In the range where a portion capable of carrying a radionuclide is used, the portion is preferably a metal ion chelating agent, 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-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]-pentanedioic acid (DOTAGA), N,N’-dipyridoxylethylenediamine-N,N’-diacetate-5,5’-bis(phosphate) (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-triazacyclononane triacetic 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(methyleneamine tetraacetic 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 (H2macropa), 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-tetraazoundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl}-1,4,8,11-tetraazoundecane (N4’), 1,4,7,10-tetraazacyclododecane-1,4.7-triacetic acid (DO3A), S-acetylmercaptoacetyltriseryl (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]triacosa-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[methyl(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(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]Nonane-3,7-diyl}bis(methylene))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’’’’,N’’’’’-hexaacetic acid (HEHA), 1,2-[{6-(carboxy)-pyridin-2-yl}-methylamino]ethane (H2dedpa), N,N’-bis{6-carboxy-2-pyridylmethyl}-ethylenediamine-N,N’-diacetic acid (H4octapa), 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-hexaazabicyclo[6.6.6]icosane (sar) and its functional derivatives, {4-[2-(biscarboxymethylamino)-ethyl]-7-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)-cyclohexyldiethylenetriamine pentaacetic 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 (H2azapa), N,N’-[[6-(carboxy)pyridin-2-yl]methyl]diethylenetriamine-N,N’,N’’-triacetic acid (H5decapa), N,N’-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N’-diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo[9.3.1] Selected from 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 (H6phospa), more preferably DOTA or DOTAGA. Preferably, the radioactive cation is bound to the chelating agent, and 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 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 166Dy, 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, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th, or 18 F-[AlF] 2+ such as 18 selected from cationic molecules containing F.

[0065] In the case of a therapeutic compound, the preferred nuclide is 177 Lu. Examples of preferred nuclides for diagnostic compounds are 68 Ga.

[0066] In preferred embodiments of the compounds of the second and third aspects, a linker Y is present and contains (a) 1, 2, 3, 4, 5 or 6 positive and / or negative charges, (b) 1, 2, 3, 4, 5 or 6 amino acids, preferably D-amino acids in said amino acids, more preferably D-α-amino acids, or consists of, (c) PEG n (wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) or consists of, and / or (d) contains a moiety capable of generating a detectable signal.

[0067] Suitable moieties capable of generating a detectable signal in accordance with item (d) of the above preferred embodiment may be fluorescent moieties or moieties that can contain or carry a radionuclide. An example of the latter is the silicon fluoride acceptor moiety (SiFA), which 18 can be used for F-labeling. As long as the compounds of the present invention containing such SiFA moieties further contain a chelating agent (such as DOTA or DOTAGA), such compounds contain two radionuclides and can thus be used for both diagnosis and treatment.

[0068] In a preferred embodiment, the SiFA moiety has a structure represented by formula (VI).

Chemical formula

[0069] The preferred attachment site of the SiFA moiety within the linker Y is the side chain of 2,3-diaminopropionic acid, the side chain consists of -CH2-NH2, 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).

[0070] The linker Y having a silicon fluoride acceptor moiety is a preferred linker Y for the compounds of all aspects of the present invention.

[0071] In a further preferred embodiment, the linker Y comprises or consists of: (a) D-Glu-urea-D-Glu; (b) optionally, one or two 2,3-diaminopropionic acid moieties which are substituted with a moiety capable of generating a detectable signal; (c) one or more amino acids selected from 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(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA) and D-Phe, being 1, 2, 3, 4, 5 or 6 consecutive amino acids, and / or (d) p-aminomethylaniline-diglycolic acid (abbreviated as pABza-DIG or AMA-DGA), and / or diglycolate (abbreviated as DIG or DGA).

[0072] Particularly preferred is that Y is Pip-phe.

[0073] The D-Glu-urea-D-Glu moiety according to item (a) of this preferred embodiment is considered to be a means for making the compound more hydrophilic.

[0074] In a more preferred embodiment of the compounds of the second and third aspects, i.e., for both the therapeutic and diagnostic agents, the terminal group T is present and (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, where the amide amine group of said Leu may be modified with ethyl (NH-ethyl) or NH2 (NH-NH2), and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)Pro-NH2), is included or consists thereof, provided that when T is an amino acid or ends with an amino acid, the carboxylic acid of said amino acid is amidated.

[0075] Particularly preferred is that T is Sta-Leu-NH2.

[0076] Regarding the preferred selection of moiety Y and T, generally, there is no distinction between the therapeutic and diagnostic compounds of the present invention.

[0077] As already further described above, in a preferred embodiment of the compounds of all aspects of the present invention, the serum or plasma is human serum or plasma. That is, of particular importance is the increase or decrease in stability in human serum or plasma, respectively.

[0078] Table 1A below shows the sequences of known GRPR binders. The hexapeptide sequences starting with Xaa1 and ending with L-His for compounds of formula (I) and starting with Xaa3 and ending with L-His for compounds of formula (II) correspond to positions 7 to 12 in the following table. As can be recognized, the GRPR binders shown in this table as a whole have tryptophan at position 8 (which corresponds to the positions of Xaa2 and Xaa4 respectively). Position 7 (which corresponds to Xaa1 and Xaa3 respectively) is highly conserved. As is apparent from the following table, in the art, it has not been recognized that the peptide bond linking positions 7 and 8 (the numbers in the table) is a target site for fine-tuning pharmacokinetic properties.

[0079] Tables 1B and 1C show the sequences of ligands acting on modified GRPR, and the effects of the introduction of either an α-Me-Trp or Bta moiety at position 8 or an Hse moiety at position 7 on different GRPR target compounds. Similar to Table 1A, the hexapeptide sequences starting with Xaa1 and ending with L-His for compounds of formula (I) and starting with Xaa3 and ending with L-His for compounds of formula (II) correspond to positions 7 to 12.

[0080] The problem arising from the metabolic degradation of GRPR-targeted linear peptides is suggested to be due to neutral endopeptidase (NEP, EC 3.4.24.11), which is known to cleave linear peptides on the N-terminal side of hydrophobic amino acids (such as tryptophan). Thus, these peptides are presumed to be cleaved at the dipeptidic Gln 7 -Trp 8 motif present in almost all compounds acting on GRPR (Table 1A). To demonstrate the increased metabolic stability in human serum or plasma when α-Me-Trp or Hse is introduced at the above positions, different GRPR-targeted ligands were synthesized and the above modifications were introduced. For almost all of the evaluated GRPR-targeted peptides shown in Table 1B, Trp 8 was replaced with α-Me-Trp 8 or Gln 7 was replaced with Hse 7 and each Gln7 -Trp 8 Compared with the derivatives containing it, the metabolic stability was increased (Table 1C). In many of these derivatives, the addition of α-Me-Trp did not dramatically decrease the affinity for GRPR. However, Gln 7 substituted with Hse 7 significantly decreased the affinity for GRPR for most ligands. However, the stabilizing effect of the Hse moiety was also observed.

