Modified GRPR antagonist peptides for cancer imaging and treatment

Abstract

The present invention relates to modified GRPR antagonist peptides for use in cancer imaging and treatment. The present application relates to a compound that binds to an endogenous receptor, said compound comprising (i) an oligopeptide comprising a dipeptide having a Trp as the C-terminal amino acid of said dipeptide, where said Trp is replaced by an alpha-amino acid Xaa2, whereby the Trp is more than the N-terminal adjacent amino acid in a peptide bond linking the Trp to the N-terminal adjacent amino acid in an otherwise identical compound. The stability of a peptide bond connecting Xaa2 and amino acid adjacent to the N terminal in serum or plasma is improved; and (ii) a moiety capable of generating therapeutically effective radiation, the moiety covalently bound to the oligopeptide.

Description

[0001] This application is a divisional application of Chinese patent application 202080087499.8, filed on October 21, 2020, entitled "Modified GRPR antagonist peptide for cancer imaging and treatment". Background Technology

[0002] Prostate cancer (PCa), one of the most common malignant diseases among men in the Western world, remains a formidable medical challenge due to low survival rates in its advanced stages. Studies have shown that earlier diagnosis leads to higher treatment success rates, thus necessitating new approaches. Over the past few decades, nuclear medicine-based diagnosis and treatment of cancer, utilizing radioactive tracers that rapidly and almost completely accumulate at the tumor site, has attracted increasing attention.

[0003] Prostate-specific membrane antigen (PSMA) tracers are frequently used for in vivo radiotherapy and imaging of prostate cancer (PCa) due to several desirable properties, such as overexpression in prostate cancer and low expression in healthy tissues, rapid clearance, and high incidence (accounting for 92% of all prostate cancers). However, the use of PSMA also has some drawbacks, such as relatively low expression in the early stages of the disease and high uptake in the kidneys and salivary glands.

[0004] As an interesting alternative, gastrin-releasing peptide receptor (GRPR) also shows good incidence in PCa (up to 100% in the early stage and up to 60% in the late stage), is overexpressed in malignant tissues, and exhibits high expression only in one healthy tissue (pancreas). This is an advantage over PSMA, as metastases in the renal region cannot be properly detected using PSMA tracers due to high renal uptake. Furthermore, a growing concern with the use of high therapeutic doses appears to be damage to the salivary glands and kidneys due to the high accumulation of PSMA tracers.

[0005] GRPR was found to show higher expression in the early stages of prostate cancer (PCa), while PSMA overexpression was observed more frequently in the later stages of the disease. Furthermore, GRPR overexpression has also been found in estrogen receptor (ER)-rich breast cancer, allowing the use of the same tracer for different cancers and sexes. Therefore, GRPR tracers are a useful tool as an alternative for patients with low PSMA expression or for better diagnosis of renal metastases. Conditional contingent therapy for early-stage prostate cancer benefits from GRPR tracers rather than PSMA tracers due to higher expression rates and lower side effects (salivary gland damage). Moreover, GRPR antagonists enable their use in different sexes because they are overexpressed in both prostate and breast cancer.

[0006] To date, both GRPR agonists and antagonists have been and are currently used in clinical settings. The development of antagonists is increasing because agonists exhibit some unpleasant side effects upon administration to patients and have poorer pharmacokinetics due to their much slower clearance from non-tumor tissues. GRPR derivatives are used significantly less clinically than PSMA ligands. However, GRPR offers clinical benefit because only 92% of all PCa tumors express PSMA, while GRPR is overexpressed in approximately 85% of all estrogen receptor (ER)-rich breast cancers.

[0007] The generally essential structure of antagonistic GRPR molecules includes a binding unit based on the C-terminal portion of natural bufotoxin or gastrin-releasing peptide (GRP) due to its sub-nanomolar affinity. A linker portion between the pharmacodynamic moiety and the N-terminal chelator is not necessarily required, as numerous reports have demonstrated beneficial pharmacokinetic effects of using the linker unit, despite the existence of tracers exhibiting good performance.

[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 treatment. It is mainly used... 68 Ga (88.9% β + E β+, 最大 = 1.89 MeV, t ½ = 68 minutes) marked for imaging, and with 177 Lu (78.6% β - E β, 最大 =0.498 MeV, t ½ = 6.7 d) is used for in vivo radiotherapy and can be applied to PCa and ER-rich breast cancer, so it is considered to date to be the gold standard among GRPR antagonists.

[0009] 68 Ga-and 177 Lu-RM2 exhibits favorable pharmacokinetics due to high tumor accumulation, rapid clearance from non-tumor tissues, and good retention within tumors over long periods in the body, resulting in high contrast and favorable therapeutic outcomes, respectively.

[0010] Nevertheless, some bufotoxin analogues are metabolically unstable in animals, which limits their expected accumulation in tumor tissues.

[0011] On the other hand, it must be mentioned that more stable GRPR derivatives show slower clearance from GRPR-rich pancreas, which must be considered before use in human treatment due to the possibility of pancreatitis.

[0012] In other malignant indications, there are many more biomarkers and targets of interest. These include neuromodulatory peptide-B receptor (bufotin-1 receptor, NMBR), bufotin receptor subtype 3 (BRS-3), and cholecystokinin-2 receptor (CCK-2R).

[0013] In view of the above, the technical problem of the present invention can be seen from providing improved radiopharmaceuticals and radiodiagnostics (especially in the field of cancer), including improvements in pharmacokinetic properties.

[0014] This technical problem has been resolved through the following published topics. Summary of the Invention

[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 having a Trp as a C-terminal amino acid of the dipeptide, wherein the Trp is replaced by an α-amino acid Xaa2, thereby increasing the stability in serum or plasma (preferably mammalian serum or plasma) compared to peptide bonds linking Trp to an N-terminal adjacent amino acid in compounds otherwise identical; and (ii) a portion capable of generating therapeutically effective radiation, the portion being covalently bound to the oligopeptide.

[0016] A receptor is a molecule capable of specifically binding to its homologous ligand. The term "homologous ligand" refers to a class of molecules and includes natural ligands and compounds according to the invention. The receptor is preferably a polypeptide or protein. It may contain multiple subunits that may be non-covalently or covalently linked together. Preferably, the receptor is a transmembrane protein or a membrane-associated protein. Preferably, the ligand binding site is located extracellularly.

[0017] The term "endogenous" means that the receptor is present in a human or animal body, including mammals, and mammals include rodents. 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 a targeting portion. It comprises or consists of the oligopeptides disclosed above. The second part is the portion that delivers the intended therapeutic effect, which, in the case of the compound of the first aspect, is radiation. Therefore, it should be understood that the treatment involves the destruction of target tissue, usually because the target tissue is or contains overproliferating tissue, such as malignant tissue.

[0019] As will become more apparent below, in other aspects of the invention, the second part is used for diagnostic purposes.

[0020] In its broadest definition, the second part is not particularly limited except that it must be radiation capable of producing a therapeutic effect. According to the invention, this capability is delivered by a radionuclide. Such a radionuclide can be present in the compound, or the compound can have a portion that is itself capable of loading a radionuclide.

[0021] The term "oligopeptide" has its generally accepted meaning in the art. It is a linear sequence of amino acids linked together by peptide bonds in a main chain. In terms of length, it is preferably 5 to 20 amino acids. This includes oligopeptides having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids. Preferably, it has 6, 7, 8, 9, or 10 amino acids. Particularly preferred are 9 or 10 amino acids, and most preferably 9 amino acids. Although the term "oligopeptide" implies peptide properties, the term also includes compounds that are not exclusively peptides in nature. Preferably, and assuming that the oligopeptide has N amino acids, at least (N-1) / 2 bonds connecting the amino acids are peptide bonds. For example, N-1, N-2, or N-3 bonds connecting the amino acids are peptide bonds.

[0022] The same considerations apply to the structural units of oligopeptides. In other words, at least N / 2 of the structural units are amino acids. For example, N, N-1, N-2, or N-3 structural units are amino acids.

[0023] The term "amino acid" refers to a molecule having both a carboxyl group and an amino group. Preferred amino acids are α-amino acids, including protein amino acids, but other amino acids, such as β-amino acids, γ-amino acids, or δ-amino acids, may also be used. Specifically, γ-amino acids may be used in the C-terminal region of the molecule; see further preferred embodiments below.

[0024] In general, naturally occurring, preferably proteogenic α-amino acids, are preferred. That said, to impart the specific technical effects described further below, one or more positions, typically no more than half the number of oligonucleotide positions, are non-naturally occurring amino acids or portions. These are also referred to herein as modified amino acids or modified portions. Such modifications can affect stereochemistry, for example, by replacing their naturally occurring L-corresponding D-amino acids with D-amino acids and / or by modifications concerning structure and composition.

[0025] In terms of the extent to which amino acids are not located at the ends of molecules, it should be understood that a given amino acid is linked to an adjacent part via a main chain peptide bond, resulting in the absence of free carboxylates and primary amines in such cases.

[0026] Within the oligopeptide, the dipeptide unit is of particular importance. The location of the dipeptide unit within the oligopeptide is not particularly limited. However, it is preferred that the dipeptide unit be located within the N-terminal half of the oligopeptide.

[0027] In the dipeptide, the C-terminal amino acid is a tryptophan derivative. In many cases, the naturally occurring ligands of the endogenous receptor are also peptides in nature and contain tryptophan at the corresponding position. The corresponding position is the position compared in a sequence alignment of the naturally occurring ligand with the compound of the first aspect.

[0028] According to the present invention, such tryptophan is modified. As will become more apparent below, preferred modifications are those that retain the indole ring. Furthermore, amino and carboxyl functional groups are retained. In this sense, the meaning of the term "derivative" is therefore limited: the derivative must be an aromatic amino acid, preferably having a binary ring, more preferably an indole ring. Furthermore, according to the present invention, the tryptophan derivative is an α-amino acid.

[0029] According to the present invention, modification of tryptophan is used to increase the stability of the peptide bond linking the tryptophan derivative (also known as Xaa2) to the N-terminal adjacent amino acid in serum or plasma.

[0030] The terms “increasing the stability of peptide bonds in serum or plasma” and “reducing the cleavage of peptide bonds in serum or plasma” are used interchangeably in this document.

[0031] Stability in serum or plasma is preferably found in mammalian serum or plasma. Particularly preferred, and for the intended application, is stability in human serum or plasma. For testing and development purposes, rodent serum or plasma, such as mouse serum or plasma, is preferred. To determine stability in serum or plasma, the compounds of the 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 both in vitro and in vivo assays. Exemplary or preferred assays are part of the appended examples. A reference compound was used to determine whether stability was increased. The reference compound was selected for evaluating the compound of the first aspect such that the only difference between the compound under consideration and the reference compound was the position Xaa2. In the reference compound, this position is tryptophan.

[0033] It should be understood that increased stability means a statistically significant increase in stability and / or an increase in stability 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 said increase is the serum / plasma half-life. A preferred parameter for determining said increase is the amount of intact radiolabeled compound after incubation in human / mouse serum or plasma for 72 ± 2 hours.

[0034] In an alternative approach, the corresponding homologous ligand of the endogenous receptor or an established therapeutic agent that binds to the same receptor (e.g., RM2 in the case of GRPR as the receptor, see also below) may be used as a reference compound.

[0035] The compounds according to the first aspect exhibit enhanced pharmacokinetic properties. The reference compounds used for comparison are as described above and are compounds different from those considered according to the first aspect, wherein the only difference is that unmodified tryptophan is present in the reference compound at the position of the Trp derivative in the compound according to the first aspect. Alternatively, the enhancement is compared with the corresponding natural ligand and / or therapeutic agents established in the art that target the same receptor. For the compounds of the first aspect considered to be GRPR ligands, the preferred compound established in the art is RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, where the chelating agent and the abbreviations for non-proteinogenic amino acids are further explained below).

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

[0037] In the context of treatment, it should be understood that high tumor uptake and / or tumor preservation are desirable. Evidence in this regard is given in the appended examples.

[0038] The above describes a technical means to achieve high tumor uptake and retention: it involves the stabilization of peptide bonds within dipeptide units contained in the compound according to the first aspect.

[0039] In a preferred embodiment of the compound 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 yet another preferred embodiment, the endogenous receptor is a peptide receptor overexpressed in cancer, such as a neuromodulatory peptide-B receptor (bufotin-1 receptor, NMBR), a gastrin-releasing peptide receptor (bufotin-2 receptor, GRPR), a bufotin receptor subtype 3 (BRS-3), or a cholecystokinin-2 receptor (CCK-2R), and wherein preferably (a) the binding has a Kk concentration of less than or equal to 50 nM, less than or equal to 15 nM, less than or equal to 5 nM, or less than or equal to 1 nM. D ; and / or (b) the compound is a GRPR antagonist, preferably having an IC50 concentration of less than or equal to 50 nM, less than or equal to 15 nM, less than or equal to 5 nM, or less than or equal to 1 nM. 50 .

