Modified GRPR antagonist peptides for cancer imaging and therapy

Abstract

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

Description

[Technical Field]

[0001] (No relevant section found in the original text) [Background technology]

[0002] Prostate cancer (PCa), a malignant disease common in men in Europe and North America, remains a medical challenge because survival rates worsen as the disease progresses. It is known that earlier diagnosis leads to higher treatment success rates, highlighting the need for new treatment methods. In recent decades, there has been growing interest in nuclear medicine-based cancer diagnosis and treatment using radioactive tracers that rapidly accumulate almost exclusively in tumor sites.

[0003] Prostate-specific membrane antigen (PSMA) tracers exhibit excellent properties such as overexpression in prostate cancer, low expression in healthy tissue, rapid clearance rate, and high incidence (92% of all prostate cancers), and are frequently used in internal radiotherapy and PCa imaging. However, PSMA has the disadvantage of being easily taken up by the kidneys and salivary glands, as well as being expressed at a low level in the early stages of the disease.

[0004] As an interesting alternative, gastrin-releasing peptide receptor (GRPR) also shows good expression in PCa (up to 100% in early stages and 60% in late stages), is overexpressed in malignant tissue, and shows high expression in only one healthy tissue (pancreas). This is advantageous compared to PSMA in cases of renal metastasis, where PSMA tracers may not be adequately detected due to high uptake in the kidney. Furthermore, damage to the salivary glands and kidneys due to high accumulation of PSMA tracers is a concern in high-dose treatment.

[0005] GRPR is highly expressed in the early stages of prostate cancer (PCa), while PSMA overexpression is more frequently observed in the later stages of the disease. Furthermore, GRPR overexpression is also found in estrogen receptor (ER)-rich breast cancer, making it possible to use the same tracer for different cancers and sexes. Therefore, GRPR tracers are a useful tool for replacing PSMA in patients with low PSMA expression and for diagnosing metastases in the renal region. In addition, in the incidental treatment of prostate cancer (early stage), using GRPR tracers instead of PSMA tracers is beneficial due to their high expression rate and low side effects (salivary gland dysfunction). Moreover, since GRPR is overexpressed in prostate cancer and breast cancer, GRPR antagonists may be usable regardless of sex.

[0006] To date, both GRPR agonists and antagonists have been and continue to be used in clinical practice. Agonists cause painful side effects after administration to patients, and their pharmacokinetics are poor due to significantly slow flushing out of non-tumor tissue, leading to ongoing development of antagonists. The number of GRPR derivatives used clinically is significantly smaller than that of PSMA ligands. However, since only 92% of all PCa tumors express PSMA, and GRPR is overexpressed in approximately 85% of all estrogen receptor (ER)-rich breast cancers, there are considered to be clinical advantages to using GRPR.

[0007] The typical structure of an antagonistic GRPR molecule includes a binding unit based on the C-terminus of a subnanomolecularly affinity native bombesin or gastrin-releasing peptide (GRP). While a linker between the pharmacologically active site and the N-terminal chelator is not strictly necessary, as tracers that perform well without it exist, many reports indicate that using a linker unit can have beneficial effects on pharmacokinetics.

[0008] Among GRPR antagonists, the derivative RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is the most commonly used agent for selective GRPR imaging and therapy. This is for imaging with 68 Ga (88.9% β + 、E β+,max =1.89 MeV, t 1 / 2 =68 minutes) and for internal radiotherapy with 177 Lu (78.6% β - 、E β,max =0.498 MeV, t 1 / 2 =6.7 days) and is mainly labeled. Since it can be applied to PCa and ER-rich breast cancer, it is currently considered the gold standard of GRPR antagonists.

[0009] 68 Both Ga-RM2 and 177 Lu-RM2 show good pharmacokinetics of high accumulation in tumors, rapid clearance from non-tumor tissues, and long retention in tumors in humans, resulting in high contrast and good therapeutic effects respectively.

[0010] Nevertheless, some bombesin analogs are metabolically unstable in animals and have limitations in the required accumulation in tumor tissues.

[0011] On the other hand, it must be mentioned that more stable GRPR derivatives have slow washout from the pancreas rich in GRPR and may cause pancreatitis, so they need to be considered before use in human therapy.

[0012] In other malignant applications, more markers and targets are being focused on. Examples include neuromedin B receptor (bombesin 1 receptor, NMBR), bombesin receptor subtype 3 (BRS-3), and cholecystokinin 2 receptor (CCK-2R).

Summary of the Invention

Problems to be Solved by the Invention

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

[0014] This technical challenge is resolved by the issues disclosed below. [Means for solving the problem]

[0015] In a first aspect, the present invention relates to a compound that binds to an endogenous receptor, comprising: (i) an oligopeptide comprising a dipeptide in which Trp is the C-terminal amino acid of the dipeptide, wherein Trp is substituted with α-amino acid Xaa2, thereby increasing the stability in serum or plasma (preferably mammalian serum or plasma) of the peptide bond linking Xaa2 to the N-terminal adjacent amino acid compared to the peptide bond linking Trp to the N-terminal adjacent amino acid in the otherwise identical compound; and (ii) a portion that can generate therapeutically effective radiation, covalently bonded to the oligopeptide.

[0016] A receptor is a molecule capable of specifically binding to its homologous ligand. The term “homologous ligand” specifies the genus of the molecule and includes both natural ligands and the compounds of the present invention. The receptor is preferably a polypeptide or protein. It may comprise a plurality of subunits that are linked to each other non-covalently or covalently. Preferably, the receptor is a transmembrane protein or a membrane-bound protein. Preferably, the ligand-binding site is located extracellularly.

[0017] The term “endogenous” means the appearance of a receptor in human or animal bodies, animals including mammals, and mammals including rodents. Preferred receptors are the subject of preferred embodiments further disclosed below.

[0018] The compound of the first embodiment comprises or consists of two parts. The first part is a target part, which comprises or consists of the oligopeptide disclosed above. The second part is a part that transmits the intended therapeutic effect, which, in the case of the compound according to the first embodiment, is radiation. Thus, since the target tissue is generally an overgrowthed tissue such as malignant tissue, or contains such tissue, the treatment is understood to involve the destruction of the target tissue.

[0019] As will become clearer below, in other embodiments of the present invention, the second part is useful for diagnostic purposes.

[0020] In its broadest definition, the second part is not particularly limited except that it must have the ability to generate therapeutically effective radiation. In accordance with the present invention, this ability is transmitted by a radionuclide. Such a radionuclide may be present in the compound, or alternatively, the compound may comprise a part which can then carry the radionuclide.

[0021] The term "oligopeptide" has a technically established meaning. It is a linear sequence of amino acids linked to one another by main-chain peptide bonds. In terms of length, 5 to 20 amino acids are preferred. This includes oligopeptides having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids. Preferably, 6, 7, 8, 9, or 10 amino acids. Particularly preferred are 9 or 10 amino acids, and most preferred are 9 amino acids. The term "oligopeptide" implies peptidic properties, but the term also includes compounds that are not peptidic in an essentially exclusively dominant sense. Preferably, assuming the oligopeptide has N amino acids, at least (N-1) / 2 bonds linking the amino acids are peptide bonds. For example, N-1, N-2, or N-3 bonds linking the amino acids are peptide bonds.

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

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

[0024] Overall, naturally occurring, preferably protein-constituting α-amino acids, are preferred. That said, for the purpose of conferring specific technical effects, one or more positions, generally less than half of the oligonucleotide positions, may be amino acids or moieties that do not exist in nature. These are also referred to herein as modified amino acids or modified moieties. Such modifications may affect stereochemistry, such as, for example, using a D-amino acid instead of a naturally occurring L-counterpart, and / or modifications relating to structure and composition.

[0025] Unless an amino acid is located at the end of a molecule, it is understood that a given amino acid is linked to an adjacent site via a main-chain peptide bond, and as a result, in such cases, there are no free carboxylic acids and primary amines.

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

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

[0028] In accordance with the present invention, such tryptophan is modified. As will become clearer below, preferred modifications are those that maintain the indole ring. Furthermore, amino and carboxyl functional groups are retained. In this sense, the meaning of the term “derivative” is limited accordingly, and the derivative must be an aromatic amino acid, preferably having a two-membered ring, more preferably an indole ring. Furthermore, in accordance with the present invention, the tryptophan derivative is an α-amino acid.

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

[0030] In this specification, the terms "increased stability of peptide bonds in serum or plasma" and "decreased cleavage of peptide bonds in serum or plasma" are used interchangeably.

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

[0032] Assays for determining stability in serum or plasma are well established in the art and include in vitro and in vivo assays. Exemplary or preferred assays are some of the examples incorporated herein. A reference compound is used for the purpose of determining whether stability is increased. The reference compound for evaluating the compound of the first embodiment is selected such that the only difference between the compound under consideration and the reference compound is position Xaa2. In the reference compound, the said position is tryptophan.

[0033] An increase in stability is understood to mean a statistically significant increase in stability and / or an increase in stability of at least 1.1 times, at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 50 times, or at least 100 times. The preferred parameter for determining the increase mentioned is the serum / plasma half-life. The preferred parameter for determining the increase mentioned is the amount of unchanged radiolabeled compound after incubation in human / mouse serum or plasma for 72 ± 2 hours.

[0034] Alternatively, established therapeutic agents that bind to the same endogenous receptor (such as RM2 when GRPR is the receptor, see also below) may be used as reference compounds.

[0035] Compounds according to the first embodiment exhibit improved pharmacokinetic properties. A reference compound for comparison is defined above, and the only deviation from the compound according to the first embodiment under consideration is the presence of unmodified tryptophan in the reference compound at the position where the compound according to the first embodiment has a Trp derivative. Alternatively, enhancement is when compared to a technically established therapeutic agent targeting the respective native ligand and / or the same receptor. To the extent that a compound according to the first embodiment that is a GRPR ligand is considered, a preferred technically established compound is RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, where chelating agent abbreviations and non-protein constituent amino acids are further described below).