[0081] Similarly, to demonstrate the decrease in metabolic stability in human serum or plasma, Bta was introduced at the above position. For most of the evaluated compounds acting on GRPR shown in Table 1B, substituting Trp 8 with Bta 8 actually decreased the metabolic stability compared with the derivatives containing each Gln 7 -Trp 8 (Table 1C). The GRPR affinity was not dramatically affected by the addition of Bta in most of the derivatives shown in Table 1B.

[0082] Therefore, it can be concluded that for GRPR target ligands, it is not important which amino acids are arranged on the N-terminal and C-terminal sides of the Gln 7 -Trp 8 dipeptide. Generally, introducing Bta 8 decreases the metabolic stability, while introducing α-Me-Trp 8 or Hse 7 increases the metabolic stability in human serum or plasma. Therefore, these modifications (α-Me-Trp 8 , Bta 8 , Hse 7 ) enable a wide range of applications for GRPR target compounds in general.

[0083]

Table 1-1

[0084]

Table 1-2

[0085]

Table 2-1

[0086]

Table 2-2

[0087]

Table 3

[0088] Preferred compounds of the present invention include derivatives of the compounds shown in Tables 1A and 1B. Said derivatives preferably differ only in that the 7-position and / or 8-position (numbering in the table) are modified according to the present invention, as opposed to the compounds of Tables 1A and 1B.

[0089] For example, in any of the compounds of Table 1A, by substituting tryptophan with α-methyltryptophan, preferred compounds according to the first and second aspects of the present invention can be obtained.

[0090] Similarly, at the 7-position of the compounds of Table 1A, Gln (or His or gln if applicable) may be substituted with Hse, and at the 8-position of the compounds of Table 1A, Trp may be substituted with Bta, thereby obtaining preferred compounds according to the third aspect of the present invention.

[0091] What applies to particularly preferred modifications of Xaa1 to Xaa4 is also applicable mutatis mutandis to any of the modifications at these four positions disclosed above herein, even in relation to the compounds of the first, second or third aspects.

[0092] A fourth aspect - which is also a preferred embodiment of the first and second aspects - the present invention provides a compound of formula (IIIa) or (IIIb). [Chemical formula]

[0093] Aspect 5 - which is also a preferred aspect of Aspect 3 - in which the present invention provides a compound of formula (IV) or (V). [Chemical formula]

[0094] In Aspect 6, the present invention provides a compound according to any one of the preceding claims for use in a medicament.

[0095] In Aspect 7, the present invention provides a pharmaceutical composition comprising or consisting of a compound according to Aspect 1, 2 or 4.

[0096] In Aspect 8, the present invention provides a diagnostic composition comprising or consisting of a compound according to Aspect 3 or 5.

[0097] Although less preferred, as a further aspect, the present invention provides a diagnostic composition comprising or consisting of a compound according to Aspect 1, 2 or 4. Also, although less preferred, a further aspect relates to a pharmaceutical composition comprising or consisting of a compound according to Aspect 3 or 5.

[0098] In the pharmaceutical and diagnostic compositions of the present invention, the compound may be the sole active agent. Also, in the pharmaceutical composition of the present invention, it is possible to use two or more compounds according to Aspect 1, 2 or 4, and in the diagnostic composition of the present invention, it is possible to use two or more compounds according to Aspect 3 or 5.

[0099] Also, although less preferred, pharmaceutical and diagnostic compositions of the present invention are envisioned in which, in addition to one or more compounds of the present invention, there are further pharmaceutically active or diagnostic active agents.

[0100] The pharmaceutical composition or diagnostic composition may further comprise a pharmaceutically or diagnostically acceptable carrier, excipient and / or diluent. 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 and the like. Compositions containing such carriers can be formulated by well-known conventional methods. These pharmaceutical compositions and diagnostic compositions can be administered to a subject at an appropriate dose. Administration of the preferred compositions can be effected by different methods, such as intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intratracheal administration, with intravenous administration being preferred. In particular, it is preferred that said administration be effected by injection. The composition may also be administered directly to the target site, for example, by particle gun delivery to an external or internal target site. The dosing regimen is determined by the attending physician and clinical factors. As is well known in the medical art, the dosage for any given patient depends on a multitude of factors including the patient's size, body surface area, age, the specific compound being administered, sex, time and route of administration, general health, as well as other drugs being administered concurrently.

[0101] The preferred dosage of the radiolabeled (e.g., 177 with Lu) compound of the present invention is from 1 to 100 GBq, from 2 to 60 GBq, from 2 to 50 GBq, from 2 to 10 GBq, or from 3 to 6 GBq.

[0102] Preferred medical applications according to the present invention are hyperproliferative diseases, more preferably malignant diseases.

[0103] Accordingly, 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) characterized by overexpression of the receptor and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumor, 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 range of the receptor being CCK-2R, medullary thyroid carcinoma (MTC).

[0104] Similarly, in a tenth aspect, the present invention provides 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) characterized by overexpression of the receptor and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumor, 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 range of the receptor being CCK-2R, medullary thyroid carcinoma (MTC).

[0105] In an eleventh aspect, the present invention provides an in vitro method of diagnosing cancer, wherein the cancer is (a) characterized by overexpression of the receptor and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumor, 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 range of the receptor being CCK-2R, medullary thyroid carcinoma (MTC), and the method comprises contacting a sample obtained from a subject with a diagnostic composition of the eighth aspect or a compound of the third or fifth aspect.

[0106] With respect to the embodiments characterized in this specification, particularly in the claims, each embodiment described in a dependent claim is intended to be combined with each embodiment of each claim (independent or dependent) on which the dependent claim depends. For example, in the case of independent claim 1 that describes three alternatives A, B, and C, dependent claim 2 that describes three alternatives D, E, and F, and claim 3 that depends on claims 1 and 2 and describes three alternatives G, H, and I, this specification, unless otherwise specified, is understood to clearly disclose 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.

[0107] Similarly, even when the independent claim and / or the dependent claim do not describe alternatives, if the dependent claim refers to a plurality of preceding claims, it is understood that 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 that refers to claim 1, and dependent claim 3 that refers to both claims 2 and 1, the combination of the subject matter of claim 3 and 1 is as clearly and distinctly disclosed as the combination of the subject matter of claims 3, 2, and 1. If there is a further dependent claim 4 that refers to any one of claims 1 to 3, the combinations of the subject matter of claim 4 and 1, claim 4, 2, and 1, claim 4, 3, and 1, and claim 4, 3, 2, and 1 are considered to be clearly and distinctly disclosed.