[0041] In a second aspect relating to the first aspect, the present invention provides compounds of formula (I). S — Y — Xaa1 — Xaa2 — L-Ala — L-Val — Xaa5 — L-His — T (I) in S is the part that can generate therapeutically active radiation; Y is an optional connector; Xaa1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln; or (ii) an α-amino acid that increases the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in all other respects. Xaa2 is a Trp or an α-amino acid that increases the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in other respects. The conditions are: Xaa1 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa2 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

[0042] The second compound is tailored for a specific endogenous receptor (GRPR). Therefore, it contains several features inherited from its natural homologous ligand (gastrin-releasing peptide (GRP)).

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

[0044] The optional connector Y may or may not be present, and in terms of its presence, it can be a means of incorporating other amino acids into the compound of the second aspect.

[0045] The optional terminal T may be, but does not have to be, a means of extending the peptide portion of the compound in the second aspect.

[0046] The reference compound used to determine whether stability in serum or plasma is increased is a compound different from the compound of formula (I) under consideration, wherein Xaa1 is Gln and Xaa2 is Trp. As noted above regarding the compounds of the first aspect, alternative reference compounds may be used, including natural ligands and pharmaceutically known in the art to bind to GRPRs (e.g., RM2).

[0047] In a preferred embodiment of the compounds of the first and second aspects, Xaa2 is: (a) modified to include Trp comprising: (i) an optionally substituted C1 to C4 alkyl moiety bonded to an α-carbon, the substituent being selected from halogens and hydroxyl groups; and / or (ii) a substituent bonded to an indole ring, the substituent being selected from N-(2,2,2-trifluoromethyl), N-methyl, N-acetyl, 5-fluoro, 5-bromo, 5-iodine, 5-chloro, 5-hydroxy, 5-methoxy, 5-methyl, 6-chloro, 7-chloro, and 7-aza; and (b) 1,2,3,4-tetrahydrodemethylhalman-3-carboxylic acid (L-Tpi).

[0048] This preferred embodiment involves a specific structural means (referred to as Xaa1–Xaa2 in the case of the compound of the second aspect) to increase the stability of the main chain peptide bond of the dipeptide moiety present in the first and second aspects.

[0049] Of these structural measures, those specified in part (a)(i) of the preferred embodiment are particularly preferred.

[0050] A more preferred embodiment is that the optionally substituted alkyl moiety is selected from –CH3, –CH2CH3, and CH n Hal 3-n Where n is 0, 1 or 2, and Hal is F, Cl, Br and / or I, for example –CF3; and preferably –CH3.

[0051] The preferred choice is Xaa2, which is α-methyltryptophan.

[0052] Preferred embodiments of the first and second aspects are derivatives of the compounds in Tables 1A and / or B. Tables 1A and B are further presented below as an explanation of the term "derivative" for the compounds in Tables 1A and B.

[0053] Particularly preferred embodiments of the compounds of the first and second aspects are compounds of formulas (IIIa and IIIb), as further disclosed below.

[0054] The third aspect of the present invention relates to compounds of formula (II). S — Y — Xaa3 — Xaa4 — L-Ala — L-Val — Xaa5 — L-His — T (II) in S is the part that can generate a detectable signal; Y is an optional connector; Xaa3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln; or (ii) an α-amino acid that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in all other respects. Xaa4 is a Trp or an α-amino acid that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects. The α-amino acid that reduces the stability of its Xaa3-Xaa4 peptide bond in serum or plasma at the Xaa4 position is not a proteogenic amino acid. The conditions are: Xaa3 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa4 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

[0055] Although showing structural similarity to the compound of formula (I) according to the second aspect, the compound of formula (II) differs in that the peptide bonds in the dipeptide portion contained in the oligopeptide have lower stability in serum or plasma.

[0056] This offers a unique but relevant technological advantage: as well established in the art, radiolabeled compounds can be used not only for therapeutic purposes but also for diagnostic purposes. In a diagnostic setting, faster degradation is desired. This is because metabolic activity in tumors is typically lower than in surrounding normal tissue, resulting in a higher tumor-to-background ratio required for faster degradation. This higher ratio allows for more sensitive, precise, and / or accurate detection of tumors and metastases.

[0057] It should be understood that the two positions Xaa3 and Xaa4 correspond to and are aligned with positions Xaa1 and Xaa2 of the compound in the second aspect, and are clearly marked only for clarity. When discussing specific structural embodiments, Xaa1 and Xaa2 on one hand, and Xaa3 and Xaa4 on the other, will generally be different. This will become more apparent in the context of the preferred embodiments of the third aspect further disclosed below.

[0058] For the purpose of determining the stability reduction, the explanations given above regarding the compounds of the first and second aspects are applicable. Therefore, in vitro and in vivo serum or plasma assays can be used. A preferred reading is the serum / plasma half-life. A more preferred reading is the amount of the intact radiolabeled compound after incubation in human / mouse plasma for 72 ± 2 hours. As mentioned above, the reference compounds used to determine the stability reduction include compounds that differ from those of formula (II) only in that positions Xaa3 and Xaa4 are Gln and Trp, respectively.

[0059] As established in the art, three-letter codes are generally used to designate amino acids. If the first letter is uppercase, it refers to the L form, and if the first letter is lowercase, it refers to the D form. For example, Trp refers to L-tryptophan, while trp refers to D-tryptophan. Explicit stereochemical indications (e.g., L-Trp and D-Trp) are also used herein.

[0060] Alternative reference compounds are the corresponding natural ligands, which are GRP in the case of GRPR receptor, or RM2 (which is antagonistic).

[0061] In a preferred embodiment of the compound of formula (II), Xaa3 is Hse and / or Xaa4 is Bta (3-benzothiophene alanine).

[0062] In a preferred embodiment of the compound in the second aspect, S is selected from the radioactive portion and the portion capable of loading a radionuclide.

[0063] In a preferred embodiment of the compound in the third aspect, S is selected from the fluorescent portion, the radioactive portion, and the portion capable of loading a radionuclide.

[0064] The two preferred embodiments described above relate to preferred implementations of part S, depending on whether it is considered a therapeutic or diagnostic compound.

[0065] Regarding the use of a portion capable of loading a radionuclide, the portion is preferably a metal ion chelating agent, preferably selected from: bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradecane-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutyryl]pentyl]-N-hydroxybutyramide (D FO), 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]-glutaric acid (DOTAGA), N,N'-dipyridoxyethylenediamine-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-triacetic acid ester (HP-D) OA3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carbooxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6].2] Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), 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-tetraazaundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl 1,4,8,11-tetraazaundecane (N4'), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), S-acetylthioacetyltriserine (MAS3), thioacetyltriglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazazolide (AAZTA), 3,6,9,15-tetraazabicyclo[9.3].1] Pentadec-1(15),11,13-trien-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentazatricyclic[15,3,2,1]eicos-1(21),17,19-trien-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanate benzyl)oxy-methyl]propene-1,3-diaminotetraacetic acid (TAME-Hex), 4- ((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutyric acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazacycloheptane-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphonic acid] (TRAP) and their functional derivatives, such as NOPO (1,4,7-Triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphonic acid]-7-[methylene(2-carboxyethyl)phosphonic acid]), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra[methylene(2-carboxyethyl)phosphonic acid] (DOTPI), 6,6′-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene))pyridinedicarboxylic acid (H2bispa2), 1,4,7,10,13-pentazacyclopentadecane-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-(carboxyl)-pyridin-2-yl}-methylamino]ethane (H2dedpa), N,N′-bis{6-carboxyl-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-tetra(carbamoylmethyl)-1,4,7,10-tetraazabicyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6].6] Eicosane (sar) and its functional derivatives, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazolidine-1-yl}-acetic acid (NETA), N,N′,N′′-tris(2-mercaptoethyl)-1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanate benzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N′-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N′-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (H2azapa), N,N′′-[[6-(carboxy)pyridin-2-yl] The chelating agent is preferably composed of: [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-trien-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; wherein a radioactive cation is preferably bound to the chelating agent, and the radioactive cation is preferably selected from... 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 containing 18 F-cation molecules, for example 18 F-[AlF] 2+ .

[0066] For therapeutic compounds, the preferred nuclide is 177 Lu. Examples of preferred nuclides for diagnostic compounds are 68 Ga.

[0067] In preferred embodiments of the compounds of the second and third aspects, the connector Y is present and (a) comprises one, two, three, four, five, or six positive and / or negative charges; (b) comprises one, two, three, four, five, or six amino acids or is composed of one, two, three, four, five, or six amino acids, preferably (a) D-amino acids, more preferably (a) D-α-amino acids; and (c) comprises PEG. n Or by PEG n The composition, wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and / or (d) contains a portion capable of generating a detectable signal.

[0068] According to item (d) of the preferred embodiment above, a suitable portion capable of generating a detectable signal may be a fluorescent portion or a portion containing or capable of loading a radionuclide. An example of the latter is that it can be used for... 18 F-labeled silicon fluoride acceptor portion (SiFA). In the case of compounds of the present invention containing such a SiFA portion, which also contain a chelating agent (e.g., DOTA or DOTAGA), such compounds would contain two radionuclides and thus could be used for the diagnosis and treatment of both.

[0069] In a preferred embodiment, the SiFA portion has a structure represented by formula (VI). in t-Bu represents tert-butyl; and The dashed lines mark the bonds that connect the said part to the rest of the compound.

[0070] The preferred connection site of the SiFA portion within the connector Y is the side chain of 2,3-diaminopropionic acid, which consists of -CH2-NH2, wherein the terminal amino group of the side chain preferably forms an amide bond with a carboxyl group, and the carboxyl group is bonded to the free valence of the SiFA portion in formula (VI).

[0071] The connector Y having a silicon fluoride acceptor portion is the preferred connector Y of the compounds in all aspects of the present invention.

[0072] In a further preferred embodiment, the connector Y comprises or consists of: (a) D-Glu-urea-D-Glu; (b) one or two 2,3-diaminopropionic acid moieties, optionally replaced by moieties capable of generating a detectable signal; (c) one, two, three, four, five, or six consecutive amino acids comprising or consisting of one or more amino acids selected from the following: 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-sulfoalanine (Ala(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA), and D-Phe; and / or (d) p-aminomethylaniline-diethylene glycol (abbreviated pABza-DIG or AMA-DGA), and / or diethylene glycolate (abbreviated DIG or DGA).

[0073] A particularly preferred option is Y = Pip-phe.

[0074] According to entry (a) of the preferred embodiment, the D-Glu-urea-D-Glu portion is considered a means of making the compound more hydrophilic.

[0075] In further preferred embodiments of the compounds of the second and third aspects, namely both therapeutic and diagnostic active agents, the terminal group T is present and comprises or consists of: (a) statine (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, noreleucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methylbutane, wherein the amide amino group of Leu may be ethyl-modified (NH-ethyl) or NH2-modified (NH-NH2); and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)-Pro-NH2); provided that if T is an amino acid or terminated with an amino acid, the carboxylic acid group of the amino acid is amidated.

[0076] The preferred form is Sta-Leu-NH2.

[0077] Regarding the preferred selection of Y and T, there is generally no difference between the therapeutic and diagnostic compounds of the present invention.

[0078] As described above, in preferred embodiments of the compounds in all aspects of the invention, the serum or plasma is human serum or plasma. In other words, it is particularly important to increase or decrease the stability in human serum or plasma, respectively.

[0079] Table 1A below shows the sequences of known GRPR binders. The hexapeptide sequences beginning with Xaa1 and ending with L-His in the case of compounds of formula (I), and beginning with Xaa3 and ending with L-His in the case of compounds of formula (II), correspond to positions 7 through 12 in the table below. It can be recognized that the GRPR binders shown throughout the table have tryptophan at position 8 (corresponding to positions Xaa2 and Xaa4, respectively). Position 7 (corresponding to Xaa1 and Xaa3, respectively) is highly conserved. It is evident from the table below that, in the art, the peptide bond connecting positions 7 and 8 (as numbered in the table) is not recognized as a target site for fine-tuning pharmacokinetic properties.

[0080] Tables 1B and 1C show the sequences of the modified GRPR addressing ligands and the effects of introducing different GRPR-targeting compounds at the α-Me-Trp or Bta moiety at position 8 or the Hse moiety at position 7. Similar to Table 1A, the hexapeptide sequences starting with Xaa1 and ending with L-His in the case of compounds of formula (I) and starting with Xaa3 and ending with L-His in the case of compounds of formula (II) correspond to positions 7 to 12.