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

[0037] In a therapeutic context, high tumor uptake and / or tumor retention is understood to be desirable. Evidence to this effect is presented in the examples incorporated herein.

[0038] The technical means for achieving high tumor uptake and retention are as described above, and involve stabilizing the peptide bonds within the dipeptide units contained in the compound according to the first embodiment.

[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 a more preferred embodiment, the endogenous receptor is a peptide receptor overexpressed in cancer diseases, such as neuromedin B receptor (bombesin 1 receptor, NMBR), gastrin-releasing peptide receptor (bombesin 2 receptor, GRPR), bombesin receptor subtype 3 (BRS-3), or cholecystokinin 2 receptor (CCK-2R), and further preferably, (a) the binding is K 50 nM or less, 15 nM or less, 5 nM or less, or 1 nM or less. D (b) the compound is a GRPR antagonist, preferably IC 50 The minimum or maximum intensity is 50 nM or less, 15 nM or less, 5 nM or less, or 1 nM or less.

[0041] In a second aspect relating to the first aspect, the present invention relates to a compound of formula (I), SY-Xaa1-Xaa2-L-Ala-L-Val-Xaa5-L-His-T(I) During the ceremony, S is the part that can generate therapeutically active radiation. Y is any linker, Xaa1 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln, or (ii) an α-amino acid that increases the stability of the Xaa1-Xaa2 peptide bond in serum or plasma compared to the case where Xaa1 is Gln and Xaa2 is Trp, and is otherwise the same compound. Xaa2 is an α-amino acid that increases the stability of Trp or the Xaa1-Xaa2 peptide bond in serum or plasma compared to the case where Xaa1 is Gln and Xaa2 is Trp, which are otherwise identical compounds. However, at the same time, Xaa1 must not be one of L-Gln, D-Gln, L-His, D-His, or Gly, and Xaa2 must not be Trp. Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala, or 2-aminoisobutyric acid (Aib), preferably Gly. T is any terminal group. Provides compounds.

[0042] The compounds of the second embodiment are tailored to a specific endogenous receptor, GRPR. Therefore, they possess several characteristics inherited from the natural congener ligand, gastrin-releasing peptide (GRP).

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

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

[0045] Furthermore, any terminal group T may, but is not necessarily, be a means of extending the peptide moiety of the compound in the second embodiment.

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

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

[0048] This preferred embodiment relates to specific structural means for achieving increased stability of the main chain peptide bonds of the dipeptide moieties present in the compounds of the first and second embodiments (designated as Xaa1-Xaa2 in the case of the compounds of the second embodiment).

[0049] Of these structural criteria, those that are particularly preferred are specified in Part (a)(i) of this preferred embodiment.

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

[0051] Preferred embodiments of the first and second aspects are derivatives of the compounds in Table 1A and / or B. For further explanation of the term “derivative” of the compounds in Table 1A and B, Tables 1A and B are provided below.

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

[0053] A third aspect of the present invention is a compound of formula (II), SY-Xaa3-Xaa4-L-Ala-L-Val-Xaa5-L-His-T(II) During the ceremony, S is the part that can generate a detectable signal. Y is any linker, Xaa3 is (i) L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln, or (ii) an α-amino acid whose stability in serum or plasma of the Xaa3-Xaa4 peptide bond is reduced compared to the case where Xaa3 is Gln and Xaa4 is Trp, and the compound is otherwise identical. Xaa4 is an α-amino acid whose stability in serum or plasma of Trp or the Xaa3-Xaa4 peptide bond is reduced compared to the case where Xaa3 is Gln and Xaa4 is Trp, which are otherwise identical compounds. The α-amino acid at position Xaa4, which reduces the stability of the Xaa3-Xaa4 peptide bond in serum or plasma, is not a protein constituent amino acid. However, at the same time, Xaa3 must not be one of L-Gln, D-Gln, L-His, D-His, or Gly, and Xaa4 must not be Trp. Xaa5 is Gly, N-Me-Gly, β-Ala, or 2-aminoisobutyric acid (Aib), preferably Gly. T is any terminal group. Regarding compounds.

[0054] The compound of formula (II) exhibits structural similarity to the compound of formula (I) according to the second embodiment, but is distinguished by the fact that the peptide bond of the dipeptide portion contained in the oligopeptide is less stable in serum or plasma.

[0055] This offers different but related technical effects. As is well established in this field, radiolabeled compounds are useful not only for therapeutic purposes but also for diagnostic purposes. In the diagnostic setting, faster degradation is desirable. This is because metabolic activity in tumors is generally lower than in surrounding normal tissue, and consequently, faster degradation is accompanied by a higher tumor / background ratio, and such a high tumor / background ratio allows for higher sensitivity, more detailed and / or more accurate detection of tumors and metastases.

[0056] It is understood that the two positions Xaa3 and Xaa4 correspond to positions Xaa1 and Xaa2 of the compound in the second embodiment, and are simply distinguished and shown for alignment and clarity. In specific structural implementations, Xaa1 and Xaa2 are generally distinguished on the one hand, and Xaa3 and Xaa4 on the other. This will become more apparent in the context of preferred embodiments of the third embodiment, which will be further disclosed below.

[0057] For the purpose of determining the decrease in stability, the above-described provisions apply mutatis mutandis to the compounds of the first and second embodiments. Therefore, in vitro and in vivo serum or plasma assays may be used. A preferred read is the serum / plasma half-life. A more preferred read is the amount of unchanged radiolabeled compound after incubation in human / mouse plasma for 72 ± 2 hours. Reference compounds for the purpose of determining the decreased stability include compounds that differ from the compound of formula (II) only in that positions Xaa3 and Xaa4 are Gln and Trp, respectively, as described above.

[0058] As is established in the art, three-letter codes are commonly used to specify amino acids. When the first letter is capitalized, the L-type is intended; when the first letter is lowercase, the D-type is intended. For example, Trp refers to L-tryptophan, and trp refers to D-tryptophan. Furthermore, explicit stereochemical designations are used herein (e.g., L-Trp, D-Trp).

[0059] The alternative reference compounds are the respective native ligands, which are GRP if the receptor is GRPR, or RM2 (which is an antagonist).

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

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

[0062] In preferred embodiments of the compound of the third embodiment, S is selected from a fluorescent moiety, a radioactive moiety, and a moiety capable of supporting a radionuclide.

[0063] The two preferred embodiments described above relate to preferred embodiments of Part S, depending on whether therapeutic or diagnostic compounds are being considered.

[0064] To the extent that a portion capable of supporting radionuclides is used, the portion is preferably a metal ion chelating agent, and preferably bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazabicyclotetradeca-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy) [C)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetraazabicyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazabicyclododecane-1,4,7,10-tetraacetic acid or 2-[1,4,7,10-tetraazabicyclododecane-4,7,10-triacetic acid]-pentane Dio acid (DOTAGA), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphat) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7, 10-Tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-Hydradinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-Triazacyclononane-1-succinate-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] Hexadecane (TE2A), 1,4,8,11-Tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), Terpyridine-bis(methyleneaminetetraacetic acid (TMT), 1,4,7,10-Tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), Triethylenetetraaminehexaacetic acid (TTHA), N,N'-Bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6(H2macropa), 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-ylmethyl)-carbamoyl]-ethyl}heptanediate bis-[(3-hydroxy-1,6-dimethyl-4 -Oxo-1,4-dihydropyridine-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-acetylmercaptoacetyl tricerine (MAS3), mercaptoacetyl triglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA), 3,6,9,15-tetraazabicyclo[9.3.1]Pentadeca-1(15),11,13-triene-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentazatricyclo[15,3,2,1]trieicosa-1(21),17,19-triene-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanatobenzyl)oxymethyl]pro Pyrene-1,3-dinitrilotetraacetic 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- Xobutanoic acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazepan-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP) and its functional derivatives, such as NOPO(1,4,7-triazacyclononane-1,4-bis[methylene(H) [Droxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid](DOTPI), 6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1] Nonane-3,7-diyl}bis(methylene))dipicolinic acid (H2bispa2), 1,4,7,10,13-pentazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA), 1,2-[{6-(carboxy)-pyridine-2-yl}methylamino]ethane (H2dedp a) N,N'-bis{6-carboxy-2-pyridylmethyl}ethylenediamine-N,N'-diacetic acid (H4octapa), 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazabicyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6. 6.6] Eicosane (sar) and its functional derivatives, {4-[2-(biscarboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid (NETA), N,N',N'', Tris(2-mercaptoethyl)1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanatobenzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N'-[1-benzyl -1,2,3-triazole-4-yl]methyl-N,N'-[6-(carboxy)pyridine-2-yl]-1,2-diaminoethane (H2azapa), N,N'-[[6-(carboxy)pyridine-2-yl]methyl]diethylenetriamine-N,N',N''-triacetic acid (H5decapa), N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo[9.3.1] Selected from pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) and N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridine-2-yl]methyl-1,2-diaminoethane (H6phospa), more preferably DOTA or DOTAGA, wherein a radioactive cation is bound to the chelating agent, and the radioactive cation is preferably... 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 86 Y, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 140 La, 142 La, 142 Pr, 143 Pr, 147 Nd, 149 Gd, 149 PM, 151 PM, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 156 EU, 157 Gd, 161 Tb, 164 Tb, 161 Ho, 166 Ho, 157 Dy, 166Dy, 165 Dy, 160 Er, 165 Er, 169 Er, 171 Er, 166 Yb, 169 Yb, 175 Yb, 167 Tm, 172 Tm, 177 Lu, 186 Re, 188 Re, 188 W, 191 Pt, 195m Pt, 194 Ir, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th, or 18 F-[AlF] 2+ such as 18 selected from cationic molecules containing F.