[0108] 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, wherein the Trp is substituted with an α-amino acid Xaa2, whereby the stability in serum or plasma of the peptide bond linking Xaa2 and the N-terminal adjacent amino acid is increased compared to the peptide bond in an otherwise identical compound linking Trp and the N-terminal adjacent amino acid, and (ii) A moiety capable of generating a therapeutically effective radiation, said moiety being covalently bonded to said oligopeptide, The compound comprising the above. 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 further, preferably, (a) The binding has a K of 15 nM or less, and / or D and / or (b) The compound is a GRPR antagonist, preferably with an IC of 15 nM or less. 50 The compound according to item 1 or 2. 4. A compound of formula (I), wherein S-Y-Xaa1-Xaa2-L-Ala-L-Val-Xaa5-L-His-T(I) In the formula, S is a moiety capable of generating a therapeutically active radiation, Y is an arbitrary linker, Xaa1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) an α-amino acid in which the stability of the Xaa1-Xaa2 peptide bond in serum or plasma is increased as compared to the case of the same compound in other respects where Xaa1 is Gln and Xaa2 is Trp, Xaa2 is Trp or an α-amino acid in which the stability of the Xaa1-Xaa2 peptide bond in serum or plasma is increased as compared to the case of the same compound in other respects where Xaa1 is Gln and Xaa2 is Trp, provided that at the same time, respectively, Xaa1 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, and Xaa2 is not Trp, Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an arbitrary terminal group, compound. 5. Xaa2 is (a) (i) an optionally substituted alkyl moiety of C1-C4 bonded to the α-carbon, wherein the substituent is selected from halogen and hydroxyl, and / or (ii) a substituent bonded to the indole ring, wherein the substituent is 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) The compound according to any one of items 1 to 4. 6. The optionally substituted alkyl moiety is selected from -CH3, -CH2CH3, and CH n Hal 3-n (wherein n is 0, 1 or 2, and Hal is F, Cl, Br and / or I), for example selected from -CF3, preferably -CH3, the compound according to item 5. 7. The compound according to any one of items 1 to 6, wherein Xaa2 is α-Me-Trp. 8. A compound of formula (II), S-Y-Xaa3-Xaa4-L-Ala-L-Val-Xaa5-L-His-T(II) wherein, S is a moiety capable of generating a detectable signal, Y is an optional linker, Xaa3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) an α-amino acid in which the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is decreased compared to the same compound in other respects where Xaa3 is Gln and Xaa4 is Trp, Xaa4 is Trp or an α-amino acid in which the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is increased compared to the same compound in other respects where Xaa3 is Gln and Xaa4 is Trp, wherein said α-amino acid at position Xaa4 that decreases the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is not a proteinogenic amino acid, provided that at the same time, respectively, Xaa3 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, and Xaa4 is not Trp, Xaa5 is Gly, N-Me-Gly, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an optional terminal group, compound. 9. The compound according to item 8, wherein Xaa3 is Hse and / or Xaa4 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 chelating agent, 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-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]-pentanedioic acid (DOTAGA), N,N’-dipyridoxylethylenediamine-N,N’-diacetate-5,5’-bis(phosphate) (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-triazacyclononane triacetic 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(methyleneamine tetraacetic acid (TMT), 1,4,7,10-tetraazacyclotridecane-N,N’,N’’,N’’’-tetraacetic acid (TRITA), triethylenetetraminehexaacetic acid (TTHA), N,N’-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2macropa), 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-tetraazoundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl}-1,4,8,11-tetraazoundecane (N4’), 1,4,7,10-tetraazacyclododecane-1,4.7-triacetic acid (DO3A), S-acetylmercaptoacetyltriserine (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]triacosa-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[methyl(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(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]{Nonane-3,7-diyl}bis(methylene))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’’’’,N’’’’’-hexaacetic acid (HEHA), 1,2-[(6-(carboxy)-pyridin-2-yl)-methylamino]ethane (H2dedpa), N,N’-bis{6-carboxy-2-pyridylmethyl}-ethylenediamine-N,N’-diacetic acid (H4octapa), 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-hexaazabicyclo[6.6.6]icosane (sar) and its functional derivatives, {4-[2-(bis(carboxymethylamino)-ethyl]-7-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)-cyclohexyldiethylenetriamine pentaacetic 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 (H2azapa), N,N’-[[6-(carboxy)pyridin-2-yl]methyl]diethylenetriamine-N,N’,N’’-triacetic acid (H5decapa), 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 (H6phospa), more preferably DOTA or DOTAGA, is selected from. Preferably, the radioactive cation binds to the 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 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, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th, or 18 F-[AlF] 2+ such as 18 selected from cationic molecules containing F. 13. Y is present, (a) containing 1, 2, 3, 4, 5 or 6 positive and / or negative charges, (b) containing or consisting of 1, 2, 3, 4, 5 or 6 amino acids, preferably D-amino acids in 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) containing a moiety capable of generating a detectable signal, The compound according to any one of items 4 to 12. 14. The linker Y is (a) D-Glu-urea-D-Glu, (b) optionally, one or two 2,3-diaminopropionic acid moieties substituted with a moiety capable of generating a detectable signal, (c) One or more amino acids selected from 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(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA) and D-Phe, including or consisting of 1, 2, 3, 4, 5 or 6 consecutive amino acids, and / or (d) p-aminomethylaniline-diglycolic acid (pABza-DIG, AMA-DGA), and / or diglycolate (DIG, DGA), The compound according to item 13, comprising or consisting of 15. T is present, (a) Statine (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, wherein the amide amine group of said Leu may be modified with ethyl (NH-ethyl) or NH2 (NH-NH2), and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)Pro-NH2), Comprising or consisting of Provided that when T is an amino acid or ends with an amino acid, the carboxylic acid of said amino acid is amidated. The compound according to any one of items 4 to 14. 16. The compound according to any one of items 1 to 15, wherein said serum or plasma is human serum or plasma. 17. A compound of formula (IIIa) or (IIIb).

Chemical formula

Brief Description of Drawings

[0109]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Mode for Carrying Out the Invention

Examples

[0110] Examples are to illustrate the present 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) delivers the chelating agents DOTA( t Bu)3 and DOTAGA( t Bu)4.

[0111] The 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 carried out manually using a Scilogex MX-RL-E Analog Rotisserie Tube Rotator (Scilogex, Rocky Hill, CT, USA).

[0112] Analytical and preparative reversed-phase high-performance liquid chromatography (RP-HPLC) is carried out using 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) are used as eluents for all HPLC operations.

[0113] For analytical measurements, a Nucleosil 100 C18 (125×4.6 mm, 5 μm particle size) column (CS GmbH, Langerwehe, Germany) is used at a flow rate of 1 mL / min. The relative gradient and the corresponding retention time t RBoth of them and the capacity coefficient K’ are cited in the text.

[0114] Preparative HPLC purification is carried out at a constant flow rate of 5 mL / min using a Multospher 100 RP 18 (250×10 mm, 5 μm particle size) column (CS GmbH, Langerwehe, Germany).