[0081] The problems caused by the metabolic degradation of linear GRPR-targeting peptides are thought to be due to neutral endopeptidases (NEP, EC3.4.24.11), which are known to cleave linear peptides at the N-terminus of hydrophobic amino acids (e.g., tryptophan). Therefore, it is hypothesized that these peptides are dipeptides, Gln, present in almost all GRPR-addressing compounds. 7 -Trp 8 The motif was cleaved (Table 1A). To demonstrate the increased metabolic stability in human serum or plasma upon introduction of α-Me-Trp or Hse at the stated position, different GRPR-targeting ligands were synthesized and the above modifications were introduced. For almost all the GRPR-targeting peptides evaluated shown in Table 1B, ligands containing their respective Gln were used. 7 -Trp 8 Compared to its derivatives, Trp 8 by α-Me-Trp 8 Or Gln 7 Hse 7 Substitution leads to enhanced metabolic stability (Table 1C). For most of these analogues, GRPR affinity was not significantly reduced by the addition of α-Me-Trp. However, for Gln... 7 Hse 7Substitution leads to a significant decrease in the affinity of GRPR for most ligands. However, a stabilizing effect of the Hse moiety can be observed.

[0082] Similarly, Bta was introduced at the stated location to demonstrate reduced metabolic stability in human serum or plasma. For most of the evaluated GRPR-addressing compounds shown in Table 1B, with each containing Gln... 7 -Trp 8 Compared to its derivatives, Bta 8 Replace Trp 8 It does indeed lead to decreased metabolic stability (Table 1C). For most of the derivatives shown in Table 1B, the addition of Bta did not significantly affect GRPR affinity.

[0083] Therefore, it can be concluded that regarding GRPR targeting ligands, which amino acids are located in Gln 7 -Trp 8 The N-terminus and C-terminus of a dipeptide are not important. Generally speaking, Bta 8 The introduction of α-Me-Trp reduces metabolic stability in human serum or plasma. 8 or Hse 7 The introduction of these modifications increases metabolic stability in human serum or plasma. Therefore, these modifications (α-Me-Trp) 8 Bta 8 and Hse 7 It can be widely used in all GRPR-targeting compounds.

[0084] Table 1C

[0085] Preferred compounds of the present invention include derivatives of the compounds shown in Tables 1A and 1B. The derivatives are preferably distinguished from the compounds in Tables 1A and 1B only by modification of the 7th and / or 8th positions (as numbered in the table) according to the present invention.

[0086] For example, in any of the compounds in Table 1A, tryptophan can be replaced with α-methyltryptophan to obtain preferred compounds according to the first and second aspects of the invention.

[0087] Similarly, at position 7 of the compounds in Table 1A, Gln (or His or gln, where applicable) can be replaced by Hse, or at position 8 of the compounds in Table 1A, Trp can be replaced by Bta, thereby obtaining the preferred compounds according to the third aspect of the invention.

[0088] The particularly preferred modifications applicable to Xaa1 to Xaa4 refer to any modifications applicable to the four positions disclosed above, whether in combination with compounds of the first, second, or third aspect.

[0089] In the fourth aspect—which is also a preferred embodiment of the first and second aspects—the invention provides compounds of formula (IIIa) or (IIIb): .

[0090] In the fifth aspect—which is also a preferred aspect of the third aspect—the invention provides a compound of formula (IV) or (V). .

[0091] In a sixth aspect, the present invention provides the use of the compound of any one of the preceding claims in a pharmaceutical.

[0092] In a seventh aspect, the present invention provides a pharmaceutical composition comprising or consisting of a compound of the first, second, or fourth aspect.

[0093] In an eighth aspect, the present invention provides a diagnostic composition comprising or consisting of a compound of the third or fifth aspect.

[0094] Although less preferred, the present invention provides, in another aspect, a diagnostic composition comprising or composed of compounds of the first, second, or fourth aspect. Also less preferred is another aspect relating to a pharmaceutical composition comprising or composed of compounds of the third or fifth aspect.

[0095] In the pharmaceutical and diagnostic compositions of the present invention, the compound may be the sole active agent. More than one compound of the first, second, or fourth aspect may also be used in the pharmaceutical compositions of the present invention, and more than one compound of the third or fifth aspect may be used in the diagnostic compositions of the present invention.

[0096] Although not preferred, pharmaceutical and diagnostic compositions of the present invention are also envisioned, wherein in addition to one or more of the compounds of the present invention, there are additional pharmaceutical or diagnostic active agents present.

[0097] Pharmaceutical or diagnostic compositions may also contain pharmaceutically or diagnostically acceptable carriers, excipients, and / or diluents. Examples of suitable carriers, excipients, and / or diluents are well known in the art and include phosphate-buffered saline solutions, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, etc. Compositions containing such carriers can be formulated using well-known conventional methods. These pharmaceutical and diagnostic compositions can be administered to an individual at appropriate doses. Appropriate compositions can be administered in various ways, such as intravenous, intraperitoneal, subcutaneous, intramuscular, local, intradermal, intranasal, or intrabronchial administration, preferably intravenous. Particularly preferred is administration by injection. The composition can also be administered directly to the target site, for example, via gene gun delivery to external or internal target sites. Dosing regimens will be determined by the attending physician and clinical factors. As is well known in the medical field, the dose for any patient depends on many factors, including the patient's body size, body surface area, age, the specific compound to be administered, sex, time and route of administration, general health condition, and other concurrently administered medications.

[0098] The radioactive labeling of the present invention (e.g., using) 177 Preferred doses of the Lu compound are 1 GBq to 100 GBq, 2 GBq to 60 GBq, 2 GBq to 50 GBq, 2 GBq to 10 GBq, or 3 GBq to 6 GBq.

[0099] The preferred medical indication according to the present invention is a proliferative disease, more preferably a malignant disease.

[0100] Therefore, in a ninth aspect, the present invention provides a pharmaceutical composition of the seventh aspect or a compound of any of the first, second, or fourth aspects for use in a method of treating cancer, wherein the cancer (a) is characterized by overexpression of the receptor; and / or (b) is selected from prostate cancer, breast cancer, neuroendocrine tumor, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), pancreatic cancer, head / necksquamous cell cancer, neuro / glioblastomas, colorectal cancer, and to some extent, the receptor is CCK-2R, medullary thyroid cancer (MTC).

[0101] Similarly, in the 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 for diagnosing cancer, wherein the cancer (a) is characterized by overexpression of the receptor; and / or (b) is selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head / neck squamous cell carcinoma, neuroblastoma / glioblastoma, colorectal cancer, and, in the case where the receptor is CCK-2R, medullary thyroid carcinoma (MTC).

[0102] In the eleventh aspect, the present invention provides an in vitro method for diagnosing cancer, said cancer (a) characterized by overexpression of said receptor; and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head / neck squamous cell carcinoma, neuroblastoma / glioblastoma, colorectal cancer, and, in the case where said receptor is CCK-2R, medullary thyroid carcinoma (MTC), wherein said method comprises contacting the diagnostic composition of the eighth aspect or the compound of the third or fifth aspect with a sample obtained from an individual.

[0103] With regard to the embodiments characterized in this specification, particularly in the claims, it is intended that each embodiment mentioned in the dependent claims be combined with each embodiment of each claim (independent or dependent) referenced by the dependent claims. For example, in cases where independent claim 1 lists three alternatives A, B, and C, dependent claim 2 lists three alternatives D, E, and F, and claim 3 is dependent on claims 1 and 2 and lists three alternatives G, H, and I, it should be understood that, unless otherwise expressly stated, the specification explicitly discloses embodiments corresponding to the following 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.

[0104] Similarly, and in cases where no alternatives are listed in the independent and / or dependent claims, it should be understood that any combination of the subject matter covered by a dependent claim is considered explicitly disclosed if the dependent claim refers to multiple of the preceding claims. For example, in the case where independent claim 1, dependent claim 2 refers to claim 1, and dependent claim 3 refers to both claims 2 and 1, the combination of the subject matter of claims 3 and 1 is as explicitly and explicitly disclosed as the combination of the subject matter of claims 3, 2, and 1. If there is another dependent claim 4 that refers to any one of claims 1 to 3, then the combination of the subject matter of claims 4 and 1, claims 4, 2 and 1, claims 4, 3 and 1, and claims 4, 3, 2, and 1 is explicitly and explicitly disclosed.

[0105] This invention includes the following items: 1. A compound that binds to an endogenous receptor, said compound comprising: (i) An oligopeptide comprising a dipeptide having a Trp as the C-terminal amino acid of the dipeptide, wherein the Trp is replaced by the α-amino acid Xaa2, thereby increasing the stability of the peptide bond linking Xaa2 to the N-terminal adjacent amino acid in serum or plasma compared to peptide bonds linking Trp to the N-terminal adjacent amino acid in otherwise identical compounds; and (ii) A portion capable of generating therapeutically effective radiation, said portion being covalently bound to the oligopeptide.

[0106] 2. The compound as described in 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.

[0107] 3. The compound as described in item 1 or 2, wherein the endogenous receptor is a peptide receptor overexpressed in cancerous diseases, such as a neuromodulatory peptide-B receptor (bufotin-1 receptor, NMBR), a gastrin-releasing peptide receptor (bufotin-2 receptor, GRPR), a bufotin receptor subtype 3 (BRS-3), or a cholecystokinin-2 receptor (CCK-2R), and preferably wherein... (a) The combination has a K value less than or equal to 15 nM. D ; and / or (b) The compound is a GRPR antagonist, preferably having an IC50 concentration of less than or equal to 15 nM. 50 .

[0108] 4. Compounds of formula (I) S — Y — Xaa1 — Xaa2 — L-Ala — L-Val — Xaa5 — L-His — T (I) in S is the part that can generate therapeutically active radiation; Y is an optional connector; Xaa1 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln; or (ii) α-amino acids that increase the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in all other respects; Xaa2 is a Trp or an α-amino acid that increases the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in other respects. The conditions are: Xaa1 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa2 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base. 5. The compound of any one of items 1 to 4, wherein Xaa2 is (a) Modified to include the following Trp: (i) an optional substituted C1 to C4 alkyl moiety bonded to an α-carbon, wherein the substituent is selected from halogens and hydroxyl groups; and / or (ii) A substituent attached to an indole ring, wherein the substituent is selected from N-(2,2,2-trifluoromethyl), N-methyl, N-acetyl, 5-fluoro, 5-bromo, 5-iodine, 5-chloro, 5-hydroxy, 5-methoxy, 5-methyl, 6-chloro, 7-chloro and 7-aza; (b) 1,2,3,4-Tetrahydrodemethylhalman-3-carboxylic acid (L-Tpi).

[0109] 6. The compound as described in item 5, wherein the optionally substituted alkyl moiety is selected from –CH3, –CH2CH3, and CH n Hal 3-n Where n is 0, 1 or 2, and Hal is F, Cl, Br and / or I, for example –CF3; and preferably –CH3.

[0110] 7. The compound of any one of items 1 to 6, wherein Xaa2 is α-Me-Trp.

[0111] 8. Compounds of formula (II) S — Y — Xaa3 — Xaa4 — L-Ala — L-Val — Xaa5 — L-His — T (II) in S is the part that can generate a detectable signal; Y is an optional connector; Xaa3 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln; or (ii) α-amino acids that reduce the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects; Xaa4 is a Trp or an α-amino acid that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects. The α-amino acid at the Xaa4 position that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is not a proteogenic amino acid. The conditions are: Xaa3 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa4 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

[0112] 9. The compound as described in item 8, wherein Xaa3 is Hse and / or Xaa4 is Bta.

[0113] 10. The compound of any one of items 4 to 7, wherein S is selected from the radioactive portion and the portion capable of loading a radionuclide.

[0114] 11. The compound as described in item 8 or 9, wherein S is selected from the fluorescent portion, the radioactive portion, and the portion capable of loading a radionuclide.

[0115] 12. The compound as described in item 10 or 11, wherein the portion capable of loading a radionuclide is a metal ion chelating agent, preferably selected from: bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradecane-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutyryl]amino]pentyl]-N-hydroxysuccinyl Amine (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]-glutaric acid (DOTAGA), N,N'-dipyridoxyethylenediamine-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-triacetic acid ester (HP-D) OA3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carbooxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6].2] Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7,10-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), 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-tetraazaundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl 1,4,8,11-tetraazaundecane (N4'), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), S-acetylthioacetyltriserine (MAS3), thioacetyltriglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazazolide (AAZTA), 3,6,9,15-tetraazabicyclo[9.3].1] Pentadec-1(15),11,13-trien-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentazatricyclic[15,3,2,1]eicos-1(21),17,19-trien-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanate benzyl)oxy-methyl]propene-1,3-diaminotetraacetic acid (TAME-Hex), 4- ((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutyric acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazacycloheptane-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphonic acid] (TRAP) and their functional derivatives, such as NOPO (1,4,7-Triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphonic acid]-7-[methylene(2-carboxyethyl)phosphonic acid]), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra[methylene(2-carboxyethyl)phosphonic acid] (DOTPI), 6,6′-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene))pyridinedicarboxylic acid (H2bispa2), 1,4,7,10,13-pentazacyclopentadecane-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-(carboxyl)-pyridin-2-yl}-methylamino]ethane (H2dedpa), N,N′-bis{6-carboxyl-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-tetra(carbamoylmethyl)-1,4,7,10-tetraazabicyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6].6] Eicosane (sar) and its functional derivatives, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazolidine-1-yl}-acetic acid (NETA), N,N′,N′′-tris(2-mercaptoethyl)-1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanate benzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N′-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N′-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (H2azap) a) 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]pentadecano-1(15),11,13-trien-3,6,9,-triacetic acid (PCTA), and N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane (H6phospa). DOTA or DOTAGA is preferred; Preferably, radioactive cations bind to the chelating agent. The radioactive cations are preferably selected from... 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 containing 18 F-cation molecules, for example 18 F-[AlF] 2+ .