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

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

[0067] A suitable portion capable of generating a detectable signal according to item (d) of the preferred embodiment above may be a fluorescent portion or a portion that contains or can support a radionuclide. An example of the latter is a silicon fluoride acceptor portion (SiFA), which is, 18 It can be used for fluorine labeling. As long as the compound of the present invention containing such a SiFA moiety further contains a chelating agent (such as DOTA or DOTAGA), such a compound contains two radionuclides and can therefore be used for both diagnostic and therapeutic purposes.

[0068] In a preferred embodiment, the SiFA portion has a structure represented by formula (VI). [ka] During the ceremony, t-Bu represents a tert-butyl group, The dashed lines indicate the bonds connecting that site to the rest of the compound.

[0069] The preferred attachment site for the SiFA portion within linker Y is the side chain of 2,3-diaminopropionic acid, wherein the side chain consists of -CH2-NH2, and the terminal amino group of the side chain preferably forms an amide bond with the carboxyl group bonded to the free valence of the SiFA portion in formula (VI).

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

[0071] In a more preferred embodiment, the linker Y is (a) D-Glu-urea-D-Glu, (b) optionally one or two 2,3-diaminopropionic acid moieties substituted with moieties capable of generating a detectable signal, (c) D- / L-aspartic acid, D- / L-ornithine, 4-amino-1-carboxymethyl-piperidine (Pip), D- / L-2,3-diaminopropionic acid, D- / L-serine, D- / L-citrulline moieties, L- A sequence of 1, 2, 3, 4, 5, or 6 amino acids comprising or consisting of one or more amino acids selected from cysteic acid (Ala(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA), and D-Phe, and / or (d)p-aminomethylaniline-diglycolic acid (abbreviated as pABza-DIG or AMA-DGA), and / or diglycolate (abbreviated as DIG or DGA).

[0072] What is particularly preferable is that Y is Pip-phe.

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

[0074] In more preferred embodiments of the compounds of the second and third embodiments, namely both therapeutic and diagnostic agents, the terminal group T is present and comprises or consists of (a) statin (Sta or (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), 2,6-dimethylheptane, Leu or β-thienyl-L-alanine (Thi), and / or (b) Leu, norleucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methylbutane, where the amidoamine group of Leu may be modified with ethyl (NH-ethyl) or NH2 (NH-NH2), and / or (c) (S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)Pro-NH2), provided that if T is an amino acid or ends in an amino acid, the carboxylic acid of the amino acid is amidated.

[0075] Of particular preference is that T is Sta-Leu-NH2.

[0076] With regard to the preferred selection of parts Y and T, there is generally no distinction between the therapeutic and diagnostic compounds of the present invention.

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

[0078] Table 1A below shows the sequences of known GRPR conjugates. The hexapeptide sequences, which begin at Xaa1 and end at L-His for compounds of formula (I) and begin at Xaa3 and end at L-His for compounds of formula (II), correspond to positions 7 through 12 in the table below. As is recognizable, the GRPR conjugates shown throughout this table have tryptophan at position 8 (corresponding to the positions of Xaa2 and Xaa4, respectively). Position 7 (corresponding to Xaa1 and Xaa3, respectively) is highly conserved. As is evident from the table below, in the art, the peptide bond linking positions 7 and 8 (numbered in the table) is not recognized as a target site for fine-tuning pharmacokinetic properties.

[0079] Tables 1B and 1C show the ligand sequences that act on modified GRPRs, as well as the effects of introducing either the α-Me-Trp or Bta moiety at position 8 or the Hse moiety at position 7 into different GRPR target compounds. Similar to Table 1A, the hexapeptide sequences that begin with Xaa1 and end with L-His in the case of compounds of formula (I), and that begin with Xaa3 and end with L-His in the case of compounds of formula (II), correspond to positions 7 through 12.

[0080] The problems arising from the metabolic degradation of GRPR-targeted linear peptides are suggested to be due to neutral endopeptidases (NEP, EC3.4.24.11) known to cleave linear peptides at the N-terminus of hydrophobic amino acids (e.g., tryptophan). Therefore, these peptides are dipeptidic Gln peptides present in almost all compounds that act on GRPR. 7 -Trp 8 It is presumed that the motif is cleaved (Table 1A). To demonstrate that introducing α-Me-Trp or Hse at the above position increases metabolic stability in human serum or plasma, different GRPR target ligands were synthesized and the above modifications were introduced. For almost all evaluated GRPR target peptides shown in Table 1B, Trp 8 α-Me-Trp 8 Replace with Gln 7 Hse 7 When replaced with each Gln7 -Trp 8 Metabolic stability was increased compared to derivatives containing (Table 1C). In many of these derivatives, the addition of α-Me-Trp did not dramatically decrease the affinity of GRPR. However, Gln 7 Hse 7 Substitution with Hse resulted in a significant decrease in GRPR's affinity for most ligands. However, a stabilizing effect from the Hse moiety was also observed.

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

[0082] Therefore, regarding GRPR target ligands, Gln 7 -Trp 8 It can be concluded that the placement of amino acids at the N-terminus and C-terminus of a dipeptide is not important. Generally, Bta 8 Introducing α-Me-Trp reduces metabolic stability, but 8 or Hse 7 Introducing these modifications (α-Me-Trp) increases metabolic stability in human serum or plasma. Therefore, these modifications (α-Me-Trp) 8 Bta 8 Hse 7 This enables a wide range of applications for GRPR target compounds in general.

[0083] [Table 1-1]

[0084] [Table 1-2]

[0085] [Table 2-1]

[0086] [Table 2-2]

[0087] [Table 3]

[0088] Preferred compounds of the present invention include derivatives of the compounds shown in Tables 1A and 1B. These derivatives are preferably different from the compounds in Tables 1A and 1B except that the 7th and / or 8th positions (numbered in the table) are modified according to the present invention.

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

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

[0091] The application of particularly preferred modifications of Xaa1 to Xaa4 applies mutatis mutandis to any of the modifications at these four positions disclosed herein, even in relation to the compounds of the first, second, or third embodiment.

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

[0093] In a fifth aspect—which is also a preferred aspect of the third aspect—the present invention provides compounds of formula (IV) or (V). [ka]

[0094] In a sixth aspect, the present invention provides a compound according to any one of the above claims for use in pharmaceuticals.

[0095] In a seventh aspect, the present invention provides a pharmaceutical composition comprising or consisting of a compound according to the first, second, or fourth aspect.

[0096] In the eighth aspect, the present invention provides a diagnostic composition comprising or consisting of a compound of the third or fifth aspect.

[0097] Although less preferred, the present invention also provides, in a further embodiment, a diagnostic composition comprising or comprising a compound of the first, second, or fourth embodiment. Furthermore, although less preferred, a further embodiment relates to a pharmaceutical composition comprising or comprising a compound of the third or fifth embodiment.

[0098] In the pharmaceutical and diagnostic compositions of the present invention, the compound may be the sole active agent. Furthermore, in the pharmaceutical composition of the present invention, it is possible to use two or more compounds of the first, second, or fourth embodiment, and in the diagnostic composition of the present invention, it is possible to use two or more compounds of the third or fifth embodiment.

[0099] Furthermore, although less desirable, pharmaceutical and diagnostic compositions of the present invention may also be envisioned that contain, in addition to one or more compounds of the present invention, further pharmaceutically active agents or diagnostic active agents.

[0100] Pharmaceutical or diagnostic compositions may further 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, water, emulsions such as oil / water emulsions, various types of wetting agents, and sterile solutions. Compositions containing such carriers can be formulated by well-known conventional methods. These pharmaceutical and diagnostic compositions can be administered to a subject in an appropriate dose. Administration of a suitable composition can be carried out by different methods, e.g., intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal, or intrabronchial administration, with intravenous administration being preferred. In particular, it is preferred that the administration be carried out by injection. The composition may also be administered directly to the target site, e.g., by microparticle gun delivery to an external or internal target site. The administration regimen is determined by the attending physician and clinical factors. As is well known in medical technology, the dosage for any one patient depends on many factors, including the patient's size, body surface area, age, the specific compound being administered, sex, time and route of administration, overall health condition, and other drugs being administered concurrently.

[0101] The present invention's radioactive labeling (for example, 177 The preferred dosage of the compound (in Lu) is 1-100 GBq, 2-60 GBq, 2-50 GBq, 2-10 GBq, or 3-6 GBq.

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

[0103] Accordingly, in the ninth aspect, the present invention provides a pharmaceutical composition of the seventh aspect or any one compound of the first, second, or fourth aspect for use in a method of treating cancer, wherein the cancer is (a) characterized by overexpression of the receptor and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head and neck squamous cell carcinoma, neuroblastoma, colorectal cancer and, in the case of the receptor being in the range of CCK-2R, medullary thyroid carcinoma (MTC).

[0104] Similarly, in a tenth aspect of the present invention, the present invention provides a diagnostic composition of the eighth aspect or a compound of the third or fifth aspect for use in a method of diagnosing cancer, wherein the cancer is (a) characterized by overexpression of the receptor and / or (b) selected from prostate cancer, breast cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head and neck squamous cell carcinoma, neuroblastoma, colorectal cancer and, in the case of the receptor being in the range of CCK-2R, medullary thyroid carcinoma (MTC).

[0105] In an eleventh aspect, the present invention provides an in vitro method for diagnosing cancer, wherein the cancer is (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 and neck squamous cell carcinoma, neuroblastoma, colorectal cancer, and medullary thyroid carcinoma (MTC) in which case the receptor is in the range of CCK-2R, and the method comprises contacting a sample obtained from the subject with a diagnostic composition of the eighth aspect or a compound of the third or fifth aspect.