[0115] Analytical and preparative radio-RP-HPLC is performed using a Nucleosil 100 C18 (5 μm, 125×4.0 mm) column (CS GmbH, Langerwehe, Germany).

[0116] Electrospray ionization mass spectra for the characterization of substances are obtained with an expression L CMS mass spectrometer (Advion Ltd., Harlow, UK). Radioactivity is detected by connecting the outlet of the ultraviolet photometer to a NaI(Tl) well-type scintillation counter of EG&G Ortec (Munich, Germany).

[0117] The radioactive probe is measured with a WIZARD 2 (registered trademark) 2480 Automatic γ-Counter (Perkin Elmer, Waltham, MA, USA), and the determination of IC 50 values is performed using GraphPad Prism 6 (GraphPad Software Inc., San Diego, CA, USA).

[0118] For radioactive TLC, a Scan-RAM (trademark) Scanner with Laura (trademark) software (LabLogic Systems Ltd., Broomhill, Sheffield, United Kindom) is used.

[0119] Example 2 Synthesis protocol Solid-phase peptide synthesis by the Fmoc strategy Peptide formation on resin Dissolve Fmoc-AA-OH (1.5 equivalents) with each side chain protected in NMP, add TBTU (1.5 equivalents), HOAt (1.5 equivalents) and DIPEA (4.5 equivalents) for preliminary activation. After activating for 10 minutes, add this solution to the free amine peptide bound to the resin and shake at room temperature for 1.5 hours. Subsequently, wash the resin with NMP, and after Fmoc deprotection, bind the next amino acid in the same manner.

[0120] Fmoc Deprotection on Resin Treat the Fmoc peptide bound to the resin with 20% piperidine (v / v) in NMP for 5 minutes and then for 15 minutes. Then, wash the resin thoroughly with NMP.

[0121] Dde Deprotection on Resin Perform Dde deprotection at room temperature for 3 hours by adding a solution of imidazole (75 equivalents), hydroxylamine hydrochloride (100 equivalents) and DCM (3 mL) in NMP (7 mL). After deprotection, wash the resin with NMP.

[0122] DOTA( t Bu)3 or DOTAGA( t Conjugation of Bu)4 The protected chelating agent DOTA( t Bu)3 or DOTAGA( t Dissolve DOTA(

[0123] Peptide Cleavage from Resin with Further Deprotection of Acid-Labile Protecting Groups After washing the fully protected resin-bound peptide with DCM, it is dissolved in a mixture of TFA / TIPS / DCM (v / v / v; 95 / 2.5 / 2.5) and shaken for 30 minutes. This solution is filtered and the resin is treated similarly for an additional 30 minutes. The filtrates from both are combined and concentrated under a nitrogen stream. The residue is dissolved in MeOH, precipitated with diethyl ether, and then the liquid is decanted and the remaining solid is dried.

[0124] residual t Deprotection of Bu / Boc Residual after peptide cleavage from resin t The removal of the Bu / Boc protecting group (see above) is carried out by dissolving the crude product in TFA and stirring at room temperature for 6 hours. After removing TFA under a nitrogen stream, the crude unprotected product is obtained.

[0125] Example 3 Materials and methods (labeling experiment) Non-radioactive complex formation nat Gallium complex formation Purified chelating agent-containing ligand (10 -3 M, 1.00 equivalent) and nat Gallium(III) nitrate hexahydrate (10 mM in Tracepur H2O, 1.50 equivalents) are diluted with Tracepur water to a final concentration of 10 -4 M and heated at 70 °C for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0126] nat Lutetium complex formation Purified chelating agent-containing ligand (10 -3 M, 1.00 equivalent) and nat Lutetium(III) chloride (20 mM in Tracepur H2O, 2.50 equivalents) are diluted with Tracepur water to a final concentration of 10 -4 M and heated at 95 °C for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0127] Radioactive labeling 125 ​​​I] Iodine Labeling IC 50 Reference ligand for research ([D-3- 125 I] I-Tyr 6 MJ9) is prepared according to the 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 of Iodo-Gen® (1,3,4,6-tetrachloro-3α,6α-diphenylglycoluril, surface-bound type), 5.0 μL (16 MBq) 125 I] NaI (74 TBq / mmol, 3.1 GBq / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany) is added. The reaction solution is incubated at room temperature for 15 minutes and purified by RP-HPLC (20 → 35% in 20 minutes): t R = 18.9 minutes, K’ = 10.46.

[0128] 177 Lu] Lutetium Labeling 177 Labeling with lutetium is performed by the procedure developed within the group. Thus, the purified chelator-containing ligand (10 -3 M in Tracepur H2O, 1 μL), sodium acetate buffer (1 M, pH = 5.50, 10 μL) and a solution of approximately 10 - 30 MBq 177 Lu] LuCl3 (0.04 M in HCl) are diluted to a total volume of 90 μL with HCl (0.04 M) and heated at 95 °C for 10 minutes. Immediately after labeling, sodium ascorbate (0.1 M, 10 μL) is added to prevent radiolysis. 177 The uptake of lutetium is determined by radio-TLC (ITLC-SG chromatography paper, mobile phase: 0.1 M trisodium citrate). The radiochemical purity of the labeled compound is determined by radio-RP-HPLC.

[0129] 99m Tc] Technetium Labeling ​​​99m Labeling with technetium is achieved by procedures developed within the group. Thus, a purified chelating agent-containing ligand (10 -3 M in Tracepur H2O, 5 μL), NaHPO4 buffer (0.05 M, pH = 11.5, 25 μL), sodium citrate buffer (0.1 M, 3 μL), SnCl2 solution (1 g / L in sodium ascorbate solution (3 g / L), 5 μL), and approximately 50 - 150 MBq 99m TcO4] - of the solution are heated to 95 °C for 10 minutes. 99m Uptake of technetium is determined by radio-TLC (ITLC-SG chromatography paper, mobile phase: isotonic NaCl). The radiochemical purity of the labeled compound is determined by radio RP-HPLC.

[0130] Example 4 Materials and Methods (in vitro experiments) n-Octanol-PBS partition coefficient, logD 7.4 Approximately 1 MBq of the 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. The suspension was mixed vigorously for 3 minutes at room temperature, then the vial was centrifuged at 9000 rpm for 5 minutes (Biofuge 15, Heraus Sepatech, Osterode, Germany), and 200 μL aliquots of both layers were measured with a γ-counter. This experiment was repeated at least 4 times.

[0131] IC 50 Determination GRPR-positive PC-3 cells were cultured in Dulbecco's modified Eagle medium / Nutrition Mixture F-12 with Glutamax-I (1:1) (Invitrigon) supplemented with 10% fetal bovine serum and maintained at 37 °C in a humidified atmosphere of 5% CO2. For the determination of GRPR affinity (IC 50 ), cells were harvested 24 ± 2 hours before the experiment and seeded in 24-well plates (1.5 × 10​5 containing individual cells).