[0116] 13. The compound of any one of items 4 to 12, wherein Y is present and (a) Contains one, two, three, four, five, or six positive and / or negative charges; (b) Contains one, two, three, four, five or six amino acids or is composed of one, two, three, four, five or six amino acids, wherein (a) D-amino acids are preferred, and (a) D-α-amino acids are more preferred; (c) Contains PEG n Or by PEG n Composition, where n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and / or (d) Includes the part that can generate a detectable signal.

[0117] 14. The compound as described in item 13, wherein the connector Y comprises or is composed of the following: (a) D-Glu-urea-D-Glu; (b) One or both of the 2,3-diaminopropionic acid moieties, which are optionally replaced by moieties capable of generating a detectable signal; (c) One, two, three, four, five, or six consecutive amino acids, said amino acids comprising or composed of one or more amino acids selected from the following: 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-sulfoalanine (Ala(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA), and D-Phe; and / or (d) p-Aminomethylaniline-diethylene glycol (pABza-DIG, AMA-DGA) and / or diethylene glycol salts (DIG, DGA).

[0118] 15. The compound of any one of items 4 to 14, wherein T is present and comprises or consists of the following: (a) Sta or (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, 2,6-dimethylheptane, Leu or β-thienyl-L-alanine (Thi); (b) Leu, ortholeucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methyl-butane, wherein the amide amino group of Leu may be ethyl-modified (NH-ethyl) or NH2-modified (NH-NH2); and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)-Pro-NH2); The condition is that if T is an amino acid or terminates with an amino acid, then the carboxylate of the amino acid is amidated.

[0119] 16. The compound as described in any of the preceding entries, wherein the serum or plasma is human serum or plasma.

[0120] 17. Compounds of formula (IIIa) or (IIIb) .

[0121] 18. Compounds of formula (IV) or (V) .

[0122] 19. Use of any of the compounds mentioned in the preceding entries in pharmaceuticals.

[0123] 20. A pharmaceutical composition comprising or consisting of any one of the compounds described in entries 1 to 7 or 10 to 17, where entries 10 to 13 refer to any one of entries 1 to 7.

[0124] 21. A diagnostic composition comprising or consisting of any one of the compounds described in entries 8, 9, 10 to 16 or 18, where entries 10 to 16 refer to entry 8 or 9.

[0125] 22. A pharmaceutical composition as described in heading 20 or a compound as described in any one of headings 1 to 7 or 10 to 17, in the case of headings 10 to 16 referencing any one of headings 1 to 7, for use in a method of treating cancer, wherein said cancer: (a) Characterized by overexpression of the receptor; and / or (b) Selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head / neck squamous cell carcinoma, neuroblastoma / glioblastoma, colorectal cancer, and medullary thyroid carcinoma (MTC) in the case where the receptor is CCK-2R.

[0126] 23. The diagnostic composition as described in item 20 or the compound of any one of items 8, 9, 10 to 16 or 18, in the case of reference to item 8 or 9 in items 10 to 16, for use in a method of diagnosing cancer, wherein said cancer: (a) Characterized by overexpression of the receptor; and / or (b) Selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head / neck squamous cell carcinoma, neuroblastoma / glioblastoma, colorectal cancer, and medullary thyroid carcinoma (MTC) in the case where the receptor is CCK-2R.

[0127] 24. An in vitro method for diagnosing cancer, wherein the cancer: (a) Characterized by overexpression of the receptor; and / or (b) Selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head / neck squamous cell carcinoma, neuroblastoma / glioblastoma, colorectal cancer, and, in the case where the receptor is CCK-2R, medullary thyroid carcinoma (MTC). The method described herein includes contacting a sample obtained from an individual with the diagnostic composition described in item 20 or any of the compounds described in any of items 8, 9, 10 to 16 or 18, where items 10 to 16 refer to item 8 or 9.

[0128] The present invention also includes the following embodiments: 1. A compound that binds to an endogenous receptor, said compound comprising (i) An oligopeptide comprising a dipeptide having a Trp as the C-terminal amino acid of the dipeptide, wherein the Trp is replaced by the α-amino acid Xaa2, thereby increasing the stability of the peptide bond linking Xaa2 to the N-terminal adjacent amino acid in serum or plasma compared to peptide bonds linking Trp to the N-terminal adjacent amino acid in otherwise identical compounds; and (ii) A portion capable of generating therapeutically effective radiation, said portion being covalently bound to the oligopeptide.

[0129] 2. The compound according to embodiment 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.

[0130] 3. The compound according to embodiment 1 or 2, wherein the endogenous receptor is a peptide receptor overexpressed in cancer, such as a neuromodulatory peptide-B receptor (bufotin-1 receptor, NMBR), a gastrin-releasing peptide receptor (bufotin-2 receptor, GRPR), bufotin receptor subtype 3 (BRS-3), or a cholecystokinin-2 receptor (CCK-2R), and preferably thereof. (a) The combination has a K value less than or equal to 15 nM. D ; and / or (b) The compound is a GRPR antagonist, preferably having an IC50 concentration of less than or equal to 15 nM. 50 .

[0131] 4. Compounds of formula (I) S — Y — Xaa1 — Xaa2 — L-Ala — L-Val — Xaa5 — L-His — T (I) in S is the part that can generate therapeutically active radiation; Y is an optional connector; Xaa1 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln; or (ii) α-amino acids that increase the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in all other respects; Xaa2 is a Trp or an α-amino acid that increases the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in other respects. The conditions are: Xaa1 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa2 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

[0132] 5. The compound according to any one of embodiments 1 to 4, wherein Xaa2 is (a) Modified to include the following Trp: (i) an alkyl moiety of C1 to C4 optionally substituted with an α-carbon, wherein the substituent is selected from halogens and hydroxyl groups; and / or (ii) A substituent attached to an indole ring, wherein the substituent is selected from N-(2,2,2-trifluoromethyl), N-methyl, N-acetyl, 5-fluoro, 5-bromo, 5-iodine, 5-chloro, 5-hydroxy, 5-methoxy, 5-methyl, 6-chloro, 7-chloro and 7-aza; (b) 1,2,3,4-Tetrahydrodemethylhalman-3-carboxylic acid (L-Tpi).

[0133] 6. The compound according to embodiment 5, wherein the optionally substituted alkyl moiety is selected from –CH3, –CH2CH3 and CH n Hal 3-nWhere n is 0, 1 or 2 and Hal is F, Cl, Br and / or I, for example –CF3; and preferably –CH3.

[0134] 7. The compound according to any one of embodiments 1 to 6, wherein Xaa2 is α-Me-Trp.

[0135] 8. Compounds of formula (II) S — Y — Xaa3 — Xaa4 — L-Ala — L-Val — Xaa5 — L-His — T (II) in S is the part that can generate a detectable signal; Y is an optional connector; Xaa3 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln; or (ii) α-amino acids that reduce the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects; Xaa4 is a Trp or an α-amino acid that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects. The α-amino acid at the Xaa4 position that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is not a proteogenic amino acid. The conditions are: Xaa3 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa4 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

[0136] 9. The compound according to embodiment 8, wherein Xaa3 is Hse and / or Xaa4 is Bta.

[0137] 10. The compound according to any one of embodiments 4 to 7, wherein S is selected from the radioactive portion and the portion capable of loading a radionuclide.

[0138] 11. The compound according to embodiment 8 or 9, wherein S is selected from the fluorescent portion, the radioactive portion, and the portion capable of loading a radionuclide.

[0139] 12. The compound according to any one of embodiments 4 to 11, wherein Y is present and (a) Contains one, two, three, four, five, or six positive and / or negative charges; (b) Contains one, two, three, four, five or six amino acids or is composed of one, two, three, four, five or six amino acids, wherein (a) D-amino acids are preferred, and (a) D-α-amino acids are more preferred; (c) Contains PEG n Or by PEG n Composition, where n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and / or (d) Includes a portion capable of generating a detectable signal; Preferably, the connector Y comprises or is composed of the following: (i) D-Glu-urea-D-Glu; (ii) One or both of the 2,3-diaminopropionic acid moieties, which are optionally replaced by moieties capable of generating a detectable signal; (iii) One, two, three, four, five, or six consecutive amino acids, said amino acids comprising or composed of one or more amino acids selected from the following: 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-sulfoalanine (Ala(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA), and D-Phe; and / or (iv) p-aminomethylaniline-diethylene glycol (pABza-DIG, AMA-DGA) and / or diethylene glycol salts (DIG, DGA).

[0140] 13. The compound according to any one of embodiments 4 to 12, wherein T is present and comprises or consists of the following: (a) Sta or (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, 2,6-dimethylheptane, Leu or β-thienyl-L-alanine (Thi); (b) Leu, ortholeucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methyl-butane, wherein the amide amino group of Leu may be ethyl-modified (NH-ethyl) or NH2-modified (NH-NH2); and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)-Pro-NH2); The condition is that if T is an amino acid or terminates with an amino acid, then the carboxylic acid portion of the amino acid is amidated.

[0141] 14. A pharmaceutical composition comprising or consisting of a compound according to any one of embodiments 1 to 7 or 10 to 13, wherein embodiments 10 to 13 refer to any one of embodiments 1 to 7.

[0142] 15. A diagnostic composition comprising or consisting of a compound according to any one of embodiments 8, 9, or 10 to 13, wherein embodiments 10 to 13 refer to embodiment 8 or 9. Attached Figure Description

[0143] The attached diagram shows: Figure 1 Analysis was performed after incubation in human plasma at 37°C for 72±2 hours. 177 Lu]RM2(t R = 15.3 minutes, 20→35% within 20 minutes). The chromatogram showed two important metabolites (t R = 2.9 minutes, 54% and t R = 8.5 minutes, 9%) and the remaining intact tracer (t R = 15.3 minutes, 36%).

[0144] Figure 2 Analysis was performed after incubation in human plasma at 37°C for 72±2 hours. 177 Lu]DOTA-[Hse 7 MJ9(t) R =16.1 minutes, 20→35% within 20 minutes). The chromatogram showed two important metabolites (t R = 3.4 minutes, 30% and t R =8.6 minutes, 8%) and the remaining intact tracer (t R = 15.3 minutes, 56%).

[0145] Figure 3 Analysis was performed after incubation in human plasma at 37°C for 72±2 hours. 177 Lu]DOTA-[Bta 8 MJ9(t) R =17.9 minutes, 20→35% within 20 minutes). The chromatogram showed two metabolites (t R = 3.1 minutes, 79% and t R= 12.3 minutes, 8%) and the remaining intact tracer (t R = 17.9 minutes, 12%).

[0146] Figure 4 Analysis was performed after incubation in human plasma at 37°C for 72±2 hours. 177 Lu]AMTG(t R = 17.0 minutes, 20→35% within 20 minutes). The chromatogram shows two metabolites (t R = 1.7 minutes, 2% and t R = 8.0 minutes, 5%) and the remaining intact tracer (t R = 17.0 minutes, 92%).

[0147] Figure 5 Analysis was performed after incubation in mouse plasma at 37°C for 6 ± 0.5 hours. 177 Lu]RM2(t R = 15.5 minutes, 20→35% within 20 minutes). The chromatogram shows three metabolites (t R = 3.1 minutes, 2%, t R = 8.2 minutes, 2% and t R =17.3 minutes, 4%) and the remaining intact tracer (t R = 17.0 minutes, 92%).

[0148] Figure 6 Analysis was performed after incubation in mouse plasma at 37°C for 6 ± 0.5 hours. 177 Lu]AMTG(t R = 17.0 minutes, 20→35% within 20 minutes). The chromatogram shows three metabolites (t R = 2.6 minutes, 2%, t R = 13.7 minutes, 2% and t R = 18.8 minutes, 5%) and the remaining intact tracer (t R = 17.0 minutes, 89%).