[0106] With respect to embodiments characterized in this specification, and in particular in the claims, each embodiment described in a dependent claim is intended to be combined with each embodiment of the respective claim (independent or dependent) on which the dependent claim depends. For example, in the case of independent claim 1 describing three options A, B, and C, dependent claim 2 describing three options D, E, and F, and claim 3 describing three options G, H, and I depending on claims 1 and 2, this specification will be understood to expressly disclose embodiments corresponding to combinations A, D, G; A, D, H; A, D, I; A, E, G; A, E, H; A, E, I; A, F, G; A, F, H; A, F, I; B, D, G; B, D, H; B, D, I; B, E, G; B, E, H; B, E, I; B, F, G; B, F, H; B, F, I; C, D, G; C, D, H; C, D, I; C, E, G; C, E, H; C, E, I; C, F, G; C, F, H; C, F, I.

[0107] Similarly, if an independent claim and / or dependent claim does not describe an alternative, but the dependent claim references multiple prior claims, it is understood that any combination of subject matter covered by it is deemed to be explicitly disclosed. For example, in the case of independent claim 1, dependent claim 2 referencing claim 1, and dependent claim 3 referencing both claims 2 and 1, the subject matter combination of claim 3 and 1 is as clearly and explicitly disclosed as the subject matter combination of claim 3, 2, and 1. If there is a further dependent claim 4 referencing any one of claims 1 through 3, the subject matter combinations of claim 4 and 1, claim 4, 2, and 1, claim 4, 3, and 1, and claim 4, 3, 2, and 1 are also clearly and explicitly disclosed.

[0108] The present invention includes the following items. 1. A compound that binds to an endogenous receptor, (i) an oligopeptide comprising a dipeptide in which Trp is the C-terminal amino acid of the dipeptide, wherein Trp is substituted with α-amino acid Xaa2, thereby increasing the stability in serum or plasma of the peptide bond linking Xaa2 to the N-terminal adjacent amino acid compared to the peptide bond linking Trp to the N-terminal adjacent amino acid in the otherwise identical compound, and (ii) A portion capable of generating therapeutically effective radiation, which is covalently bonded to the oligopeptide, The compound comprising the above. 2. The compound according to item 1, wherein the N-terminal adjacent amino acid in the dipeptide is L-Gln, D-Gln, L-His, D-His, or Gly, preferably L-Gln. 3. The endogenous receptor is a peptide receptor that is overexpressed in cancer diseases, such as neuromedin B receptor (bombesin 1 receptor, NMBR), gastrin-releasing peptide receptor (bombesin 2 receptor, GRPR), bombesin receptor subtype 3 (BRS-3), or cholecystokinin 2 receptor (CCK-2R), and more preferably, (a) The bond is K with a mass of 15 nM or less D It has, and / or (b) The compound is a GRPR antagonist, preferably IC 50 It is 15 nM or less. Compounds listed in item 1 or 2. 4. A compound of formula (I), SY-Xaa1-Xaa2-L-Ala-L-Val-Xaa5-L-His-T(I) During the ceremony, S is the part that can generate therapeutically active radiation. Y is any linker, Xaa1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) an α-amino acid in which the stability of the Xaa1-Xaa2 peptide bond in serum or plasma is increased compared to the same compound in other respects where Xaa1 is Gln and Xaa2 is Trp, Xaa2 is Trp or an α-amino acid in which the stability of the Xaa1-Xaa2 peptide bond in serum or plasma is increased compared to the same compound in other respects where Xaa1 is Gln and Xaa2 is Trp, provided that at the same time, respectively, Xaa1 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, and Xaa2 is not Trp, Xaa5 is Gly, N-Me-Gly, D-Ala, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an arbitrary terminal group, Compound. 5. Xaa2 is (a) (i) an optionally substituted alkyl moiety having 1 to 4 carbon atoms bonded to the α-carbon, wherein the substituent is selected from halogen and hydroxyl, and / or (ii) a substituent bonded to the indole ring, wherein the substituent is selected from N-(2,2,2-trifluoromethyl), N-methyl, N-acetyl, 5-fluoro, 5-bromo, 5-iodo, 5-chloro, 5-hydroxy, 5-methoxy, 5-methyl, 6-chloro, 7-chloro and 7-aza, Trp modified to include (b) 1,2,3,4-tetrahydronorharman-3-carboxylic acid (L-Tpi) The compound according to any one of items 1 to 4. 6. The optionally substituted alkyl moiety is selected from -CH3, -CH2CH3, and CH n Hal 3-n (where n is 0, 1 or 2, and Hal is F, Cl, Br and / or I), for example selected from -CF3, preferably -CH3, the compound according to item 5. 7. The compound according to any one of items 1 to 6, wherein Xaa2 is α-Me-Trp. 8. A compound of formula (II), S-Y-Xaa3-Xaa4-L-Ala-L-Val-Xaa5-L-His-T(II) wherein, S is a moiety capable of generating a detectable signal, Y is an optional linker, Xaa3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (ii) an α-amino acid in which the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is decreased compared to the case of the same compound in other respects where Xaa3 is Gln and Xaa4 is Trp, Xaa4 is Trp or an α-amino acid in which the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is increased compared to the case of the same compound in other respects where Xaa3 is Gln and Xaa4 is Trp, The α-amino acid at position Xaa4 that decreases the stability of the Xaa3-Xaa4 peptide bond in serum or plasma is not a proteinogenic amino acid, provided that at the same time, respectively, Xaa3 is not any one of L-Gln, D-Gln, L-His, D-His and Gly, and Xaa4 is not Trp, Xaa5 is Gly, N-Me-Gly, β-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, T is an optional terminal group, Compound. 9. The compound according to item 8, wherein Xaa3 is Hse and / or Xaa4 is Bta. 10. The compound according to any one of items 4 to 7, wherein S is selected from a radioactive moiety and a moiety capable of carrying a radionuclide. 11. The compound according to item 8 or 9, wherein S is selected from a fluorescent moiety, a radioactive moiety and a moiety capable of carrying a radionuclide. 12. The portion capable of supporting radionuclides is a metal ion chelating agent, preferably bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazabicyclotetradeca-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutano Il-amino-pentyl-N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetraazabicyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazabicyclododecane-1,4,7,10-tetraacetic acid or 2-[1,4,7,10-tetraazabicyclododecane-4,7,10-triacetic acid]-pentanediol (DOTAGA ), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphat) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-teto Laazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinate-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] Hexadecane (TE2A), 1,4,8,11-Tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), Terpyridine-bis(methyleneaminetetraacetic acid (TMT), 1,4,7,10-Tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), Triethylenetetraaminehexaacetic acid (TTHA), N,N'-Bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6(H2macropa), 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-ylmethyl)-carbamoyl]-ethyl}heptanediate bis-[(3-hydroxy-1,6-dimethyl-4 -Oxo-1,4-dihydropyridine-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-acetylmercaptoacetyl tricerine (MAS3), mercaptoacetyl triglycine (MAG3), 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA), 3,6,9,15-tetraazabicyclo[9.3.1]Pentadeca-1(15),11,13-triene-2,10-dione (TBPD), 9-oxa-3,6,12,15,21-pentazatricyclo[15,3,2,1]trieicosa-1(21),17,19-triene-2,7,11,16-tetradione (OPTT), 2-[bis(carboxymethyl)aminomethyl]-2-[(4-isothiocyanatobenzyl)oxymethyl]pro Pyrene-1,3-dinitrilotetraacetic 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- Xobutanoic acid (Me-3,2-HOPO), 2,20-(6-((carboxymethyl)amino)-1,4-diazepan-1,4-diyl)diacetic acid) (DATA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP) and its functional derivatives, such as NOPO(1,4,7-triazacyclononane-1,4-bis[methylene(H) [Droxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid](DOTPI), 6,6'-({9-hydroxy-1,5-bis(methoxycarbonyl)-2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1] Nonane-3,7-diyl}bis(methylene))dipicolinic acid (H2bispa2), 1,4,7,10,13-pentazacyclopentadecane-N,N',N'',N''',N''''-pentaacetic acid (PEPA), 1,4,7,10,13,16-hexazacyclohexadecane-N,N',N'',N''',N'''',N'''''-hexaacetic acid (HEHA), 1,2-[{6-(carboxy)-pyridin-2-yl}methylamino]ethane (H2dedpa), N,N'-bis{6-carboxy-2-pyridylmethyl}ethylenediamine Min-N,N'-diacetic acid (H4octapa), 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazabicyclododecane (TCMC), 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (sar) and its functional derivatives, {4-[2-(biscarboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]tri Zonan-1-yl}-acetic acid (NETA), N,N',N'', Tris(2-mercaptoethyl)1,4,7-triazacyclononane (TACN-TM), 2-(p-isothiocyanatobenzyl)-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A''-DTPA), N,N'-[1-benzyl-1,2,3-triazole-4-yl]methyl-N,N'-[6-(carboxy)pyridine-2-yl]-1,2-diaminoethane (H2azapa), N,N'-[[6-(carboxy)pyridine-2-yl]methyl]diethylenetriamine Selected from -N,N',N''-triacetic acid (H5decapa), N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA), and N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridine-2-yl]methyl-1,2-diaminoethane (H6phospa), more preferably DOTA or DOTAGA. Preferably, the radioactive cation is bound to the chelating agent, The radioactive cation is preferably, 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 86 Y, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 140 La, 142 La, 142 Pr, 143 Pr, 147 Nd, 149 Gd, 149 PM, 151 PM, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 156 EU, 157 Gd, 161 Tb, 164 Tb, 161 Ho, 166 Ho, 157 Dy, 166 Dy, 165 Dy, 160 Er, 165 Er, 169 Er, 171 Er, 166 Yb, 169 Yb, 175 Yb,167 Tm, 172 Tm, 177 Lu, 186 Re, 188 Re, 188 W, 191 Pt, 195m Pt, 194 Ir, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th, or 18 F-[AlF] 2+ like 18 Selected from cationic molecules containing F. 13.Y exists, (a) comprising 1, 2, 3, 4, 5 or 6 positive and / or negative charges, (b) comprising or consisting of 1, 2, 3, 4, 5 or 6 amino acids, preferably D-amino acids among the said amino acids, more preferably D-α amino acids, (c)PEG n (wherein the expression n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) contains, consists of, and / or (d) A portion that can generate a detectable signal, A compound listed in any one of items 4 through 12. 14. The linker Y is (a) D-Glu-urea-D-Glu, (b) Optionally, one or two 2,3-diaminopropionic acid moieties that are replaced with moieties capable of generating a detectable signal, (c) One or more amino acids selected from D- / L-aspartic acid, D- / L-ornithine, 4-amino-1-carboxymethyl-piperidine (Pip), D- / L-2,3-diaminopropionic acid, D- / L-serine, D- / L-citrulline moiety, L-cysteic acid (Ala(SO3H)), aminovaleric acid (Ava), 4-aminobenzoic acid (PABA), and D-Phe, or a sequence of 1, 2, 3, 4, 5, or 6 amino acids, and / or (d) p-aminomethylaniline-diglycolic acid (pABza-DIG, AMA-DGA), and / or diglycolate (DIG, DGA), A compound described in item 13, which contains or consists of the following. 15. T exists, (a) Statins (Sta or (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), 2,6-dimethylheptane, Leu or β-thienyl-L-alanine (Thi), (b) Leu, norleucine (Nle), Pro, Met, or 1-amino-1-isobutyl-3-methylbutane, where the amidoamine group of Leu may be modified with ethyl (NH-ethyl) or NH2 (NH-NH2), and / or (c)(S)-1-((S)-2-amino-4-methylpentyl)pyrrolidine-2-carboxamide (Leu-ψ(CH2N)Pro-NH2), including or consisting of However, if T is an amino acid or ends in an amino acid, the carboxylic acid of the amino acid is amidated. A compound listed in any one of items 4 through 14. 16. The serum or plasma is human serum or plasma, and is one of the compounds described in any one of items 1 to 15. 17. Compounds of formula (IIIa) or (IIIb). [ka] 18. Compounds of formula (IV) or (V). [ka] 19. A compound specified in any one of items 1 through 18, for use in pharmaceuticals. 20. To the extent that items 10 to 16 refer back to any one of items 1 to 7, a pharmaceutical composition comprising or comprising any compound described in any one of items 1 to 7 or 10 to 17. 21. A diagnostic composition comprising or comprising any compound described in any one of items 8, 9, 10 to 16, or 18, to the extent that items 10 to 16 refer back to item 8 or 9. 22. A pharmaceutical composition of item 20 or, to the extent that items 10 to 16 refer back to any one of items 1 to 7, a compound of any one of items 1 to 7 or 10 to 17, for use in a method of treating 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 and neck squamous cell carcinoma, neuroblastoma, colorectal cancer, and, if the receptor is in the CCK-2R range, medullary thyroid carcinoma (MTC). 23. A diagnostic composition of item 21 for use in a method for diagnosing cancer, or a compound of any one of items 8, 9, 10 to 16 or 18, to the extent that items 10 to 16 refer back to item 8 or 9, wherein the cancer is (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 and neck squamous cell carcinoma, neuroblastoma, colorectal cancer, and, if the receptor is in the CCK-2R range, medullary thyroid carcinoma (MTC). 24. An in vitro method for diagnosing cancer, wherein the cancer is (a) characterized by overexpression of the receptor, and / or (b) Prostate cancer, breast cancer, neuroendocrine tumor, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, head and neck squamous cell carcinoma, neuro / glioblastoma, colorectal cancer, and, within the range where the receptor is CCK-2R, medullary thyroid cancer (MTC), The method comprises contacting a compound according to any one of items 8, 9, 10 to 16 or 18 with a sample obtained from a subject, in the range where the diagnostic composition of item 20 or items 10 to 16 refer back to item 8 or 9.