[0132] After removing the culture medium, the cells are washed once with 500 μL of HBSS (Hank's balanced salt solution, Biochrom, Berlin, Germany, supplemented with 1% bovine serum albumin (BSA)) and left to equilibrate for 9 minutes at room temperature in 200 μL of HBSS (1% BSA). Next, as a control, 25 μL of HBSS (1% BSA) or each ligand with an increased concentration (10 -10 M to 10 -4 M) in HBSS is added per well, followed by the addition of 25 μL of [D-3- 125 I]I-Tyr 6 MJ9 (2.0 nM).

[0133] All experiments are performed in triplicate for each concentration. After incubation for 2 hours at room temperature, the medium is removed and the experiment is terminated by continuously rinsing with 300 μL of HBSS. The media from both steps are combined into one fraction, representing the amount of free radiolabeled reference. Subsequently, the cells are lysed with 300 μL of 1 M NaOH for at least 15 minutes and combined with the 300 μL of NaOH from the next washing step. Quantification of the bound radiolabeled reference and the free radiolabeled reference is performed using a γ-counter. The determination of IC 50 for each ligand was repeated twice.

[0134] Internalization For internalization studies, PC-3 cells are harvested 24 ± 2 hours before the experiment and seeded into 24-well plates (1.5 × 10 5 cells / well). After removing the culture medium, the cells are washed once with 500 μL of DMEM / F-12 (5% BSA) and left to equilibrate for at least 15 minutes at 37 °C in 200 μL of DMEM / F-12 (5% BSA). Each well is treated and blocked with 25 μL of DMEM / F-12 (5% BSA) or 25 μL of nat Lu]RM2 (10 -3 M). Next, 25 μL of 125 I / 177Add Lu-labeled GRPR ligand (10 nM) and incubate the cells at 37 °C for 60 minutes.

[0135] Place the 24-well plate on ice for 1 minute and terminate the experiment by continuously removing the medium. Wash each well with 300 μL of ice-cold PBS and combine the fractions from these first two steps to represent the amount of free radiolabeled reference. Remove surface binding activity by incubating with 300 μL of ice-cold acidic wash solution (0.02 M NaOAc, pH = 5.0) for 10 minutes at room temperature and then rinsing again with 300 μL of ice-cold PBS. Determine internalization activity by incubating with 300 μL NaOH (1 M) and combining with the fraction from the subsequent 300 μL NaOH (1 M) wash step.

[0136] Each experiment (control and blockade) is performed 6 times. Quantify the activities of free, surface-bound, and internalized by γ-counter. The data are corrected for non-specific internalization.

[0137] Plasma study Apply a slightly modified procedure published by Linder et al. to determine in vitro metabolic stability. Immediately after labeling, add human (200 μL) or mouse (100 μL) plasma and incubate the mixture at 37 °C for 72 ± 2 hours (or 6 ± 0.5 hours). Treat with ice-cold EtOH (150 μL [human], 100 μL [mouse]) and ice-cold MeCN (450 μL [human], 300 μL [mouse]) and centrifuge at 13000 rpm for 20 minutes to precipitate the protein. Decant the supernatant and further analyze by radioactive RP-HPLC.

[0138] Example 5 Materials and methods (in vitro experiments) All animal experiments were conducted in accordance with the general German animal protection regulations (German Animal Protection Law, amended on May 18, 2018, Art. 141 Gv. 29.3.2017 I 626, approval number ROB-55.2-2532.Vet_02-18-109) and the institutional guidelines on animal care and use. To establish tumor xenografts, PC-3 cells (5×10 6 cells per 200 μL) were suspended in a 1:1 mixture (v / v) of Dulbecco's modified Eagle's 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 subcutaneously injected into the right shoulder of 6- to 10-week-old female CB17-SCID mice (Charles River Laboratories International Inc., Sulzfeld, Germany). Mice were used in the experiment when the tumor volume reached 125-500 mm 3 (2-3 weeks after inoculation).

[0139] Biodistribution Approximately 1-5 MBq (100-200 pmol) of the radiolabeled GRPR antagonist was injected into the tail vein of PC-3 tumor-bearing mice, and the mice were sacrificed at 1, 4, or 24 h p.i. (n = 4). Selected organs were excised, weighed, and measured with a γ-counter (Perkin Elmer, Waltham, MA, USA).

[0140] μSPECT / CT imaging Imaging studies were performed using a MILabs VECTer 4Performed using a small animal SPECT / PET / OI / CT scanner (MILabs, Utrecht, the Netherlands). The data were reconstructed using MILabs Rec software (version 10.02) and the pixel-based Similarity-Regulated Ordered Subsets Expectation Maximization (SROSEM) algorithm, and then analyzed using PMOD 4.0 software (PMOD TECHNOLOGIES LLC, Zurich, Switzerland). For the SPECT study, mice were anesthetized with isoflurane and injected with 2 - 4 MBq (100 - 200 pmol) of radiolabeled tracer via the tail vein. Static images were recorded at 1 hour and 28 hours p.i. with an acquisition time of 45 - 60 minutes using the HE-GP-RM collimator and stepwise multi-planar bed movement.

[0141] Example 6 Results GRPR reference ligand [Chemical formula]

[0142] Exemplary synthetic antagonist GRPR ligands of the present invention [Chemical formula]

[0143] HPLC nat Ga]RM2 (10 → 90% MeCN in 15 minutes): t R = 6.7 minutes, K’ = 3.47. Calculated monoisotopic mass (C 78 H 115 GaN 20 O 19 ): 1704.8, detected: m / z = 1706.6 [M + H] + , 854.1 [M + 2H] 2+ . nat Ga]DOTA-[Hse​​7 MJ9 (10 → 90% MeCN in 15 minutes): t R = 6.8 minutes, K’ = 3.53. Calculated monoisotopic mass (C 77 H 114 GaN 19 O 19 ): 1677.8, detected: m / z = 1679.3 [M+H] + , 840.4 [M+2H] 2+ . nat Ga]DOTA-[Bta 8 MJ9 (10 → 90% MeCN in 15 minutes): t R = 7.0 minutes, K’ = 3.67. Calculated monoisotopic mass (C 78 H 114 GaN 19 O 19 S): 1721.7, detected: m / z = 1723.7 [M+H] + , 862.3 [M+2H] 2+ . nat Ga]AMTG (10 → 90% MeCN in 15 minutes): t R = 6.9 minutes, K’ = 3.60. Calculated monoisotopic mass (C 79 H 117 GaN 20 O 19 ): 1718.8, detected: m / z = 1720.0 [M+H] + , 860.6 [M+2H] 2+ . nat Ga]AMTG2 (10 → 90% MeCN in 15 minutes): t R = 6.9 minutes, K’ = 3.31. Calculated monoisotopic mass (C 82 H 121 GaN 20 O 21 ): 1790.8, detected: m / z = 896.3 [M+2H] 2+ , 1792.6 [M+H] + . nat Lu]RM2 (10 → 90% MeCN in 15 minutes): t R ​​​​=6.6 min, K’ = 3.40. Calculated monoisotopic mass (C 78 H 115 LuN 20 O 19 ): 1810.8, detected: 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 min, K’ = 3.53. Calculated monoisotopic mass (C 77 H 114 LuN 19 O 19 ): 1783.8, detected: 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, detected: m / z = 1828.9 [M+H] + , 915.1 [M+2H] 2+ . nat Lu]AMTG (10 → 90% MeCN in 15 min): t R = 6.8 min, K’ = 3.53. Calculated monoisotopic mass (C 79 H 117 LuN 20 O 19 ): 1824.8, detected: 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, detected: m / z = 949.5 [M + 2H] 2+ , 1897.6 [M + H] + . nat Lu]NeoBOMB1 (10 → 90% MeCN in 15 minutes): t R = 9.6 minutes, K’ = 5.00. Calculated monoisotopic mass (C 77 H 107 LuN 18 O 18 ): 1746.7, detected: m / z = 874.5 [M + 2H] 2+ , 1747.3 [M + H] + .