[0149] Figure 7 Analysis was performed after incubation in mouse plasma at 37°C for 72±2 hours. 177 Lu]RM2(t R = 15.5 minutes, 20→35% within 20 minutes). The chromatogram shows several small metabolites as well as the remaining intact tracer (t). R = 15.5 minutes, 67%).

[0150] Figure 8Analysis was performed after incubation in mouse plasma at 37°C for 72±2 hours. 177 Lu]AMTG(t R = 17.0 minutes, 20→35% within 20 minutes). The chromatogram shows several metabolites as well as the remaining intact tracer (t). R = 17.0 minutes, 59%).

[0151] Figure 9 : On CB17-SCID mice carrying PC-3 tumors (100 pmol per mouse) [ 177 Lu]RM2 (white), [ 177 Lu]DOTA-[Hse 7 MJ9 (black) and [ 177 Lu]DOTA-[Bta 8 Biodistribution of MJ9 (shaded line) in selected organs at pi 1 hour (in %ID / g). Data are presented as mean ± SD (n=4).

[0152] Figure 10 In CB17-SCID mice carrying PC-3 tumors [ 177 Lu]RM2 (white), [ 177 Lu]DOTA-[Hse 7 MJ9 (black) and [ 177 Lu]DOTA-[Bta 8 MJ9 (shaded line) ratio of tumor to background in selected organs at pi 1 hour. Data are expressed as mean ± SD (n=4).

[0153] Figure 11 : On CB17-SCID mice carrying PC-3 tumors (100 pmol per mouse) [ 177 Lu]RM2 (white), [ 177 Lu]NeoBOMB1 (grey), [ 177 Lu]DOTA-[Hse 7 MJ9 (Black), 177 Lu]DOTA-[Bta 8 MJ9 (shaded line), [ 177 Lu]AMTG (dashed line) and [ 177 Biodistribution of Lu]AMTG2 (square) in selected organs at pi 24 hours (in %ID / g). Data are presented as mean ± SD (n=4).

[0154] Figure 12 In CB17-SCID mice carrying PC-3 tumors [177 Lu]RM2 (white), [ 177 Lu]NeoBOMB1 (grey), [ 177 Lu]DOTA-[Hse 7 MJ9 (Black), 177 Lu]DOTA-[Bta 8 MJ9 (shaded line), [ 177 [177Lu]AMTG (dashed line) and [177Lu]AMTG2 (square) are the tumor-to-background ratios of selected organs at pi 24 hours. Data are expressed as mean ± SD (n=4).

[0155] Figure 13 : On CB17-SCID mice carrying PC-3 tumors (100 pmol per mouse) [ 99m Tc]N4-asp-MJ9 (gray, shaded), [ 99m Tc]N4-asp-[Bta 8 MJ9 (gray dashed line), [ 99m Tc]N4-[Hse 7 MJ9 (grey, brick) and [ 99m Tc]N4-[α-Me-Trp 8 Biodistribution of MJ9 (grey, square) in selected organs at pi 1 hour (in %ID / g). Data are presented as mean ± SD (n=4).

[0156] Figure 14 : On CB17-SCID mice carrying PC-3 tumors (100 pmol per mouse) [ 99m Tc]N4-asp-MJ9 (gray, shaded), [ 99m Tc]N4-asp-[Bta 8 MJ9 (gray dashed line), [ 99m Tc]N4-[Hse 7 MJ9 (grey, brick) and [ 99m Tc]N4-[α-Me-Trp 8 Biodistribution of MJ9 (gray, square) in selected organs at pi 4 hours (n = 1) (in %ID / g).

[0157] Figure 15 In CB17-SCID mice carrying PC-3 tumors [ 99m Tc]N4-asp-MJ9 (gray, shaded), [ 99m Tc]N4-asp-[Bta 8 MJ9 (gray dashed line), [99m Tc]N4-[Hse 7 MJ9 (grey, brick) and [ 99m Tc]N4-[α-Me-Trp 8 [MJ9 (gray, square) tumor-to-background ratio in selected organs at pi 1 hour. Data are expressed as mean ± SD (n=4).]

[0158] Figure 16 In CB17-SCID mice carrying PC-3 tumors [ 99m Tc]N4-asp-MJ9 (gray, shaded), [ 99m Tc]N4-asp-[Bta 8 MJ9 (gray dashed line), [ 99m Tc]N4-[Hse 7 MJ9 (grey, brick) and [ 99m Tc]N4-[α-Me-Trp 8 The ratio of tumor to background in a selected organ at pi 1 hour for MJ9 (gray, square) (n = 1).

[0159] Figure 17 : On CB17-SCID mice carrying PC-3 tumors (200 pmol per mouse) [ 99m Tc]N4-asp-MJ9、[ 99m Tc]N4-asp-[Bta 8 MJ9, [ 99m Tc]N4-[Hse 7 MJ9 and [ 99m Tc]N4-[α-Me-Trp 8 The maximum intensity projection (dorsolateral) of MJ9 at 1 hour pi (top) and 4 hours pi (bottom). PC-3 tumors are indicated by white arrows.

[0160] Figure 18 : On CB17-SCID mice carrying PC-3 tumors (100 pmol per mouse) [ 177 Lu]GT50 (dark gray, shaded lines), [ 177 Lu]GT51 (dark gray dashed line), [ 177 Lu]GT52 (dark gray, brick-like), [ 177 Biodistribution of Lu]GT53 (dark gray, square) in selected organs at pi 24 hours (in %ID / g). Data are presented as mean ± SD (n=4).

[0161] Figure 19: On CB17-SCID mice carrying PC-3 tumors (100 pmol per mouse) [ 177 Lu]RM2 (top) and [ 177 Lu]AMTG (bottom) maximum intensity projection (dorsolateral) at pi 1, 4, 8, 24 and 28 hours. PC-3 tumors are indicated by white arrows. Detailed Implementation

[0162] The embodiments illustrate the present invention.

[0163] Example 1: Materials and Methods (General) Fmoc-(9-fluorenylmethoxycarbonyl-) and all other protected amino acid analogs were purchased from Bachem (Bubendorf, Switzerland), Sigma-Aldrich (Munich, Germany), or Iris Biotech (Marktredwitz, Germany). H-Rink amides ChemMatrix ® Resins (35-100 mesh particle size, 0.4 mmol / g-0.6 mmol / g loading) were purchased from Sigma-Aldrich (Munich, Germany). Chematech (Dijon, France) supplied the chelating agent DOTA. t Bu)3 and DOTAGA( t Bu)4.

[0164] All necessary solvents and other organic reagents were purchased from Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich (Munich, Germany), or VWR (Darmstadt, Germany). Peptide solid-phase synthesis was performed manually using a Scilogex MX-RL-EAnalog Rotisserie Tube Rotator (Scilogex, Rocky Hill, CT, USA).

[0165] Analytical and preparative reversed-phase high-performance chromatography (RP-HPLC) was performed using a Shimadzu gradient system (ShimadzuDeutschland GmbH, Neufahrn, Germany), each equipped with an SPD-20 AUV / Vis detector (220 nm, 254 nm). Acetonitriles (0.1% TFA) in different gradients in water (0.1% TFA) were used as eluents for all HPLC operations.

[0166] For analytical measurements, a Nucleosil 100 C18 column (125 × 4.6 mm, 5 μm particle size) (CS GmbH, Langerwehe, Germany) was used at a flow rate of 1 mL / min. Specific gradients and corresponding retention times t are cited in the text. R And the capacity factor K'.

[0167] Preparative HPLC purification was performed using a Multospher 100 RP 18 (250 × 10 mm, 5 μm particle size) column (CS GmbH, Langerwehe, Germany) at a constant flow rate of 5 mL / min.

[0168] Analytical and preparative radioactive RP-HPLC were performed using a Nucleosil 100 C18 (5 μm, 125 × 4.0 mm) column (CS GmbH, Langerwehe, Germany).

[0169] Electrospray ionization mass spectrometry used for characterizing substances in expression L Acquired on a CMS mass spectrometer (Advion Ltd., Harlow, UK). Radioactivity was detected by connecting the outlet of the UV spectrophotometer to a NaI(Tl) well-type scintillation counter from EG&G Ortec (Munich, Germany).

[0170] Radioactive probes via WIZARD 2® Measured using a 2480 automated gamma counter (Perkin Elmer, Waltham, MA, USA) and IC determined using a GraphPad Prism 6 (GraphPad Software Inc., San Diego, CA, USA). 50 value.

[0171] For radiation TLC, use with Laura TM Software Scan-RAM TM Scanner (LabLogic Systems Ltd., Broomhill, Sheffield, United Kingdom).

[0172] Example 2: Synthesis Scheme Solid-phase peptide synthesis following the Fmoc strategy Peptide formation on resin The corresponding side-chain protected Fmoc-AA-OH (1.5 equivalents) was dissolved in NMP and pre-activated by adding TBTU (1.5 equivalents), HOAt (1.5 equivalents), and DIPEA (4.5 equivalents). After activation for 10 minutes, the solution was added to the resin-bound free amine peptide and shaken at room temperature for 1.5 hours. Subsequently, the resin was washed with NMP, and after Fmoc deprotection, the next amino acid was similarly conjugated.

[0173] Fmoc on resin for protection The resin-bound Fmoc peptides were treated with 20% piperidine in NMP (v / v) for 5 minutes, followed by treatment for 15 minutes. The resin was then thoroughly washed with NMP.

[0174] Dde on resin for protection Deprotection of the resin was performed by adding a solution of imidazole (75 equivalents), hydroxylamine hydrochloride (100 equivalents), and DCM (3 mL) to NMP for 3 hours at room temperature. After deprotection, the resin was washed with NMP.

[0175] DOTA t Bu)3 or DOTAGA( t Bu)4 junction The protected chelating agent DOTA ( t Bu)3 or DOTAGA( t Bu4 (1.5 equivalents) was dissolved in NMP and pre-activated by adding TBTU (1.5 equivalents), HOAt (1.5 equivalents), and DIPEA (4.5 equivalents). After activation for 10 minutes, the solution was added to resin-bound N-terminal deprotected peptide (1.0 equivalent) and shaken at room temperature for 3 hours. Subsequently, the resin was washed with NMP and DCM.

[0176] Peptide cleavage from resin via additional deprotection of acid-instable protecting groups The fully protected resin-bound peptides were washed with DCM and then dissolved in a mixture of TFA / TIPS / DCM (v / v / v; 95 / 2.5 / 2.5) and shaken for 30 minutes. The solution was filtered off and the resin was treated again in the same manner for 30 minutes. The two filtrates were combined and concentrated under a nitrogen stream. After dissolving the residue in MeOH and precipitating in diethyl ether, the liquid was decanted and the remaining solids were dried.

[0177] Remaining t Bu / Boc's protection The crude product was dissolved in TFA and stirred at room temperature for 6 hours, thereby proceeding with the cleavage of the remaining peptides after cleavage from the resin. tRemoval of the Bu / Boc protecting group (see above). After removing TFA under a nitrogen stream, a crude unprotected product was obtained.

[0178] Example 3: Materials and Methods (Labeling Experiment) Cold complex [ nat Ga] gallium complex Purified ligands containing chelating agents (in Tracepur H2O 10) -3 m, 1.00 equivalent) and [ nat Ga]Ga(NO3)3 •6 H2O (10 mM, 1.50 equivalent in Tracepur H2O) was diluted with Tracepur water to a final concentration of 10. -4 m, then heat to 70°C for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0179] [ nat Lu] lutetium complex Purified ligands containing chelating agents (in Tracepur H2O 10) -3 m, 1.00 equivalent) and [ nat LuCl3 (20 mM, 2.50 equivalents in Tracepur H2O) was diluted with Tracepur water to a final concentration of 10. -4 m, then heat to 95°C for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0180] Radioactive labeling [ 125 I] Iodine labeling ICs are fabricated according to previously published procedures. 50 The reference ligand for the study ([D-3-[ 125 I]I-Tyr 6 [MJ9]. In short, 0.2 mg of [D-Tyr] 6 MJ9 was dissolved in 20 µL of Tracepur water and 280 µL of TRIS buffer (25 mm TRISHCl, 0.4 M NaCl, pH = 7.9). The solution was then added to a volume containing 150 µg of Iodo-Gen. ® After adding 5.0 µL (16 MBq) to a vial containing (1,3,4,6-tetrachloro-3α,6α-diphenylglyurea, surface-bound) [ 125[I]NaI (74 TBq / mmol, 3.1 GBq / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany). The reaction solution was incubated at room temperature for 15 minutes, and then purified by RP-HPLC (20→35% within 20 minutes): t R = 18.9 minutes, K' = 10.46.