Brief Description of Drawings

[0109] [Figure 1] It is a diagram of the analysis results of [177Lu]RM2 (tR = 15.3 minutes, 20% to 35% in 20 minutes) after incubation in human plasma at 37°C for 72 ± 2 hours. The chromatogram shows two important metabolites (tR = 2.9 minutes, 54% and tR = 8.5 minutes, 9%) and the remaining unchanged tracer (tR = 15.3 minutes, 36%). [Figure 2] It is a diagram of the analysis results of [177Lu]DOTA-[Hse7]MJ9 (tR = 16.1 minutes, 20% to 35% in 20 minutes) after incubation in human plasma at 37°C for 72 ± 2 hours. The chromatogram shows two important metabolites (tR = 3.4 minutes, 30% and tR = 8.6 minutes, 8%) and the remaining unchanged tracer (tR = 15.3 minutes, 56%). [Figure 3] It is a diagram of the analysis results of [177Lu]DOTA-[Bta8]MJ9 (tR = 17.9 minutes, 20% to 35% in 20 minutes) after incubation in human plasma at 37°C for 72 ± 2 hours. The chromatogram shows two metabolites (tR = 3.1 minutes, 79% and tR = 12.3 minutes, 8%) and the remaining unchanged tracer (tR = 17.9 minutes, 12%). [Figure 4]This figure shows the analysis results of [177Lu]AMTG (tR=17.0 min, 20-35% in 20 minutes) in human plasma after incubation at 37°C for 72 ± 2 hours. The chromatogram shows two metabolites (tR=1.7 min, 2% and tR=8.0 min, 5%) and the remaining unchanged tracer (tR=17.0 min, 92%). [Figure 5] This figure shows the analysis results of [177Lu]RM2 (tR=15.5 min, 20→35% in 20 minutes) in mouse plasma after incubation at 37°C for 6 ± 0.5 hours. The chromatogram shows three metabolites (tR=3.1 min, 2%, tR=8.2 min, 2%, and tR=17.3 min, 4%) and the remaining unchanged tracer (tR=17.0 min, 92%). [Figure 6] This figure shows the analysis results of [177Lu]AMTG (tR=17.0 min, 20-35% in 20 minutes) in mouse plasma after incubation at 37°C for 6 ± 0.5 hours. The chromatogram shows three metabolites (tR=2.6 min, 2%, tR=13.7 min, 2%, and tR=18.8 min, 5%) and the remaining unchanged tracer (tR=17.0 min, 89%). [Figure 7] This figure shows the analysis results of [177Lu]RM2 (tR=15.5 min, 20-35% change in 20 minutes) in mouse plasma after incubation at 37°C for 72 ± 2 hours. The chromatogram shows several small amounts of metabolites and the remaining unchanged tracer (tR=15.5 min, 67%). [Figure 8] This figure shows the analysis results of [177Lu]AMTG (tR=17.0 min, 20-35% change in 20 minutes) in mouse plasma after incubation at 37°C for 72 ± 2 hours. The chromatogram shows several metabolites and the remaining unchanged tracer (tR=17.0 min, 59%). [Figure 9]This figure shows the biodistribution (%ID / g) of [177Lu]RM2 (white), [177Lu]DOTA-[Hse7]MJ9 (black), and [177Lu]DOTA-[Bta8]MJ9 (shaded) in selected organs at 1 hour pi in PC-3 tumor-carrying CB17-SCID mice (100 pmol each). Data are expressed as mean ± SD (n=4). [Figure 10] This figure shows the tumor / background ratios for selected organs at 1 hour pi for [177Lu]RM2 (white), [177Lu]DOTA-[Hse7]MJ9 (black), and [177Lu]DOTA-[Bta8]MJ9 (shaded) in PC-3 tumor-carrying CB17-SCID mice. Data are expressed as mean ± SD (n=4). [Figure 11] This figure shows the biodistribution (in %ID / g) of [177Lu]RM2 (white), [177Lu]NeoBOMB1 (gray), [177Lu]DOTA-[Hse7]MJ9 (black), [177Lu]DOTA-[Bta8]MJ9 (shaded), [177Lu]AMTG (dots), and [177Lu]AMTG2 (squares) in selected organs at 24-hour pi in PC-3 tumor-carrying CB17-SCID mice (100 pmol each). Data are expressed as mean ± SD (n=4). [Figure 12] This figure shows the tumor / background ratios for selected organs of [177Lu]RM2 (white), [177Lu]NeoBOMB1 (gray), [177Lu]DOTA-[Hse7]MJ9 (black), [177Lu]DOTA-[Bta8]MJ9 (slashes), [177Lu]AMTG (dots), and [177Lu]AMTG2 (squares) in PC-3 tumor-carrying CB17-SCID mice at 24-hour pi. Data are expressed as mean ± SD (n=4). [Figure 13]This figure shows the biodistribution (at %ID / g) of [99mTc]N4-asp-MJ9 (gray, diagonal lines), [99mTc]N4-asp-[Bta8]MJ9 (gray, dots), [99mTc]N4-[Hse7]MJ9 (gray, bricks), and [99mTc]N4-[α-Me-Trp8]MJ9 (gray, squares) in selected organs at 1 hour pi in PC-3 tumor-carrying CB17-SCID mice (100 pmol each). Data are expressed as mean ± SD (n=4). [Figure 14] This figure shows the biodistribution (n=1) (at %ID / g) of [99mTc]N4-asp-MJ9 (gray, diagonal), [99mTc]N4-asp-[Bta8]MJ9 (gray, dots), [99mTc]N4-[Hse7]MJ9 (gray, bricks), and [99mTc]N4-[α-Me-Trp8]MJ9 (gray, squares) in selected organs at 4 hours pi in PC-3 tumor-carrying CB17-SCID mice (100 pmol each). [Figure 15] This figure shows the tumor / background ratios for selected organs at 1 hour pi for [99mTc]N4-asp-MJ9 (gray, diagonal), [99mTc]N4-asp-[Bta8]MJ9 (gray, dots), [99mTc]N4-[Hse7]MJ9 (gray, bricks), and [99mTc]N4-[α-Me-Trp8]MJ9 (gray, squares) in PC-3 tumor-carrying CB17-SCID mice. Data are expressed as mean ± SD (n=4). [Figure 16] This figure shows the tumor / background ratio (n=1) in selected organs for [99mTc]N4-asp-MJ9 (gray, diagonal), [99mTc]N4-asp-[Bta8]MJ9 (gray, dots), [99mTc]N4-[Hse7]MJ9 (gray, bricks), and [99mTc]N4-[α-Me-Trp8]MJ9 (gray, squares) in PC-3 tumor-carrying CB17-SCID mice at 1 hour pi. [Figure 17]This figure shows the maximum intensity projections (dorsal) of [99mTc]N4-asp-MJ9, [99mTc]N4-asp-[Bta8]MJ9, [99mTc]N4-[Hse7]MJ9, and [99mTc]N4-[α-Me-Trp8]MJ9 at 1-hour pi (top) and 4-hour pi (bottom) in PC-3 tumor-carrying CB17-SCID mice (200 pmol each). PC-3 tumors are indicated by white arrows. [Figure 18] This figure shows the biodistribution (at %ID / g) of [177Lu]GT50 (dark gray, diagonal lines), [177Lu]GT51 (dark gray, dots), [177Lu]GT52 (dark gray, bricks), and [177Lu]GT53 (dark gray, squares) in selected organs at 24-hour pi in PC-3 tumor-carrying CB17-SCID mice (100 pmol each). Data are expressed as mean ± SD (n=4). [Figure 19] This figure shows the maximum intensity projections (dorsal) of [177Lu]RM2 (top) and [177Lu]AMTG (bottom) at 1, 4, 8, 24, and 28 hours pi in PC-3 tumor-carrying CB17-SCID mice (100 pmol each). PC-3 tumors are indicated by white arrows. [Modes for carrying out the invention] [Examples]