[0144] Determination of hydrophilicity (n-octanol / l-PBS partition coefficient, logD 7.4 ) 177 The determined n-octanol / PBS partition coefficients (logD 7.4 ) of the Lu-labeled compounds are shown in Table 2. For all compounds, either DOTA or DOTAGA was used as the chelating agent. 177 Among the Lu-labeled GRPR ligands, it was found that the reference RM2 was the most hydrophilic and the 3-benzothienylalanine (Bta)-modified derivative was the most lipophilic.

[0145]

Table 4

[0146] Determination of affinity for GRPR The synthesized compounds showed comparable affinities, but the homoserine derivatives had a slightly reduced affinity. Also, nat Ga] gallium complex ligands nat Lu] lutetium complex counterparts showed similarly high affinities (Table 3). The non-radioactive standard [D-3-I-Tyr 6 MJ9 showed particularly high affinity, and all IC​50 It was suggested to be suitable as a competing radiolabel reference for the experiment.

[0147]

Table 5

[0148] Internalization To demonstrate the antagonism of the modified statin-based GRPR ligands, the internalization into PC-3 cells was determined. All 177 Lu-labeled compounds showed low internalization as expected from the antagonists (Table 4). 177 The internalization of [Lu]RM2 showed a good correlation with the results of other published studies.

[0149]

Table 6

[0150] Plasma study The in vitro stability of the synthetic GRPR ligands was measured in human plasma (Figures 1 - 4), while the stabilized ligands 177 [Lu]AMTG and the reference 177 [Lu]RM2 were further analyzed in mouse plasma. Therefore, only 100 μL of mouse plasma was added to the tracer solution (final volume 200 μL) immediately after labeling. According to Linder et al. (Bioconjugate Chem. 20, 1171 - 1178 (2009)), since mouse plasma has a faster metabolism than human plasma, the experiment was terminated after incubation at 37 °C for 6 ± 0.5 h (Figures 5 and 6). However, due to the small volume of the mouse mixture, additional investigations were carried out after incubation at 37 °C for 72 ± 2 h (Figures 7 and 8). Four 177 [Lu]-labeled GRPR ligands were compared after incubation in human plasma at 37 °C for 72 ± 2 h (Figures 1 - 4), and significant differences were found in the amount of unchanged tracer. The reference ligand 177The in vitro stability of [[Lu]]RM2 (Figure 1) was determined to be only 33.5 ± 2.7% at that time point, 177 [[Lu]]DOTA-[Hse 7 MJ9 (40.1 ± 1.4%) and 177 [[Lu]]AMTG (77.6 ± 10.1%) increased after incubation at 37 °C for 72 ± 2 hours. The most lipophilic derivative 177 [[Lu]]DOTA-[Bta 8 MJ9 (19.0 ± 1.7%) had the lowest stability among these four compounds. The second reference ligand 177 [[Lu]]NeoBOMB1 exhibited an unchanged tracer amount of 60.8 ± 1.2% after the same time period.

[0151] Reference compounds 177 [[Lu]]RM2 (Figures 5 and 7) and the stabilized derivative 177 [[Lu]]AMTG (Figures 6 and 8) were further investigated in mouse plasma to examine the possibility of differences between humans and animals. According to Linder et al., the metabolism in mouse plasma after about 6 hours is equivalent to that in human plasma after about 3 days. Therefore, when measuring the stability of these two ligands in mouse plasma after 6 hours, the unchanged 177 [[Lu]]AMTG (tR = 17.0 minutes, 89% and 92% respectively, Figures 6 and 4) was found to be in equivalent amounts, while 177 the unchanged ligand of [[Lu]]RM2 was significantly biased (tR = 15.5 minutes, 92% and 36% respectively, Figures 5 and 1).

[0152] Examining these two tracers in mouse plasma after a longer time period (incubated at 37 °C for 72 ± 2 hours), 177 [[Lu]]RM2 (Figure 7) 177 was cleaved by mouse endopeptidase in more parts than [[Lu]]AMTG (Figure 8), but the amount of unchanged tracer still seemed high (67% and 59% respectively), and it was speculated that there was a significant difference between human and animal plasma, especially for the reference compound.

[0153] From these observations, stabilization 177 Lu]AMTG shows better performance than the reference ligand in humans in vivo, but not necessarily in mice, indicating that

[0154] Biodistribution and μSPECT / CT studies Reference compounds 177 Lu]RM2 as well as diagnostic ligands 177 Lu]DOTA-[Hse 7 MJ9 and 177 Lu]DOTA-[Bta 8 MJ9 were investigated for their in vivo pharmacokinetics in CB17-SCID mice at 1 h p.i. and 24 h p.i., while the 177 Lu]AMTG, 177 Lu]AMTG2 and a second reference 177 Lu]NeoBOMB1 were only investigated at 24 h p.i. (100 pmol each). The data are compared to the references shown in Figures 9 to 12.

[0155] All destabilized compounds show an excellent pharmacokinetic profile compared to the reference ligand in mice at 1 h p.i. (Figures 9 and 10). In any organ, the uptake of the diagnostic ligands is equal to or lower than the reference, and especially for the GRPR-positive pancreas, a rapid washout from this organ is emphasized, presumably due to high metabolism at the destabilized positions. Interestingly, the uptake of both diagnostic ligands into tumors is superior to the reference compound (Figure 9), 177 leading to the hypothesis that high-level tumor enrichment as achieved with

[0156] Lu]RM2 is possible. Furthermore, since metabolism in tumors is not faster than in non-tumor organs, no negative washout effect from tumors was observed at 1 h p.i., despite the destabilization of the binding of the diagnostic derivatives. 177 Lu]DOTA-[Hse 7MJ9 showed the best contrast between tumor and non-tumor organs at 1 h p.i., while the reference was the worst among these three.