[0181] [ 177 Lu] lutetium mark use[ 177 Lu]lutetium labeling was accomplished using a procedure developed internally by the group. Therefore, the solution containing the purified chelating agent ligand (in Tracepur H2O 10) -3 (m, 1 µL), sodium acetate buffer (1 m, pH = 5.50, 10 µL) and approximately 10-30 MBq [ 177 LuCl3 (0.04 M in HCl) was diluted with HCl (0.04 M) to a total volume of 90 µL, and then heated to 95 °C for 10 minutes. Sodium ascorbate (0.1 M, 10 µL) was added immediately after labeling to prevent radiodegradation. 177 The incorporation of lutetium (Lu) was determined by radioactive TLC (ITLC-SG chromatographic paper, mobile phase: 0.1 mL trisodium citrate). The radiochemical purity of the labeled compound was determined by radioactive RP-HPLC.

[0182] [ 99m Tc] Technetium marker use[ 99m [Tc] Technetium labeling was performed using a procedure developed internally by the group. Therefore, a solution containing the purified chelating agent (in Tracepur H2O for 10 minutes) was prepared. -3 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] − Heat to 95°C for 10 minutes. 99m The incorporation of technetium [Tc] was determined by radioactive TLC (ITLC-SG chromatographic paper, mobile phase: isotonic NaCl). The radiochemical purity of the labeled compound was determined by radioactive RP-HPLC.

[0183] Example 4: Materials and Methods (In Vitro Experiment) octanol-PBS distribution coefficient, logD7.4 In Eppendorf tubes, approximately 1 MBq of labeled tracer was dissolved in 1 mL of a 1:1 mixture (v / v) of phosphate-buffered saline (PBS, pH = 7.4) and n-octanol. After vigorously mixing the suspension for 3 minutes at room temperature, the vials were centrifuged at 9000 rpm for 5 minutes (Biofuge 15, Heraus Sepatech, Osterode, Germany), and then 200 μL aliquots of the two layers were measured using a gamma counter. This experiment was repeated at least four times.

[0184] IC 50 Measurement GRPR-positive PC-3 cells were cultured in Dublecco modified Eagle medium / nutrient mixture F-12 with Glutamax-I (1:1) supplemented with 10% fetal bovine serum (FBS) (Invitrigon) and maintained at 37°C in a humidified 5% CO2 atmosphere. To determine GRPR affinity (IC50), 50 Cells were harvested 24 ± 2 hours before the experiment and seeded in 24-well plates (1.5 × 10⁻⁶ cells per well). 5 (1 cell, 1 mL / well)

[0185] After removing the culture medium, the cells were washed once with 500 µL of HBSS (Hank's balanced salt solution (Biochrom, Berlin, Germany, with 1% bovine serum albumin (BSA)) and then equilibrated in 200 µL of HBSS (1% BSA) for 9 minutes at room temperature. Next, 25 µL of HBSS (1% BSA) was added to each well as either a control or an increasing concentration of the corresponding ligand (10 mmol / L in HBSS). -10 m–10 -4 A solution of m) was prepared, followed by the addition of 25 µL of [D-3-] in HBSS (1% BSA). 125 I]I-Tyr 6 MJ9 (2.0 nm).

[0186] For each concentration, all experiments were performed in triplicate. After incubation at room temperature for 2 hours, the experiment was terminated by removing the culture medium and continuously washing with 300 µL HBSS. The culture medium from both steps was combined into a single fraction representing the amount of the bound radiolabeled reference. Cells were then lysed with 300 µL of 1 m NaOH for at least 15 minutes and combined with the 300 µL NaOH from the subsequent washing step. Quantification of the bound and bound radiolabeled references was performed using a gamma counter.

[0187] IC of each ligand 50 The measurement was repeated twice.

[0188] Internalization For internalization studies, PC-3 cells were harvested 24 ± 2 hours before the experiment and seeded in 24-well plates (1.5 × 10⁻⁶). 5 Cells / well, 1 mL. After removing the culture medium, wash the cells once with 500 µL DMEM / F-12 (5% BSA) and equilibrate in 200 µL DMEM / F-12 (5% BSA) at 37°C for at least 15 minutes. Each well is then rinsed with 25 µL DMEM / F-12 (5% BSA) or 25 µL […]. nat Lu] RM2 (10 -3 M) was used for blocking treatment. Next, 25 µL of [the solution] was added. 125 I / 177 The cells were incubated with Lu-labeled GRPR ligand (10 nM) at 37°C for 60 minutes.

[0189] Experiments were terminated by placing the 24-well plate on ice for 1 minute and sequentially removing the culture medium. Each well was washed with 300 µL of ice-cold PBS, and the fractions from the first two steps were combined to represent the amount of free radiolabeled reference. Surface-binding activity was removed by incubating cells with 300 µL of ice-cold acid wash solution (0.02 M NaOAc, pH = 5.0) at room temperature for 10 minutes, followed by a second wash with 300 µL of ice-cold PBS. Internalization activity was determined by incubating cells in 300 µL of NaOH (1 m) and combining the fractions from the subsequent wash step with 300 µL of NaOH (1 m).

[0190] Each experiment (control and block) was performed six times. Free, surface-bound, and internalized activities were quantified using a gamma counter. Data were corrected for nonspecific internalization.

[0191] plasma research In vitro metabolic stability was determined using a slightly modified procedure published by Linder et al. Immediately after labeling, human (200 µL) or mouse (100 µL) plasma was added, and the mixture was incubated at 37 °C for 72 ± 2 h (or 6 ± 0.5 h). Protein precipitates were treated with ice-cold EtOH (150 µL [human], 100 µL [mouse]) and ice-cold MeCN (450 µL [human], 300 µL [mouse]), followed by centrifugation at 13,000 rpm for 20 min. The supernatant was decanted and further analyzed using radioactive RP-HPLC.

[0192] Example 5: Materials and Methods (In Vivo Experiment) All animal experiments were conducted in accordance with German general animal welfare regulations (German animal protection act, amended 18.05.2018, Art. 141 G v. 29.3.2017 I 626, approval number ROB-55.2-2532.Vet_02-18-109) and institutional guidelines for the care and use of animals. To establish tumor xenografts, PC-3 cells (5 × 10⁶) were used. 6 Cells were suspended in Dulbecco modified Eagle's medium / Ham's F-12 (DMEM / F-12) at 200 µL per cell in Glutamax-I (1:1) and Cultrex. ® A 1:1 mixture (v / v) of Basement Membrane Matrix Type 3 (Trevigen Inc., Gaithersburg, MD, USA) was subcutaneously injected into the right shoulder of 6- to 10-week-old female CB17-SCID mice (Charles River Laboratories International Inc., Sulzfeld, Germany). The tumor volume was 125 mm. 3 Up to 500 mm 3 The experiment was conducted using mice 2 to 3 weeks after vaccination.

[0193] Biological distribution Approximately 1 to 5 MBq (100 to 200 pmol) of radiolabeled GRPR antagonist was injected into the tail vein of mice carrying PC-3 tumors, and the mice were sacrificed at pi 1, 4, or 24 hours (n = 4). Selected organs were removed, weighed, and measured using a gamma counter (Perkin Elmer, Waltham, MA, USA).

[0194] µSPECT / CT imaging At MILabs VECTor 4Imaging studies were performed on a small animal SPECT / PET / OI / CT system (MILabs, Utrecht, the Netherlands). Data were reconstructed using MILabs Rec software (version 10.02) and the Similarity-Regulated Ordered Subsets Expectation Maximization (SROSEM) algorithm, followed by data analysis using PMOD 4.0 software (PMOD TECHNOLOGIES LLC, Zurich, Switzerland). For SPECT studies, mice were anesthetized with isoflurane and injected with 2 to 4 MBq (100 to 200 pmol) of radiolabeled tracer via the tail vein. Still images were recorded at pi 1 and 28 hours. Acquisition times were 45 to 60 minutes using an HE-GP-RM collimator and progressive multiplane bed movement.

[0195] Example 6: Results GRPR reference ligand RM2 (2) NeoBOMB1 (3) .

[0196] Exemplary Synthesized Antagonistic GRPR Ligands of the Present Invention [Hse 7 MJ9-DOTA(4) [Bta 8 MJ9-DOTA(5) AMTG (6) AMTG2 (7) .

[0197] HPLC [ nat Ga]RM2 (10→90% MeCN within 15 minutes): t R = 6.7 minutes, K' = 3.47.

[0198] Calculated mass of a single isotope (C 78 H 115 GaN 20 O 19m / z = 1704.8, measured value: m / z = 1706.6 [M+H] + 854.1 [M+2H] 2+ .

[0199] [ nat Ga]DOTA-[Hse 7 MJ9 (10→90% MeCN within 15 minutes): t R = 6.8 minutes, K' = 3.53.

[0200] Calculated mass of a single isotope (C 77 H 114 GaN 19 O 19 m / z = 1677.8, measured value: m / z = 1679.3 [M+H] + 840.4 [M+2H] 2+ .

[0201] [ nat Ga]DOTA-[Bta 8 MJ9 (10→90% MeCN within 15 minutes): t R = 7.0 minutes, K' = 3.67.

[0202] Calculated mass of a single isotope (C 78 H 114 GaN 19 O 19 S): 1721.7, Measured value: m / z = 1723.7 [M+H] + 862.3 [M+2H] 2+ .

[0203] [ nat Ga]AMTG (10→90% MeCN within 15 minutes): t R = 6.9 minutes, K' = 3.60.

[0204] Calculated mass of a single isotope (C 79 H 117 GaN 20 O 19 m / z = 1718.8, measured value: m / z = 1720.0 [M+H] + 860.6 [M+2H] 2+ .

[0205] [ nat Ga]AMTG2 (10→90% MeCN within 15 minutes): t R= 6.9 minutes, K' = 3.31.

[0206] Calculated mass of a single isotope (C 82 H 121 GaN 20 O 21 ):1790.8,Measured value:m / z = 896.3 [M+2H] 2+ 1792.6 [M+H] + .

[0207] [ nat Lu]RM2 (10→90% MeCN within 15 minutes): t R = 6.6 minutes, K' = 3.40.

[0208] Calculated mass of a single isotope (C 78 H 115 LuN 20 O 19 m / z = 1810.8, measured value: m / z = 1812.2 [M+H] + 906.8 [M+2H] 2+ .

[0209] [ nat Lu]DOTA-[Hse 7 MJ9 (10→90% MeCN within 15 minutes): t R = 6.8 minutes, K' = 3.53.

[0210] Calculated mass of a single isotope (C 77 H 114 LuN 19 O 19 m / z = 1783.8, measured value: m / z = 1784.9 [M+H] + 893.6 [M+2H] 2+ .

[0211] [ nat Lu]DOTA-[Bta 8 MJ9 (10→90% MeCN within 15 minutes): t R = 7.0 minutes, K' = 3.67.

[0212] Calculated mass of a single isotope (C 78 H 114 LuN 19 O 19 S): 1827.8, Measured value: m / z = 1828.9 [M+H] +915.1 [M+2H] 2+ .

[0213] [ nat Lu]AMTG (10→90% MeCN within 15 minutes): t R = 6.8 minutes, K' = 3.53.

[0214] Calculated mass of a single isotope (C 79 H 117 LuN 20 O 19 m / z = 1824.8, measured value: m / z = 1826.3 [M+H] + 913.6 [M+2H] 2+ .

[0215] [ nat Lu]AMTG2 (10→90% MeCN within 15 minutes): t R = 7.0 minutes, K' = 3.38.

[0216] Calculated mass of a single isotope (C 82 H 121 LuN 20 O 21 ): 1896.8, Measured value: m / z = 949.5 [M+2H] 2+ , 1897.6 [M+H] + .

[0217] [ nat Lu]NeoBOMB1 (10→90% MeCN within 15 minutes): t R = 9.6 minutes, K' = 5.00.

[0218] Calculated mass of a single isotope (C 77 H 107 LuN 18 O 18 m / z = 1746.7, measured value: m / z = 874.5 [M+2H] 2+ 1747.3 [M+H] + .

[0219] Hydrophilicity determination (octanol-PBS distribution coefficient, logD) 7.4 ) Definite 177 The distribution coefficient (logD) of the n-octanol / PBS of the Lu-labeled compound 7.4 Listed in Table 2. For all compounds, DOTA or DOTAGA is used as a chelating agent.177 Among the Lu-labeled GRPR ligands, the reference RM2 was found to be the most hydrophilic, while the derivative modified with 3-benzothiophene alanine (Bta) was the most lipophilic.

[0220] Table 2: Distribution coefficients of radiolabeled GRPR ligands (logD) 7.4 Values). Data are expressed as mean ± SD (n = 8).

[0221] Determination of GRPR affinity The synthesized compounds exhibited affinities within a similar range, while the affinity of homoserine derivatives decreased slightly. All [ nat Gallium (Ga) complex ligands due to their [ nat Lu] lutetium complexation counterparts exhibit higher affinity (Table 3). Cold standard [D-3-I-Tyr] 6 MJ9 exhibits exceptionally high affinity, indicating its suitability as a base for all ICs. 50 Competitive radiolabeling reference for the experiment.