[0110] The examples illustrate the present invention. Example 1 Materials and methods (general) Fmoc-(9-Fluorenylmethoxycarbonyl-) and all other protected amino acid analogs are purchased from Bachem (Bubendorf, Switzerland), Sigma-Aldrich (Munich, Germany), or Iris Biotech (Marktredwitz, Germany). H-Rink amide ChemMatrix® resin (35-100 mesh particle size, 0.4-0.6 mmol / g filling) is purchased from Sigma-Aldrich (Munich, Germany). Chematech (Dijon, France) provides the chelating agent DOTA( t Bu)3 and DOTAGA( t Send Bu)4.

[0111] Required solvents and other organic reagents should be purchased from either Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich (Munich, Germany), or VWR (Darmstadt, Germany). Solid-phase peptide synthesis should be performed manually using a Scilogex MX-RL-E Analog Rotisserie Tube Rotator (Scilogex, Rocky Hill, CT, USA).

[0112] Analytical and preparative reverse-phase high-pressure chromatography (RP-HPLC) was performed using a Shimadzu gradient system (Shimadzu Deutschland GmbH, Neufahrn, Germany) equipped with an SPD-20A UV / Vis detector (220 nm, 254 nm). Different gradients of acetonitrile (0.1% TFA) in water (0.1% TFA) were used as eluents for all HPLC operations.

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

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

[0115] Radioactive RP-HPLC for analysis and preparative sampling will be performed using a Nucleosil 100 C18 (5 μm, 125 × 4.0 mm) column (CS GmbH, Langerwehe, Germany).

[0116] Electrospray ionization mass spectroscopy for characterizing materials is expression L The results are obtained using a CMS mass spectrometer (Advion Ltd., Harlow, UK). Radioactivity is detected by connecting the outlet of the ultraviolet photometer to a NaI(Tl) well scintillation counter at EG&G Ortec (Munich, Germany).

[0117] The radioactive probe is WIZARD 2 (Registered Trademark) 2480 Automatic γ-Counter (Perkin Elmer, Waltham, MA, USA) was used for measurement, IC 50 The values ​​were determined using GraphPad Prism 6 (GraphPad Software Inc., San Diego, CA, USA).

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

[0119] Example 2 Synthesis protocol Solid-phase peptide synthesis using the Fmoc strategy Peptide formation on resin Each side chain-protected Fmoc-AA-OH (1.5 equivalents) is dissolved in NMP, and pre-activation is performed by adding TBTU (1.5 equivalents), HOAt (1.5 equivalents), and DIPEA (4.5 equivalents). After activation for 10 minutes, this solution is added to the free amine peptides bound to the resin and shaken at room temperature for 1.5 hours. Subsequently, the resin is washed with NMP, and after Fmoc deprotection, the next amino acids are bound in the same manner.

[0120] Fmoc deprotection on resin The Fmoc peptide bound to the resin is treated with 20% piperidine (v / v) in NMP for 5 minutes, followed by 15 minutes. The resin is then thoroughly washed with NMP.

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

[0122] DOTA( t Bu)3 or DOTAGA( t Bu)4 Conjugation DOTA is a protected chelating agent. t Bu)3 or DOTAGA( t Dissolve Bu)4 (1.5 equivalents) in NMP, and pre-activate by adding TBTU (1.5 equivalents), HOAt (1.5 equivalents), and DIPEA (4.5 equivalents). After activation for 10 minutes, add this solution to the resin-bound N-terminal deprotection peptide and shake at room temperature for 3 hours. Subsequently, wash the resin with NMP and DCM.

[0123] Peptide cleavage from resins with further deprotected acid-unstable protecting groups. After washing the fully protected resin-bound peptide with DCM, dissolve it in a mixture of TFA / TIPS / DCM (v / v / v; 95 / 2.5 / 2.5) and shake for 30 minutes. Filter this solution and treat the resin in the same manner for another 30 minutes. Combine both filtrates and concentrate under a nitrogen stream. Dissolve the residue in MeOH, precipitate with diethyl ether, then decant the liquid and dry the residual solid.

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

[0125] Example 3 Materials and methods (labeling experiment) Non-radioactive complex formation [ nat Ga] Gallium complex generation Purified chelating agent-containing ligand (Tracepur H2O 10 -3 M, 1.00 equivalent) and [ nat Ga]Ga(NO3)3·6H2O (10 mM, 1.50 equivalents in Tracepur H2O) is diluted with Tracepur water to a final concentration of 10 -4 Dilute to M and heat at 70°C for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0126] [ nat Formation of Lu]Lutetium complex Purified chelating agent-containing ligand (Tracepur H2O 10 -3 M, 1.00 equivalent) and [ nat Lu]LuCl3 (20 mM in Tracepur H2O, 2.50 equivalents) is dissolved in Tracepur water to a final concentration of 10 -4 Dilute to M and heat at 95°C for 30 minutes. After cooling to room temperature, the crude product is obtained.

[0127] radioactive label [ 125I] Iodine label I C 50 Reference ligand for research ([D-3-[ 125 I]I-Tyr 6 [MJ9) is prepared according to the previously published procedure. Briefly, 0.2 mg of [D-Tyr 6 Dissolve MJ9 in 20 μL of Tracepur water and 280 μL of TRIS buffer (25 mM TRIS HCl, 0.4 M NaCl, pH=7.9). Add the solution to a vial containing 150 μg Iodo-Gen(registered trademark) (1,3,4,6-tetrachloro-3α,6α-diphenylglycolyl, surface-bound), then add 5.0 μL (16 MBq) [ 125 Add [I]NaI (74 TB q / mmol, 3.1 GB q / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany). Incubate the reaction solution at room temperature for 15 minutes, then RP-HPLC (20 → 35%) over 20 minutes: R It was purified using a method involving 18.9 minutes and a K' of 10.46.

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

[0129] [ 99m [Tc] Technetium labeling [ 99m Labeling with [Tc]technetium is achieved using a procedure developed within the group. Therefore, purified chelating agent-containing ligand (Tracepur H2O) is used. -3 (M, 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 the solution to 95°C for 10 minutes. 99m The uptake of [Tc]technetium is determined by radioactive TLC (ITLC-SG chromatography paper, mobile phase: isotonic NaCl). The radiochemical purity of the labeled compound is determined by radioactive RP-HPLC.

[0130] Example 4 Materials and methods (in vitro experiment) n-octanol-PBS partition coefficient, logD 7.4 Approximately 1 MBq of labeled tracer was dissolved in 1 mL of a 1:1 mixture (v / v) of phosphate-buffered saline (PBS, pH=7.4) and n-octanol in an Eppendorf tube. After vigorously mixing the suspension at room temperature for 3 minutes, the vial was centrifuged at 9000 rpm for 5 minutes (Biofuge 15, Heraus Sepatech, Osterode, Germany), and 200 μL aliquots of both layers were measured using a gamma counter. This experiment was repeated at least four times.

[0131] I C 50 decision GRPR-positive PC-3 cells were cultured in Dublecco-modified Eagle medium / Nutrition Mixture F-12 with Glutamax-I (1:1) (Invitrigon) supplemented with 10% fetal bovine serum and maintained at 37°C in a humidified atmosphere with 5% CO2. GRPR affinity (IC) 50 To determine the optimal cell size, harvest the cells 24 ± 2 hours before the experiment and seed them in a 24-well plate (1.5 × 10⁶ cells per 1 mL / well).5 (Contains individual cells).

[0132] After removing the culture medium, the cells are washed once with 500 μL of HBSS (Hank's equilibrium salt solution, Biochrom, Berlin, Germany, supplemented with 1% bovine serum albumin (BSA)), and then equilibrated in 200 μL of HBSS (1% BSA) at room temperature for 9 minutes. Next, the cells are mixed with HBSS (1% BSA) as a control or with increased concentrations of each ligand (10% BSA in HBSS). -10 M~10 -4 Add 25 μL of the solution containing M) per well, then [D-3-[ in HBSS (1% BSA)] 125 I]I-Tyr 6 Add 25 μL of MJ9 (2.0 nM).