[0157] As a potential for therapeutic applications, three ligands, 177 Lu]NeoBOMB1, stabilized 177 Lu]AMTG and 177 Lu]AMTG2 were examined in CB17-SCID mice at 24 h p.i. (Figs. 11 and 12). The pharmacokinetic profiles confirm the suggestion that the destabilizing ligands are washed out more rapidly from the tumor after a longer time period. All four ligands compared were retained similarly in normal tissues, but in the tumor, 177 Lu]RM2, 177 Lu]AMTG, 177 Lu]AMTG2 were still present in large amounts and the destabilizing compounds were in small amounts, showing a significant difference in retention. 177 Lu]NeoBOMB1 also showed high tumor retention in the tumor, but also in the pancreas. For all derivatives, the uptake into bone was not fully complexed with their respective chelating agents 177 Lu]LuCl3 (Fig. 11).

[0158] 177 Lu]RM2, 177 Lu]AMTG, 177 Lu]AMTG2 showed higher tumor retention at 24 h p.i. than other derivatives in this series (Fig. 11). Considering the tumor / background ratio after that time period, 177 Lu]AMTG and [177 Lu]AMTG2 showed excellent tumor-to-blood and tumor-to-muscle ratios (Fig. 12). Both the destabilizing ligand and 177 Lu]NeoBOMB1 were shown to have a lower tumor / background ratio than the reference. At 1, 4, 8, 24 and 28 h p.i. in PC-3 tumor-bearing mice (100 pmol each) 177 Lu]RM2 and 177 ​Imaging studies of [[Lu]]AMTG showed the in vivo distribution over time (Figure 19). Both conjugates showed good pharmacokinetics, with rapid clearance from GRPR-positive tissues (pancreas, intestine) and high retention in tumors, respectively. The background activity was 177 In the case of [[Lu]]AMTG, the clearance from the pancreas was particularly slow, which was expected to be due to its high metabolic stability in vivo.

[0159] In conclusion, considering the results, both destabilized ligands exceeded the reference in mice at 1 h p.i., but were significantly inferior in mice at 24 h p.i., which 177 [[Lu]]DOTA-[Bta 8 MJ9 was found to be most metabolically unstable in vitro, which correlated well with the observations in plasma studies. As previously mentioned, metabolism in non-tumor tissues is faster than in tumor tissues, leading to the well-known washout effect of GRPR antagonists. Gln 7 -Trp 8 When the [[Gln-Trp]] binding is further destabilized, it is washed out faster from the background but not from the tumor, and an excellent contrast is obtained compared to the reference at 1 h p.i. However, after a longer time period, a significantly faster washout from the tumor was observed, confirming the hypothesis that the enzymatic degradation of the more lipophilic 177 [[Lu]]DOTA-[Bta 8 MJ9 increases. Therefore, it may be useful as a diagnostic agent.

[0160] Another destabilized derivative 177 [[Lu]]DOTA-[Hse 7 MJ9 showed only slight in vitro stability in human plasma, but in vivo behavior in mice showed rapid clearance from non-tumor tissues at 1 h p.i. and slight retention in tumors at 24 h p.i., suggesting low metabolic stability.

[0161] Stabilized compounds 177Lu]AMTG demonstrated particularly excellent overall performance considering in vitro and in vivo results. It showed good affinity for PC-3 cells expressing GRPR, moderate lipophilicity, the highest metabolic stability in human plasma, 177 Lu]RM2 and was confirmed to have pharmacokinetic properties equal to or better than those of RM2. Since AMTG has high in vitro metabolic stability in human plasma, it may have the potential to compete with or outperform the current gold standards (RM2, NeoBOMB1) of GRPR-targeted ligands in the targeted radiotherapy of GRPR-expressing male malignancies.

[0162] Example 7 99m [[Tc]N4-containing ligand Test compound [Chemical formula]

[0163] In vitro data Determined n-octanol-PBS partition coefficient (logD 7.4 ) and 99m [[Tc]-labeled compound's binding affinity for GRPR (IC 50 ) are shown in Table 5. For all compounds, N4(6-(carboxy))-1,4,4,11-tetraazoundecane) was used as the chelating agent.

[0164] [Table 7]

[0165] In this series, 99m [[Tc]N4-asp-MJ9 was found to be the most hydrophilic, while the other three compounds were also found to be more lipophilic, although to the same extent. All conjugates had IC values in the same low nanomolar range 50 ​However, homoserine and α-methyltryptophan derivatives had slightly reduced GRPR affinity compared to the other two ligands in this series.

[0166] 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]N4-asp-MJ9(8), [ 99m Tc]N4-asp-[Bta 8 ]MJ9 and [ 99m Tc]N4-[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]N4-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]N4-[Hse 7 ]MJ9 was found to have the highest tumor uptake and the second lowest pancreatic uptake in this series.[ 99m Tc]N4-[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]N4-asp-MJ9 was favored (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.

[0167] A 4-hour p.i. biodistribution study revealed the in vivo time course of these 99m Tc-labeled ligands (Figure 15). On the other hand, 99m Tc]N4-[α-Me-Trp 8 MJ9 showed increased tumor accumulation compared to 1-hour p.i., while all other derivatives in this series showed decreased tumor values. This further strengthens the suggestion of improved metabolic stability by α-methyltryptophan modification. 99m In the case of 177 Tc] technetium, this is not desirable for diagnostic reasons, as high tumor uptake at 1 hour p.i. (not only at 4 hours p.i.) and rapid clearance from background organs are desired. Nevertheless, this modification is very useful for therapeutic compounds, such as the 99m Tc]N4-asp-[Bta 8 MJ9, which is highlighted by the enhanced metabolic instability in the uptake values of most organs at 4 hours p.i. The tumor / background ratio at 4 hours p.i. is shown in Figure 16, but the 99m Tc]N4-asp-MJ9 and 99m Tc]N4-[Hse 7 MJ9 have been shown to be the highest for most organs.

[0168] The excellent contrast at 1 hour p.i. enabled by the destabilizing modifications homoserine and 3-benzothienylalanine was further emphasized by μSPECT / CT imaging (Figure 17). 99m Tc]N4-asp-[Bta 8 MJ9 and 99m Tc]N4-[Hse 7 MJ9 showed slightly enhanced contrast compared to unmodified 99m Tc]N4-asp-MJ9 despite their high lipophilicity. 99m Tc]N4-[α-Me-Trp8 Since MJ9 has high metabolic stability and slow clearance in the pancreas and intestine, it is expected to have inferior contrast to the other three derivatives, which is not favorable for diagnosis.