[0222] Table 3: Binding affinity of the synthesized bufotoxin antagonist to GRPR. Using PC-3 cells (1.5 × 10⁻⁶ cells / year). 5 (cells / well) and [D-3-] 125 I]I-Tyr 6 MJ9 (c = 0.2 nM) was used as a radiolabeled reference (2 hours, room temperature, HBSS + 1% BSA). Data are expressed as mean ± SD (n = 3).

[0223] Internalization To demonstrate the antagonistic properties of the modified gastrin-based GRPR ligand, internalization in PC-3 cells was determined. As expected of the antagonist, all... 177 The Lu-labeled compounds all showed low internalization (Table 4). 177 The internalization of Lu]RM2 showed good correlation with the results of other published studies.

[0224] Table 4: In PC-3 cells (37℃, DMEM / F-12 + 5% BSA, 1.5 × 10⁻⁶), 5 A summary of the 1-hour chemoactivation activity (c = 1 nM) determined by each cell pore, as a percentage of the activity used. For non-specific binding (10... -3 m [ nat Lu]RM2) corrects the data and is expressed as mean ± SD (n = 6).

[0225] plasma research The in vitro stability of the synthesized GRPR ligand was determined in human plasma. Figures 1 to 4 Furthermore, stable ligands were analyzed in mouse plasma. 177 Lu]AMTG and reference [ 177 [Lu]RM2. Therefore, immediately after labeling, only 100 µL of mouse plasma was added to the tracer solution (final volume 200 µL). According to Linde et al. (Bioconjugate Chem. 20, 1171-1178 (2009)), metabolism is faster in mouse plasma than in human plasma; therefore, the experiment was terminated after incubation at 37°C for 6 ± 0.5 hours. Figure 5 and Figure 6 However, due to its small size, the mouse mixture was additionally examined after incubation at 37°C for 72±2 hours. Figure 7 and Figure 8 ).

[0226] After incubation at 37°C for 72±2 hours, all four types of human plasma were compared. 177 Lu-labeled GRPR ligands ( Figures 1 to 4 The amount of intact tracer showed significant differences. After this time span, the reference ligand [ 177 Lu]RM2( Figure 1 The in vitro stability of [ ] was determined to be only 33.5 ± 2.7%, while [ 177 Lu]DOTA-[Hse 7 MJ9 (40.1±1.4%) and [ 177 The concentration of Lu]AMTG (77.6±10.1%) was higher after incubation at 37°C for 72±2 hours. Among these four compounds, the derivative with the strongest lipophilicity […]. 177 Lu]DOTA-[Bta 8 MJ9 (19.0±1.7%) exhibited the lowest stability. The second reference ligand [ 177 Lu]NeoBOMB1 showed 60.8 ± 1.2% of the complete tracer dose after the same time span.

[0227] The reference compound was further examined in mouse plasma. 177 Lu]RM2( Figure 5 and Figure 7 ) and stable derivatives[ 177 Lu]AMTG( Figure 6 and Figure 8This study aimed to determine potential differences between human and animal plasma. According to Linder et al., metabolism in mouse plasma approximately 6 hours after ingestion was comparable to that in human plasma approximately 3 days after ingestion. Therefore, the stability of both ligands was determined in mouse plasma 6 hours after ingestion, showing comparable amounts of intact [[...]]. 177 Lu]AMTG(t R = 17.0 minutes, respectively Figure 6 89% and Figure 4 ,92%), but [ 177 The intact ligand of Lu]RM2 has a significant deviation (t) R = 15.5 minutes, respectively Figure 5 92% and Figure 1 ,36%).

[0228] Examination of the two tracers in mouse plasma over a longer time span (incubation at 37°C for 72 ± 2 hours) showed that, 177 Lu]RM2( Figure 7 ) in comparison [ 177 Lu]AMTG ( Figure 8 More sites were cleaved by mouse endopeptidase, but despite this, the amount of intact tracer appeared to be higher (67% and 59%, respectively), leading to the hypothesis that there are significant differences between human and animal plasma, especially for the reference compound.

[0229] Considering these observations, stable [ 177 Lu]AMTG exhibits superior performance to the reference ligand in humans, but this is not necessarily the case in mice.

[0230] Biodistribution and µSPECT / CT studies The reference compound was examined at 1 hour and 24 hours post-pi in CB17-SCID mice. 177 Lu]RM2 and diagnostic ligands[ 177 Lu]DOTA-[Hse 7 MJ9 and [ 177 Lu]DOTA-[Bta 8 The in vivo pharmacokinetics of MJ9, and the therapeutic ligands [ 177 Lu]AMTG、[ 177 Lu]AMTG2 and the second reference [ 177 Lu]NeoBOMB1 was studied only at pi 24 hours (100 pmol per animal). Data and Figures 9 to 12 The references shown are compared.

[0231] Compared to the reference ligand in mice, both unstable compounds exhibited superior pharmacokinetic profiles at pi 1 h. Figure 9 and Figure 10 For each organ, the uptake of the diagnostic ligands was equal to or lower than the reference value, particularly for the GRPR-positive pancreas, which highlighted faster clearance from the organ, likely due to higher metabolism at the unstable site. Interestingly, tumor uptake of both diagnostic ligands was superior to that of the reference compound. Figure 9 This leads to the hypothesis that tumor enrichment may reach even higher levels, as through [ 177 Lu]RM2 is achievable. Furthermore, since metabolism in tumors is not as rapid as in non-tumor organs, there is no negative clearance effect from the tumor at pi1 hour, despite the instability of the bonds in the diagnostic derivatives.

[0232] As shown in the tumor-to-background ratio ( Figure 10 ), [ 177 Lu]DOTA-[Hse 7 MJ9 showed the highest contrast between tumor and non-tumor organs at pi 1 hour, while the reference showed the worst contrast among the three.

[0233] For potential therapeutic applications, three ligands and […] were investigated in CB17-SCID mice at 24 hours post-pi. 177 Lu]NeoBOMB1 and stable [ 177 Lu]AMTG and [ 177 Lu]AMTG2( Figure 11 and Figure 12 Pharmacokinetic profiles confirmed the recommendation for faster clearance of unstable ligands from tumors over a longer time span. While retention of all four comparative ligands was similar in normal tissues, tumor retention differed significantly because a large amount of […] remained in the tumor. 177 Lu]RM2、[ 177 Lu]AMTG and [ 177 Lu]AMTG2, but only a small number of unstable compounds. 177 Lu]NeoBOMB1 also showed high tumor retention, but also high pancreatic retention. Bone uptake of all derivatives was achieved through […]. 177 Lu]LuCl3 to explain ( Figure 11 ).

[0234] [ 177 Lu]RM2、[ 177 Lu]AMTG and [ 177Lu]AMTG2 showed higher tumor retention at 24 hours compared to other derivatives in the series. Figure 11 Considering the tumor-to-background ratio after this time span, [ 177 Lu]AMTG and [ 177 Lu]AMTG2 showed excellent tumor-to-blood ratio and tumor-to-muscle ratio ( Figure 12 Unstable ligands and [ 177 The tumor-to-background ratio of Lu]NeoBOMB1 was lower than that of the control. In mice carrying PC-3 tumors (100 pmol per mouse) [ 177 Lu]RM2 and [ 177 Imaging studies of Lu]AMTG at 1, 4, 8, 24, and 28 hours showed its in vivo distribution over time. Figure 19 Both conjugates exhibited favorable pharmacokinetics, demonstrating rapid clearance from GRPR-positive tissues (pancreas, intestine) and high retention in tumors. 177 In the case of Lu]AMTG, background activity is cleared more slowly, especially from the pancreas, which is expected due to increased metabolic stability in vivo.

[0235] In summary, considering the results, both unstable ligands performed better than the control in mice at 1 hour post-pi, but significantly worse at 24 hours post-pi, which is consistent with […]. 177 Lu]DOTA-[Bta 8 MJ9 correlated well with observations in plasma studies because the compound exhibited minimal metabolic stability in vitro. As previously mentioned, metabolism in non-tumor tissues was faster than in tumor tissues, leading to the clearance of well-known GRPR antagonists. At 1 hour post-pi, Gln... 7 -Trp 8 Further instability of the bonds led to faster clearance from the background (rather than from the tumor), producing better contrast compared to the reference. However, significantly faster tumor clearance was observed over longer time spans, confirming the presence of more lipophilic […]. 177 Lu]DOTA-[Bta 8 The hypothesis of increased enzymatic degradation of MJ9 suggests that it may be a useful diagnostic agent.

[0236] Another unstable derivative [ 177 Lu]DOTA-[Hse 7MJ9 did not exhibit low in vitro stability in human plasma, but its behavior in mice showed lower stability, as it exhibited faster clearance from non-tumor tissues at 1 hour post-pi and minimal retention within tumors at 24 hours post-pi, confirming the suggestion of lower metabolic stability.

[0237] Considering both in vitro and in vivo results, stable compounds [ 177 The LuAMTG exhibits exceptionally good overall performance. (Compared to [...]) 177 Compared to RM2, it exhibits good affinity for GRPR-expressing PC-3 cells, reasonable lipophilicity, the highest metabolic stability in human plasma, and the same or enhanced pharmacokinetic properties. Due to its enhanced in vitro metabolic stability in human plasma, AMTG may have the potential to compete with or even outperform the current gold standard among GRPR-targeting ligands (RM2, NeoBOMB1) for targeted radiotherapy of male GRPR-expressing malignancies.

[0238] Example 7: Containing [ 99m Tc]N4 ligands The compounds examined N4-asp 4 -Pip 5 -D-Phe 6 -Gln 7 -Trp 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH2(8) N4-asp 4 -Pip 5 -D-Phe 6 -Gln 7 -Bta 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH2(9) N4-Pip 5 -D-Phe 6 -Hse 7 -Trp 8-Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH2(10) N4-Pip 5 -D-Phe 6 -Gln 7 -α-Me-Trp 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH2(11) .

[0239] In vitro data Determined distribution coefficient of n-octanol / PBS (logD) 7.4 )as well as 9m The binding affinity (IC50) of Tc-labeled compounds to GRPR 50 The compounds are listed in Table 5. For all compounds, N4(6-(carboxyl))-1,4,4,11-tetraazaundecane is used as a chelating agent.

[0240] Table 5: Distribution coefficient (logD) 7.4 value) and [ 99m Tc]N4-asp-MJ9 (8), [ 99m Tc]N4-asp-[Bta 8 MJ9(9), [ 99m Tc]N4-[Hse 7 MJ9(10) and [ 99m Tc]N4-[α-Me-Trp 8 MJ9(11) binding affinity to GRPR (IC) 50 In PC-3 cells (1.5 × 10⁻⁶), 5 (cells / well) and [D-3-[ 125 I]I-Tyr 6 MJ9 (c = 0.2 nM) was used as a radiolabeling reference to determine binding affinity (2 hours, room temperature, HBSS + 1% BSA). MJ9: Pip 5 -D-Phe 6 -Gln 7 -α-Me-Trp8 -Ala 9 -Val 10 -Gly 11 -His 12 -Sta 13 -Leu 14 -NH2.

[0241] In this series, it was found that [ 99m Tc]N4-asp-MJ9 is the most hydrophilic, while the other three compounds show similar but more lipophilic values. All conjugates exhibit IC50 values ​​in a fairly low nanomolar range. 50 Values ​​(unlabeled). However, compared to the other two ligands in this series, homoserine and α-methyltryptophan derivatives exhibited slightly decreased GRPR affinity.

[0242] In vivo data In CB17-SCID mice, at pi 1 and 4 hours (200 pmol each) 99m The in vivo pharmacokinetics of Tc-labeled ligands (8), (9), (10), and (11) were investigated. 99m Tc]N4-asp-MJ9 (8), [ 99m Tc]N4-asp-[Bta 8 MJ9 and [ 99m Tc]N4-[Hse 7 MJ9 exhibited excellent pharmacokinetics at 1 hour post-pi, with high tumor accumulation and low overall background accumulation. Figure 13 ). 99m Tc]N4-asp-[Bta 8 MJ9 exhibited the lowest uptake in GRPR-positive pancreas, highlighting faster clearance from the organ due to a higher metabolic rate at its unstable location. 99m Tc]N4-[Hse 7 MJ9 showed the highest tumor uptake and the second lowest pancreatic uptake in the series. 99m Tc]N4-[α-Me-Trp 8 MJ9 showed the highest pancreatic accumulation, likely due to enhanced metabolic stability resulting from α-methyltryptophan modification, as described in previous sections. The tumor-to-background ratio at 1 hour post-contraction was primarily favorable for […]. 99m [Tc]N4-asp-MJ9, thus benefiting from enhanced hydrophilicity due to additional aspartic acid modification. Figure 14 However, assuming in [ 177 Lu]DOTA-asp-[Bta8 MJ9 and [ 177 Lu]DOTA-[Hse 7 In the case of MJ9, if the two compounds do indeed show similarities to [ 99m If the hydrophilicity is similar to that of Tc]N4-asp-MJ9, the tumor-to-background ratio will be improved.