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

[0134] internalization For internalization studies, PC-3 cells were harvested 24 ± 2 hours before the experiment and seeded in a 24-well plate (1.5 × 10⁶). 5 Cells / well). After removing the culture medium, wash the cells once with 500 μL DMEM / F-12 (5% BSA) and equilibrate by standing in 200 μL DMEM / F-12 (5% BSA) at 37°C for at least 15 minutes. Each well is then filled with 25 μL DMEM / F-12 (5% BSA) or 25 μL [ nat Lu]RM2(10 -3 Process with M) and block. Next, 25 μL 125 I / 177Add Lu-labeled GRPR ligand (10 nM) and incubate the cells at 37°C for 60 minutes.

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

[0136] Each experiment (control and blockade) is performed six times. Free, surface-binding, and internalization activity are quantified using a γ-counter. Data are corrected for nonspecific internalization.

[0137] plasma research The procedure published by Linder et al. was slightly modified and applied to determine in vitro metabolic stability. Immediately after labeling, human (200 μL) or mouse (100 μL) plasma was added, and the mixture was incubated at 37°C for 72 ± 2 hours (or 6 ± 0.5 hours). The mixture was treated with ice-cold EtOH (150 μL [human], 100 μL [mouse]) and ice-cold MeCN (450 μL [human], 300 μL [mouse]), and the protein was precipitated by centrifugation at 13000 rpm for 20 minutes. The supernatant was decanted and further analyzed by radioactive RP-HPLC.

[0138] Example 5 Materials and methods (in vitro experiment) All animal experiments were conducted in accordance with Germany's general animal protection regulations (German Animal Protection Act, amended on May 18, 2018, Art.141Gv.29.3.2017I626, approval number ROB-55.2-2532.Vet_02-18-109) and institutional guidelines for animal care and use. To establish tumor xenografts, PC-3 cells (5 × 10⁶ cells per 200 μL) were used. 6 Cells were suspended in a 1:1 mixture (v / v) of Dulbecco's Modified Eagle Medium / Ham F-12 (DMEM / F-12) containing Glutamax-I (1:1) and Cultrex® Basement Membrane Matrix Type 3 (Trevigen Inc., Gaithersburg, MD, USA), and subcutaneously inoculated into the right shoulder of 6-10 week old female CB17-SCID mice (Charles River Laboratories International Inc., Sulzfeld, Germany). The mice had tumor volumes of 125-500 mm². 3 The samples were used in the experiment 2-3 weeks after vaccination.

[0139] Biological distribution Approximately 1–5 MBq (100–200 pmol) of radiolabeled GRPR antagonist was injected into the tail vein of PC-3 tumor-bearing mice, and the mice were sacrificed at 1, 4, or 24 hours pi (n=4). Selected organs were excised, weighed, and measured using a gamma counter (Perkin Elmer, Waltham, MA, USA).

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

[0141] Example 6 result GRPR reference ligand [ka]

[0142] Exemplary synthetic antagonistic GRPR ligands of the present invention [ka]

[0143] HPLC [ nat Ga]RM2 (10 → 90% MeCN in 15 minutes): t R =6.7 minutes, K'=3.47. Calculated monoisotopic mass (C 78 H 115 GaN 20 O 19 ): 1704.8, detected: m / z=1706.6[M+H] + , 854.1[M+2H] 2+ . [ nat Ga]DOTA-[Hse7 ]MJ9 (10→90% MeCN in 15 minutes):t R =6.8 minutes, K'=3.53. Calculated monoisotope mass (C 77 H 114 GaN 19 O 19 ): 1677.8, detected: m / z = 1679.3 [M+H] + , 840.4[M+2H] 2+ . [ nat Ga]DOTA-[Bta 8 ]MJ9 (10→90% MeCN in 15 minutes):t R =7.0 min, K'=3.67. Calculated monoisotope mass (C 78 H 114 GaN 19 O 19 S): 1721.7, Detected: m / z = 1723.7 [M + H] + , 862.3[M+2H] 2+ . [ nat Ga]AMTG (10 → 90% MeCN in 15 minutes): t R =6.9 minutes, K'=3.60. Calculated monoisotope mass (C 79 H 117 GaN 20 O 19 ): 1718.8, detected: m / z=1720.0[M+H] + , 860.6[M+2H] 2+ . [ nat Ga]AMTG2 (10 → 90% MeCN in 15 minutes): t R =6.9 minutes, K'=3.31. Calculated monoisotope mass (C 82 H 121 GaN 20 O 21 ): 1790.8, detected: m / z=896.3[M+2H] 2+ , 1792.6[M+H] + . [ nat Lu]RM2 (10→90% MeCN in 15 minutes):t R=6.6 minutes, K'=3.40. Calculated monoisotope mass (C 78 H 115 LuN 20 O 19 ): 1810.8, Detected: m / z = 1812.2 [M+H] + , 906.8[M+2H] 2+ . [ nat Lu]DOTA-[Hse 7 ]MJ9 (10→90% MeCN in 15 minutes):t R =6.8 minutes, K'=3.53. Calculated monoisotope mass (C 77 H 114 LuN 19 O 19 ): 1783.8, detected: m / z = 1784.9 [M+H] + , 893.6[M+2H] 2+ . [ nat Lu]DOTA-[Bta 8 ]MJ9 (10→90% MeCN in 15 minutes):t R =7.0 min, K'=3.67. Calculated monoisotope mass (C 78 H 114 LuN 19 O 19 S): 1827.8, Detection: m / z = 1828.9 [M + H] + , 915.1[M+2H] 2+ . [ nat Lu]AMTG (10→90% MeCN in 15 minutes):t R =6.8 minutes, K'=3.53. Calculated monoisotope mass (C 79 H 117 LuN 20 O 19 ): 1824.8, detected: m / z = 1826.3 [M+H] + , 913.6[M+2H] 2+ . [ nat Lu]AMTG2 (10→90% MeCN in 15 minutes):t R =7.0 min, K'=3.38. Calculated monoisotope mass (C 82 H 121 LuN 20 O 21 ): 1896.8, Detected: m / z = 949.5 [M+2H] 2+ , 1897.6[M+H] + . [ nat Lu]NeoBOMB1 (10→90% MeCN in 15 minutes):t R =9.6 minutes, K'=5.00. Calculated monoisotope mass (C 77 H 107 LuN 18 O 18 ): 1746.7, detected: m / z=874.5[M+2H] 2+ , 1747.3[M+H] + .

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

[0145] [Table 4]

[0146] Determining GRPR affinity The synthesized compounds showed similar affinity, but the homoserine derivative showed a slight decrease in affinity. Also, [ nat Ga] gallium complex ligand is, nat It showed high affinity, similar to that of its lutetium complex counterpart [Lu] (Table 3). The non-radioactive standard [D-3-I-Tyr 6 MJ9 shows particularly high compatibility with all ICs.50 This suggests that it is suitable as a competitive radioactive label reference in the experiment.

[0147] [Table 5]

[0148] internalization To demonstrate the antagonistic effect of modified statin-type GRPR ligands, we decided to internalize them into PC-3 cells. 177 Lu-labeled compounds showed low internalization, as expected from antagonists (Table 4). 177 Internalization of Lu]RM2 showed good correlation with the results of other published studies.

[0149] [Table 6]

[0150] plasma research The in vitro stability of synthetic GRPR ligands was measured in human plasma (Figures 1-4), while the stabilized ligands [ 177 Lu]AMTG and reference[ 177 Lu]RM2 was further analyzed in mouse plasma. Therefore, only 100 μL of mouse plasma was added to the tracer solution (final volume 200 μL) immediately after labeling. According to Linder et al. (Bioconjugate Chem. 20, 1171-1178 (2009)), mouse plasma is metabolized faster than human plasma, so the experiment was terminated after incubation at 37°C for 6 ± 0.5 hours (Figures 5 and 6). However, because the mouse mixture was small in volume, it was further examined after incubation at 37°C for 72 ± 2 hours (Figures 7 and 8). 4 177 When Lu-labeled GRPR ligands were incubated in human plasma at 37°C for 72 ± 2 hours and then compared (Figures 1-4), a significant difference was observed in the amount of unchanged tracer. Reference ligand [ 177The in vitro stability of Lu]RM2 (Figure 1) was determined to be only 33.5 ± 2.7% during that time period, 177 Lu]DOTA-[Hse 7 ]MJ9 (40.1±1.4%) and [ 177 Lu]AMTG (77.6±10.1%) increased after incubation at 37°C for 72±2 hours. The most lipophilic derivative [ 177 Lu]DOTA-[Bta 8 ]MJ9 (19.0±1.7%) was the least stable of these four compounds. The second reference ligand is [ 177 Lu]NeoBOMB1 showed an unchanged tracer volume of 60.8±1.2% after the same time period.

[0151] Reference compound [ 177 Lu]RM2 (Figures 5 and 7) and stabilized derivatives [ 177 To investigate potential differences between humans and animals, Lu]AMTG (Figures 6 and 8) was further examined in mouse plasma. According to Linder et al., metabolism in mouse plasma after approximately 6 hours is equivalent to metabolism in human plasma after approximately 3 days. Therefore, when the stability of these two ligands in mouse plasma after 6 hours was measured, the unchanged [ 177 Lu]AMTG (tR=17.0 mins, 89% and 92% respectively, Figure 6 and Figure 4) were found to be in equivalent amounts, but [ 177 The unchanged ligand for Lu]RM2 showed significant bias (tR=15.5 min, 92%, Figure 5 and 36%, Figure 1, respectively).

[0152] When we examined these two tracers in mouse plasma after a longer period of time (incubating at 37°C for 72 ± 2 hours), [ 177 Lu]RM2 (Figure 7) is [ 177 Although more of the tracer was cleaved by mouse endopeptidase than Lu]AMTG (Figure 8), the amount of unchanged tracer was still high (67% and 59%, respectively), suggesting that there are significant differences between human and animal plasma, particularly regarding the reference compound.

[0153] From these observations, stabilization [ 177 This study shows that Lu]AMTG performs better than its reference ligand in vivo in humans, but this is not necessarily the case in mice.