[0169] Example 8 Bombesin-SiFA derivative Test compound

[0170] [Table 8]

[0171] In vitro data Determined n-octanol-PBS partition coefficient (logD 7.4 ) and the binding affinity of the bombesin-SiFA compound to GRPR (IC 50 ) are shown in Table 6. For all compounds, DOTAGA was used as the chelating agent.

[0172] [Table 9]

[0173] All four compounds in this series showed similar hydrophilicity. The IC 50 values were in the same range for 177 Lu]GT50 and 177 Lu]GT52, and 177 Lu]GT51 and 177 Lu]GT53 showed a slight increase.

[0174] Biodistribution study All four compounds contain 18 an SiFA moiety for 18F labeling and 68 a chelating agent for 68Ga- or 177 177Lu-labeling. This is 18 [18F] nat 68Ga / nat 177Lu] ligand and 19 [18F] 68 68Ga / 177Regardless of which ligand is applied, since they cannot be chemically distinguished, radiolabeled hybrid-based ligands are an ideal theranostic pair and thus can be considered a useful feature. 177 The biodistributions of Lu-labeled ligands GT50, GT51, GT52, and GT53 were evaluated in CB17-SCID mice at 24 h p.i. (100 pmol each). All derivatives showed generally low background retention, except for the liver and kidney (Figure 18). Tumor retention was 177 Lu]RM2, 177 Lu]AMTG, and 177 Lu]AMTG2 (Figure 11). All bombesin-SiFA conjugates need to be optimized, especially considering the high retention in the kidney and somewhat high retention in the liver. However, the ligands evaluated in this series demonstrated the functionality of the radiolabeled hybrid-based concept.

Claims

**Claim 1** A compound that binds to an endogenous receptor, (i)An oligopeptide comprising the dipeptide in which Trp is the C-terminal amino acid of the dipeptide, wherein the Trp is substituted with the α-amino acid Xaa ２ such that the stability in serum or plasma of the peptide bond linking Xaa ２ 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, and (ii) a moiety capable of generating a therapeutically effective radiation, said moiety being covalently bound to said oligopeptide, said compound comprising the above. **Claim 2** The compound according to claim 1, wherein the amino acid adjacent to the N-terminus in said dipeptide is L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln. **Claim 3** Said 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 15 nM or less, and / or Ｄ and (b) The compound is a GRPR antagonist, preferably having an IC ５０ of 15 nM or less. the compound according to claim 1 or 2. **Claim 4** A compound of formula (I), S - Y - Xaa １ -Xaa ２ -L - Ala - L - Val - Xaa ５ -L - His - T(I) wherein, S is a moiety capable of generating a therapeutically active radiation, Y is an arbitrary 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 an α - amino acid that increases compared to the case of a compound identical in other respects where Xaa １ is Gln and Xaa ２ is Trp. Xaa ２ is Trp or Xaa １ -Xaa ２ The stability of the peptide bond in serum or plasma is an α-amino acid that increases compared to the case of a compound identical in other respects where Xaa １ is Gln and Xaa ２ is Trp, and is an α-amino acid that increases compared to the case of a compound identical in other respects However, at the same time, each of Xaa １ is not any one of L-Gln, D-Gln, L-His, D-His, and Gly, but Xaa ２ is conditioned not to be Trp, Xaa ５ is Gly, N-Me-Gly, D-Ala, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an arbitrary terminal group, said compound. **Claim 5** Xaa ２ is (a) (i) An optionally substituted alkyl moiety of C1-C4 bonded to the α-carbon, the substituent being selected from halogen and hydroxyl, the alkyl moiety, and / or (ii) A substituent bonded 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 the above, (b) 1,2,3,4-tetrahydronorharman-3-carboxylic acid (L-Tpi), the compound according to any one of claims 1 to 4. **Claim 6** wherein said optionally substituted alkyl moiety is —CH ３ , —CH ２ CH ３ , and CH ｎ Hal ３－ｎ (wherein n is 0, 1 or 2, and Hal is F, Cl, Br and / or I), for example —CF ３ selected from, preferably —CH ３ , the compound according to claim 5. **Claim 7** Xaa ２ The compound according to any one of claims 1 to 6, wherein Xaa is α-Me-Trp. **Claim 8** A compound of formula (II), S-Y-Xaa ３ -Xaa ４ -L-Ala-L-Val-Xaa ５ -L-His-T(II) wherein, S is a moiety capable of generating a detectable signal, Y is an arbitrary 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 an α-amino acid that decreases compared to the case of a compound that is identical in other respects where Xaa ３ is Gln and Xaa ４ is Trp, Xaa ４ is Trp or Xaa ３ -Xaa ４ The stability of the peptide bond in serum or plasma is an α-amino acid that decreases as compared with the case of a compound identical in other respects where Xaa ３ is Gln and Xaa ４ is Trp, and is an α-amino acid that decreases as compared with the case of a compound identical in other respects Xaa ３ -Xaa ４ The amino acid at position Xaa that decreases the stability of the peptide bond in serum or plasma ４ is not a proteinogenic amino acid However, at the same time, each of Xaa ３ is not any one of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa ４ is conditioned not to be Trp, Xaa ５ is Gly, N-Me-Gly, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an arbitrary terminal group, said compound. **Claim 9** Xaa ３ is Hse and / or Xaa ４ is Bta, the compound according to claim 8. **Claim 10** The compound according to any one of claims 4 to 7, wherein S is selected from a radioactive moiety and a moiety capable of carrying a radionuclide. **Claim 11** The compound according to claim 8 or 9, wherein S is selected from a fluorescent moiety, a radioactive moiety and a moiety capable of carrying a radionuclide. **Claim 12** Y is present, (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 (wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), comprising or consisting of, and / or (d) Comprising a moiety capable of generating a detectable signal Preferably, said linker Y is (i) D-Glu-urea-D-Glu (ii) Optionally, one or two 2,3-diaminopropionic acid moieties substituted with a moiety capable of generating a detectable signal (iii) One or more amino acids selected from 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 comprising, or consisting of, 1, 2, 3, 4, 5 or 6 consecutive amino acids, and / or (iv) p-aminomethylaniline-diglycolic acid (pABza-DIG, AMA-DGA), and / or diglycolate (DIG, DGA) Comprising, or consisting of, them The compound according to any one of claims 4 to 11.

13. T is present (a) Statine (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, wherein the amidoamine group of said Leu is ethyl (NH-ethyl) or NH ２ (NH-NH ２ ) may be modified, 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 them Provided that when T is an amino acid or ends with an amino acid, the carboxylic acid of said amino acid is amidated The compound according to any one of claims 4 to 12.

14. In the range where claims 10 to 13 refer back to any one of claims 1 to 7, a pharmaceutical composition comprising, or consisting of, the compound according to any one of claims 1 to 7 or 10 to 13.

15. In the range where claims 10 to 13 refer back to claim 8 or 9, a diagnostic composition comprising, or consisting of, the compound according to any one of claims 8, 9 or 10 to 13.

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