[0243] Biodistribution studies at pi 4 hours highlight these... 99m The time course of Tc-labeled ligands in vivo ( Figure 15 ).and[ 99m Tc]N4-[α-Me-Trp 8 MJ9 showed enhanced tumor accumulation compared to 1 hour post-pi, while all other derivatives in the series showed reduced tumor values. This further reinforces the suggestion of increased metabolic stability due to α-methyltryptophan modification. 99m In the case of Tc[technetium], this is undesirable because, for diagnostic purposes, high tumor uptake at 1 hour pi (and not just 4 hours pi) and faster clearance from background organs are desirable. However, this modification is beneficial for therapeutic compounds, such as those mentioned above. 177 Lu-labeled ligands are very useful. The faster removal of these compounds from background organs is beneficial for diagnosis. 99m Tc]N4-asp-[Bta 8 MJ9 is ideally suited for use due to its enhanced metabolic instability, as highlighted by its uptake values ​​at pi 4 hours in most organs. Tumor to background ratios at pi 4 hours are shown in... Figure 16 The text shows the effects on most organs. 99m Tc]N4-asp-MJ9 and [ 99m Tc]N4-[Hse 7 ]MJ9 is the highest.

[0244] The excellent contrast at 1 hour pi, resulting from the destabilization modification of homoserine and 3-benzothiophene alanine, was further highlighted by µSPECT / CT imaging. Figure 17 ). and unmodified [ 99m Compared to Tc]N4-asp-MJ9, [ 99m Tc]N4-asp-[Bta 8 MJ9 and [ 99m Tc]N4-[Hse 7 MJ9 all showed slightly enhanced contrast, despite their increased lipophilicity. As expected, 99m Tc]N4-[α-Me-Trp 8MJ9 showed poor contrast compared to the other three derivatives because its increased metabolic stability led to slower pancreatic and intestinal clearance, which is detrimental to diagnosis.

[0245] Example 8: Toad peptide-SiFA derivative The compounds examined

[0246] MJ9: H2N-Leu-Sta-His-Gly-Val-Ala-Trp-Gln-d-Phe-Pip- In vitro data Determined distribution coefficient of n-octanol / PBS (logD) 7.4 ) and the binding affinity (IC50) of bufotoxin-SiFA compound to GRPR. 50 Listed in Table 6. For all compounds, DOTAGA was used as a chelating agent.

[0247] Table 6: Distribution Coefficient (logD) 7.4 (value) and 177 / nat The binding affinity (IC) of Lu-labeled GT50, GT51, GT52, and GT53 to GRPR 50 In PC-3 cells (1.5 × 10⁻⁶), 5 (cells / well) and [D-3-] 125 I]I-Tyr 6 MJ9 (c = 0.2 nM) was used as a reference for radiolabeling to determine binding affinity (2 hours, room temperature, HBSS + 1% BSA).

[0248] All four compounds in this series exhibit similar hydrophilicity. 177 Lu]GT50 and [ 177 Lu]GT52 IC 50 The value is within a considerable range, while [ 177 Lu]GT51 and [ 177 Lu]GT53 IC 50 The value increased slightly.

[0249] Biological distribution study All four compounds contain ingredients for... 18 The F-marked SiFA portion and used for 68 Ga mark or 177 Lu-labeled chelating agents. This is a useful feature because radioactive hybrid ligands provide ideal therapeutic diagnostic pairs, as they are chemically indistinguishable, regardless of whether [[ 18F][ nat Ga / nat Lu] ligand or [ 19 F][ 68 Ga / 177 [Lu] ligand. Evaluation in CB17-SCID mice. 177 Biodistribution of Lu-labeled ligands GT50, GT51, GT52, and GT53 at 24 hours post-pi (100 pmol per animal). Except for the liver and kidneys, all derivatives showed low overall background retention. Figure 18 ).and[ 177 Lu]RM2、[ 177 Lu]AMTG and [ 177 Compared to Lu]AMTG2, tumor preservation was reduced ( Figure 11 All bufotin-SiFA conjugates must be optimized, especially considering high renal retention and slightly enhanced liver retention. However, the ligands evaluated in this series demonstrate functionality based on the concept of radioactive hybrids.

Claims

1. Compounds of formula (I) S — Y — Xaa1 — Xaa2 — L-Ala — L-Val — Xaa5 — L-His — T (I) in S is the part capable of generating therapeutically active radiation. It is a metal ion chelating agent selected from: bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradecane-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutyryl]pentyl]-N-hydroxybutyramide (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]-glutaric acid (DOTAGA), N,N'-dipyridoxyethylenediamine-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-triacetic acid ester (H P-DOA3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6].2] Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7,10-tetraazacyclotetrazane-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}pimelic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 6-carboxy-1,4,8,11-tetraazaundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl}-1,4,8,11-tetraazaundecane (N4'), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), S-acetylmercaptoacetyltriserine (MAS3), mercaptoacetyltriglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazazolide (AAZTA), 3,6,9,15-tetraazabicyclo[9.3].1] Pentadec-1(15),11,13-trien-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentazatricyclic[15,3,2,1]eicos-1(21),17,19-trien-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanate benzyl)oxy-methyl]propene-1,3-dinitrostetraacetic acid (TAME-Hex), 4 -((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutyric acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazacycloheptane-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphonic acid] (TRAP) and its functional derivatives, such as NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphonic acid]-7-[methylene(2-carboxyethyl)phosphonic acid]) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra[methylene(2-carboxyethyl)phosphonic acid] (DOTPI), 6,6′-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene))pyridinedicarboxylic acid (H2bispa2), 1,4,7,10,13-pentazazepinepentadecane-N,N′,N′′,N′′′,N′′′′-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N′,N′′′,N′′′′,N′′′′′-hexaacetic acid (HEHA) 1,2-[{6-(carboxyl)-pyridin-2-yl}-methylamino]ethane (H2dedpa), N,N′-bis{6-carboxyl-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-tetra(carbamoylmethyl)-1,4,7,10-tetraazabicyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6].6] Eicosane (sar) and its functional derivatives, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazolidine-1-yl}-acetic acid (NETA), N,N′,N′′-tris(2-mercaptoethyl)-1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanate benzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N′-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N′-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (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]pentadecano-1(15),11,13-trien-3,6,9,-triacetic acid (PCTA), and N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane (H6phospa); Y is an optional connector; Xaa1 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln; or (ii) α-amino acids that increase the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in all other respects; Xaa2 is a Trp or an α-amino acid that increases the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to compounds in which Xaa1 is Gln and Xaa2 is Trp in other respects. The conditions are: Xaa1 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa2 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

2. The compound according to claim 1, wherein... Xaa1 is L-Gln, D-Gln, or L-His; Xaa2 is α-Me-Trp; Xaa5 is Gly, N-Me-Gly, D-Ala, or β-Ala; and T is Sta-Leu-NH2, Leu-ψ(CH2N)-Pro-NH2, Leu-NHEt or NH-CH[CH2-CH(CH3)2]2, Sta is (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid.

3. The compound according to claim 1 or 2, wherein Xaa1 is L-Gln.

4. The compound according to claim 1 or 2, wherein Xaa5 is Gly.

5. Compounds of formula (II) S — Y — Xaa3 — Xaa4 — L-Ala — L-Val — Xaa5 — L-His — T (II) in S is the portion capable of generating a detectable signal; it is a metal ion chelating agent selected from: bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradecane-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutyryl]pentyl]-N-hydroxybutyramide (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]-glutaric acid (DOTAGA), N,N'-dipyridoxyethylenediamine-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-triacetic acid ester (H P-DOA3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6].2] Hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneaminetetraacetic acid) (TMT), 1,4,7,10-tetraazacyclotetrazane-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}pimelic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 6-carboxy-1,4,8,11-tetraazaundecane (N4), 6-{p-[(carboxymethoxy)acetyl]-aminobenzyl}-1,4,8,11-tetraazaundecane (N4'), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), S-acetylmercaptoacetyltriserine (MAS3), mercaptoacetyltriglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazazolide (AAZTA), 3,6,9,15-tetraazabicyclo[9.3].1] Pentadec-1(15),11,13-trien-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentazatricyclic[15,3,2,1]eicos-1(21),17,19-trien-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanate benzyl)oxy-methyl]propene-1,3-dinitrostetraacetic acid (TAME-Hex), 4 -((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutyric acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazacycloheptane-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphonic acid] (TRAP) and its functional derivatives, such as NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphonic acid]-7-[methylene(2-carboxyethyl)phosphonic acid]) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra[methylene(2-carboxyethyl)phosphonic acid] (DOTPI), 6,6′-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene))pyridinedicarboxylic acid (H2bispa2), 1,4,7,10,13-pentazazepinepentadecane-N,N′,N′′,N′′′,N′′′′-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N′,N′′′,N′′′′,N′′′′′-hexaacetic acid (HEHA) 1,2-[{6-(carboxyl)-pyridin-2-yl}-methylamino]ethane (H2dedpa), N,N′-bis{6-carboxyl-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-tetra(carbamoylmethyl)-1,4,7,10-tetraazabicyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6].6] Eicosane (sar) and its functional derivatives, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazolidine-1-yl}-acetic acid (NETA), N,N′,N′′-tris(2-mercaptoethyl)-1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanate benzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N′-[1-benzyl-1,2,3-triazol-4-yl]methyl-N,N′-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (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]pentadecano-1(15),11,13-trien-3,6,9,-triacetic acid (PCTA), and N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane (H6phospa); Y is an optional connector; Xaa3 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln; or (ii) α-amino acids that reduce the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects; Xaa4 is a Trp or an α-amino acid that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma compared to compounds in which Xaa3 is Gln and Xaa4 is Trp in other respects. The α-amino acid at the Xaa4 position that reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is not a proteogenic amino acid. The conditions are: Xaa3 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and Xaa4 is not Trp at the same time; Xaa5 is Gly, N-Me-Gly, β-Ala, or 2-aminoisobutyric acid (Aib); preferably Gly; and T is an optional end base.

6. The compound according to claim 5, wherein... Xaa3 is L-Gln, D-Gln, or L-His; Xaa4 is Bta; Xaa5 is Gly, N-Me-Gly, or β-Ala; and T is Sta-Leu-NH2, Leu-ψ(CH2N)-Pro-NH2, Leu-NHEt or NH-CH[CH2-CH(CH3)2]2, Sta is (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid.

7. The compound according to claim 6, wherein Xaa3 is L-Gln.

8. The compound according to claim 6, wherein Xaa5 is Gly.

9. The compound according to any one of claims 1 to 8, wherein the metal ion chelating agent is selected from DOTA or DOTAGA.

10. The compound according to any one of claims 1 to 9, wherein Y (a) Contains one, two, three, four, five, or six positive and / or negative charges; (b) Contains one, two, three, four, five or six amino acids or is composed of one, two, three, four, five or six amino acids; (c) Contains PEG n Or by PEG n Composition, where n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and / or (d) Includes the part that can generate a detectable signal.

11. The compound according to claim 10, wherein the amino acid in (b) is a D-amino acid.

12. The compound according to claim 10, wherein the amino acid in (b) is a D-α-amino acid.

13. The compound according to any one of claims 11 to 12, wherein the connector Y comprises or is composed of the following: (i) D-Glu-urea-D-Glu; (ii) One or both of the 2,3-diaminopropionic acid moieties, which are optionally replaced by moieties capable of generating a detectable signal; (iii) One, two, three, four, five, or six consecutive amino acids, said amino acids comprising or composed of one or more amino acids selected from the following: 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-sulfoalanine (Ala(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA), and D-Phe; and / or (iv) p-aminomethylaniline-diethylene glycol (pABza-DIG, AMA-DGA) and / or diethylene glycol salts (DIG, DGA).

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof, or consisting of a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof.

15. A diagnostic composition comprising a compound according to any one of claims 1 to 13 and a diagnostically acceptable carrier, excipient and / or diluent or any combination thereof, or consisting of a compound according to any one of claims 1 to 13 and a diagnostically acceptable carrier, excipient and / or diluent or any combination thereof.

16. Use of the compound according to any one of claims 1 to 13 in the preparation of a medicament for treating cancer.

17. Use of the compound according to claim 16, wherein the cancer is selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head / neck squamous cell carcinoma, neuroblastoma / glioblastoma, colorectal cancer, and, in the case where the receptor is CCK-2R, medullary thyroid carcinoma (MTC).

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