[0154] Biological distribution and μSPECT / CT research Reference compound [ 177 Lu]RM2 and diagnostic ligands[ 177 Lu]DOTA-[Hse 7 ]MJ9 and[ 177 Lu]DOTA-[Bta 8 The in vivo pharmacokinetics of MJ9 were investigated at 1 hour pi and 24 hours pi in CB17-SCID mice, whereas the therapeutic ligand [ 177 [Office]AMTG, 177 Lu]AMTG2 and second reference[ 177 Lu]NeoBOMB1 was only examined at 24-hour intervals (100 pmol each). The data are compared with the references shown in Figures 9 to 12.

[0155] Both destabilized compounds exhibited superior pharmacokinetic profiles compared to the reference ligand in mice at 1 hour pi (Figures 9 and 10). In all organs, uptake of the diagnostic ligands was comparable to or lower than that of the reference, and in the GRPR-positive pancreas in particular, rapid flushing from this organ was highlighted, likely due to increased metabolism at the destabilized site. Interestingly, uptake of both diagnostic ligands into tumors was superior to that of the reference compound (Figure 9), [ 177 We hypothesized that high levels of tumor enrichment, similar to those achieved with Lu]RM2, were possible. Furthermore, because metabolism in tumors is not as fast as in non-tumor organs, no negative flushing effect from the tumor was observed at 1 hour pi, despite the destabilization of the binding of the diagnostic derivative.

[0156] As shown in the tumor / background ratio (Figure 10), [ 177 Lu]DOTA-[Hse 7MJ9 showed the best contrast between tumor and non-tumor organs at 1 hour pi, but reference was the worst of the three.

[0157] As potential applications for therapeutic purposes, there are three ligands, 177 Lu]NeoBOMB1, stabilized[ 177 Lu]AMTG and [ 177 Lu]AMTG2 was examined in CB17-SCID mice over 24 hours (Figures 11 and 12). The pharmacokinetic profiles confirm the suggestion that destabilizing ligands are flushed out of tumors more quickly over longer time periods. In normal tissue, all four ligands compared were retained similarly, but in tumors, [ 177 Lu]RM2, [ 177 [Office]AMTG, 177 Because a large amount of Lu]AMTG2 was still present and only a small amount of the destabilizing compound, there was a significant difference in retention. 177 Lu]NeoBOMB1 also showed high tumor retention in tumors, and it also showed high tumor retention in the pancreas. For all derivatives, bone uptake was not completely complexed with each chelating agent. 177 This can be explained by Lu]LuCl3 (Figure 11).

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

[0159] In conclusion, considering the results, both destabilized ligands outperformed the reference in mice at 1 hour pi, but were significantly inferior in mice at 24 hours pi, which suggests that [ 177 Lu]DOTA-[Bta 8 MJ9 exhibited the lowest metabolic stability in vitro, which correlated well with observations in plasma studies. As mentioned earlier, metabolism in non-tumor tissues is faster than in tumor tissues, leading to the well-known flushing effect of GRPR antagonists. Gln 7 -Trp 8 As the binding became more destabilized, it was washed away more quickly from the background but not from the tumor, resulting in better contrast compared to the 1-hour pi reference. However, after longer time intervals, significantly faster washing away from the tumor was observed, and more lipophilic [ 177 Lu]DOTA-[Bta 8 The hypothesis that enzymatic degradation of MJ9 increases was confirmed. Therefore, it may be useful as a diagnostic agent.

[0160] Another destabilizing derivative [ 177 Lu]DOTA-[Hse 7 MJ9 showed only slight in vitro stability in human plasma, but its in vivo behavior in mice showed rapid clearance from non-tumor tissue at 1 hour pi and slight retention within tumors at 24 hours pi, suggesting low metabolic stability.

[0161] Stabilizing compounds [ 177Lu]AMTG showed particularly excellent overall performance considering the in vitro and in vivo results. Good affinity to GRPR-expressing PC-3 cells, moderate lipophilicity, and best metabolic stability in human plasma, 177 It was confirmed that AMTG has pharmacokinetic properties equivalent to or better than Lu]RM2. Due to its high in vitro metabolic stability in human plasma, AMTG may have the potential to compete with or even surpass the current gold standards (RM2, NeoBOMB1) for GRPR-expressing malignancies in targeted radiotherapy.

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

[0163] in vitro data The determined n-octanol-PBS partition coefficient (logD 7.4 ) and 99m Binding affinity of Tc-labeled compound to GRPR (IC) 50 The results are shown in Table 5. For all compounds, N4(6-(carboxy))-1,4,4,11-tetraazaundecane) was used as a chelating agent.

[0164] [Table 7]

[0165] In this series, [ 99m Tc]N4-asp-MJ9 was found to be the most hydrophilic, but the other three compounds were similar, though more lipophilic. All conjugates exhibited similar low-nanomolear ICs. 50The values ​​(unlabeled) were shown. However, homoserine and α-methyltryptophan derivatives showed slightly lower GRPR affinity compared to the other two ligands in this series.

[0166] in vivo data 99m The in vivo pharmacokinetics of Tc-labeled ligands (8), (9), (10), and (11) were investigated in CB17-SCID mice at 1-hour pi and 4-hour pi (200 pmol each). 99m Tc]N4-asp-MJ9(8),, 99m Tc]N4-asp-[Bta 8 ]MJ9 and[ 99m Tc]N4-[Hse 7 ]MJ9 showed high tumor levels, low overall background accumulation, and excellent pharmacokinetics at 1 hour pi (Figure 13). In GRPR-positive pancreas, [ 99m Tc]N4-asp-[Bta 8 MJ9 showed the lowest uptake, which highlights rapid flushing out of this organ due to a high metabolic rate in an unstable position. 99m Tc]N4-[Hse 7 MJ9 was found to have the highest tumor uptake and the second lowest pancreatic uptake in this series. 99m Tc]N4-[α-Me-Trp 8 ]MJ9 accumulates most in the pancreas, which is presumed to be due to improved metabolic stability by α-methyltryptophan modification, as already mentioned in the previous section. The tumor / background ratio at 1 hour pi is mostly [ 99m Tc]N4-asp-MJ9 was favorable (Figure 14). However, [ 177 Lu]DOTA-asp-[Bta 8 ]MJ9 and[ 177 Lu]DOTA-[Hse 7 ]MJ9 is[ 99m It was hypothesized that if the Tc]N4-asp-MJ9 exhibited similar hydrophilicity, the tumor / background ratio would improve.

[0167] Based on 4-hour pi biodistribution studies, these 99m The in vivo time course of Tc-labeled ligands was revealed (Figure 15). On the other hand, [ 99m Tc]N4-[α-Me-Trp 8 In MJ9, tumor accumulation increased compared to 1-hour pi, but all other derivatives in this series resulted in decreased tumor levels. This further strengthens the suggestion that α-methyltryptophan modification improves metabolic stability. 99m In the case of [Tc]technetium, this is undesirable because, for diagnostic reasons, high tumor uptake at 1 hour pi (not just 4 hour pi) and rapid clearance from background organs are desired. Nevertheless, this modification is undesirable for therapeutic compounds, such as those mentioned above. 177 It is very useful for Lu-labeled ligands. Faster clearance from background organs is beneficial for diagnostic compounds, [ 99m Tc]N4-asp-[Bta 8 MJ9 is ideally usable due to enhanced metabolic instability, highlighted by the uptake values ​​of most organs at 4-hour pi. The tumor / background ratio at 4-hour pi is shown in Figure 16, but for most organs [ 99m Tc]N4-asp-MJ9 and [ 99m Tc]N4-[Hse 7 It has been revealed that the MJ9 is the best.

[0168] The excellent contrast at 1 hour pi, made possible by the destabilizing modifications homoserine and 3-benzothienylalanine, was further enhanced by μSPECT / CT imaging (Figure 17). 99m Tc]N4-asp-[Bta 8 ]MJ9 and[ 99m Tc]N4-[Hse 7 Despite having high lipophilicity, MJ9 is unmodified [ 99m Compared to Tc]N4-asp-MJ9, the contrast is slightly enhanced. 99m Tc]N4-[α-Me-Trp8 MJ9 has high metabolic stability and slow clearance in the pancreas and intestines, so it is expected to have lower contrast than the other three derivatives, which is undesirable for diagnosis.

[0169] Example 8 Bombesin-SiFA derivative Test compound

[0170] [Table 8]

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

[0172] [Table 9]

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

[0174] Research on biological distribution All four compounds are, 18 The SiFA portion for F labeling, 68 Ga- or 177 Contains a chelating agent for Lu-labeling. 18 F nat Ga / nat Lu] ligand and [ 19 F 68 Ga / 177Since radioactive hybrid-based ligands are chemically indistinguishable regardless of which of the Lu] ligands is applied, they form an ideal theranostic pair, making this a useful feature. 177 The biodistribution of Lu-labeled ligands GT50, GT51, GT52, and GT53 was evaluated in CB17-SCID mice at 24-hour pi (100 pmol each). All derivatives showed generally low background retention except in the liver and kidneys (Figure 18). Tumor retention was [ 177 Lu]RM2, [ 177 Lu]AMTG and [ 177 The levels were reduced compared to Lu]AMTG2 (Figure 11). All bombesin-SiFA conjugates need to be optimized, especially considering the high retention in the kidneys and slightly higher retention in the liver. However, the ligands evaluated in this series demonstrated the functionality of the radioactive hybrid-based concept.

Claims

1. A compound of formula (IIIa) or (IIIb). 【Chemistry 1】

2. A compound of formula (IV) or (V). 【Chemistry 2】

3. １７７ The compound according to claim 1 or 2, which is labeled with Lu.

4. ６８ The compound according to claim 1 or 2, which is labeled with Ga.

5. A pharmaceutical composition comprising or consisting of a compound according to any one of claims 1 to 4.

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