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CN-122005879-A - Modified GRPR antagonist peptides for cancer imaging and treatment

CN122005879ACN 122005879 ACN122005879 ACN 122005879ACN-122005879-A

Abstract

The present application relates to modified GRPR antagonist peptides for use in cancer imaging and treatment. The present application relates to a compound that binds to an endogenous receptor, said compound comprising (i) an oligopeptide comprising a dipeptide having a Trp that is the C-terminal amino acid of said dipeptide, wherein said Trp is replaced with an alpha-amino acid Xaa 2 , whereby the stability of the peptide bond connecting Xaa 2 to the N-terminal adjacent amino acid in serum or plasma is increased compared to the peptide bond connecting Trp to the N-terminal adjacent amino acid in an otherwise identical compound, and (ii) a moiety capable of producing a therapeutically effective radiation, said moiety being covalently bound to said oligopeptide.

Inventors

  • WESTER HANS-JUERGEN
  • T. Beijing

Assignees

  • 慕尼黑工业大学

Dates

Publication Date
20260512
Application Date
20201021
Priority Date
20191219

Claims (17)

  1. 1. A compound of formula (I) S — Y — Xaa 1 — Xaa 2 — L-Ala — L-Val — Xaa 5 — L-His — T (I) Wherein the method comprises the steps of S is a moiety capable of generating therapeutically active radiation, which is a metal ion chelator selected from bis (carboxymethyl) -1,4,8, 11-tetraazabicyclo [6.6.2] hexadecane (CBTE a), cyclohexyl-1, 2-diamine tetraacetic acid (CDTA), 4- (1, 4,8, 11-tetraazacyclotetradec-1-yl) -methylbenzoic acid (CPTA), N' - [5- [ acetyl (hydroxy) amino ] pentyl ] -N- [5- [ [4- [ 5-aminopentyl- (hydroxy) amino ] -4-oxobutanoyl ] amino ] pentyl ] -N-hydroxysuccinamide (DFO), 4, 11-bis (carboxymethyl) -1,4,8, 11-tetraazabicyclo [6.6.2] hexadecane (DO 2A), 1,4,7, 10-tetraazacyclododecane-N, N ', N ' ', N ' ' ' -tetraacetic acid (DOTA), alpha- (2-carboxyethyl) -1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid or 2- [1,4,7, 10-tetraazacyclododecane-4, 7, 10-triacetic acid ] -glutaric acid (DOTAGA), N ' -bipyridyloxy ethylenediamine-N, N ' -diacetate-5, 5' -bis (phosphate) (DPDP), Diethylene Triamine Pentaacetic Acid (DTPA), ethylene diamine-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), hydroxyethylenediamine triacetic acid (HEDTA), 1- (p-nitrobenzyl) -1,4,7, 10-tetraazadecane-4, 7, 10-triacetate (HP-DOA 3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), 1,4, 7-triazacyclononane-1-succinic acid-4, 7-diacetic acid (NODASA), 1- (1-carboxy-3-carboxypropyl) -4,7- (carboxy) -1,4, 7-triazacyclononane (NODAGA), 1,4, 7-triazacyclononane triacetic acid (NOTA), 4, 11-bis (carboxymethyl) -1,4,8, 11-tetraazabicyclo [6.6.2] hexadecane (TE 2A), 1,4,8, 11-tetraazacyclododecane-1, 4,8, 11-tetraacetic acid (TETA), terpyridine-bis (methylenetetraacetic acid) (TMT), 1,4,7, 10-tetraazacyclotridecane-N, N ', N ' ', N ' ' -tetraacetic acid (TRITA), Triethylenetetramine Hexaacetic Acid (TTHA), N' -bis [ (6-carboxy-2-pyridinyl) methyl ] -4, 13-diaza-18-crown-6 (H 2 macropa), 4-amino-4- {2- [ (3-hydroxy-1, 6-dimethyl-4-oxo-1, 4-dihydro-pyridin-2-ylmethyl) -carbamoyl ] -ethyl } heptanedioic acid bis- [ (3-hydroxy-1, 6-dimethyl-4-oxo-1, 4-dihydro-pyridin-2-ylmethyl) -amide ] (THP), 6-carboxy-1, 4,8, 11-tetraazaundecane (N4), 6- { p [ (carboxymethoxy) acetyl ] -aminobenzyl } -1,4,8, 11-tetraazaundecane (N4'), 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid (DO 3A), S-acetylmercaptoacetyl trisserine (MAS 3), mercaptoacetyl trisglycine (MAG 3), 1, 4-bis (hydroxycarbonylmethyl) -6- [ bis (hydroxycarbonylmethyl) ] amino-6-methylparaben-1, 4-diaza (AAZTA), 3,6,9,15-tetraazabicyclo [9.3.1] pentadecane-1 (15), 11, 13-triene-2, 10-dione (TBPD), 9-oxa-3,6,12,15,21-pentaazatricyclo [15,3,2,1] eicosa-1 (21), 17, 19-triene-2,7,11,16-tetradione (OPTT), 2- [ bis (carboxymethyl) aminomethyl ] -2- [ (4-isothiocyanatobenzyl) oxy-methyl ] propene-1, 3-dinitroso-tetraacetic 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-oxobutanoic acid (Me-3, 2-HOPO), 2,20- (6- ((carboxymethyl) amino) -1, 4-diazacycloheptane-1, 4-diyl) diacetic acid) (DATA), 1,4, 7-triazacyclononane-1, 4, 7-tris [ methyl (2-carboxyethyl) phosphinic acid ] (TRAP) and functional derivatives thereof, for example NOPO (1, 4, 7-triazacyclononane-1, 4-bis [ methylene (hydroxymethyl) phosphinic acid ] -7- [ methylene (2-carboxyethyl) phosphinic acid ]), 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetrakis [ methylene (2-carboxyethyl) phosphinic acid ] (DOTPI), 6,6'- ({ 9-hydroxy-1, 5-bis (methoxycarbonyl) -2, 4-bis (pyridin-2-yl) -3, 7-diazabicyclo [3.3.1] nonan-3, 7-diyl } bis (methylene)) pyridinedicarboxylic acid (H2 bispa 2), 1,4,7,10, 13-pentaazacyclopentadecane-N, N', N '', N '' ', N' '' -pentaacetic acid (PEPA), 1,4,7,10,13, 16-hexaazacyclohexanecetyl-N, N ', N' ', N' '', N '' '' -hexaacetic acid (HEHA), 1,2- [ {6- (carboxy) -pyridin-2-yl } -methylamino) ethane (H 2 dedpa), a process for preparing a pharmaceutical composition, N, N '-bis { 6-carboxy-2-pyridylmethyl } -ethylenediamine-N, N' -diacetic acid (H 4 octapa), 4, 10-bis (carboxymethyl) -1,4,7, 10-tetraazabicyclo [5.5.2] tetradecane (CB-DO 2A), 1,4,7, 10-tetrakis (carbamoylmethyl) -l,4,7, 10-Tetraazacyclododecane (TCMC), 1, 8-diamino-3,6,10,13,16,19-hexaazabicyclo [6.6.6] eicosane (sar) and functional derivatives thereof, {4- [2- (bis-carboxymethyl-amino) -ethyl ] -7-carboxymethyl- [1,4,7] triazolin-1-yl } -acetic acid (NETA), N ', N ' ' -tris (2-mercaptoethyl) -1,4, 7-triazacyclononane (TACN-TM), 2- (p-isothiocyanate-cyclohexyldiethylenetriamine pentaacetic acid (CHX-A ' ' -DTPA), N ' - [ 1-benzyl-1, 2, 3-triazol-4-yl ] methyl-N, N ' - [6- (carboxy) pyridin-2-yl ] -1, 2-diaminoethane (H 2 azapa), N, N ' ' - [ [6- (carboxy) pyridin-2-yl ] methyl ] diethylenetriamine-N, N ', N ' ' -triacetic acid (H 5 decapa), N ' -bis (2-hydroxy-5-sulfobenzyl) ethylenediamine-N, N ' -diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo [9.3.1] pentadecano-1 (15), 11, 13-triene-3, 6,9, -triacetic acid (PCTA), and N, N ' - (methylenephosphonate) -N, N ' - [6- (methoxycarbonyl) pyridin-2-yl ] methyl-1, 2-diaminoethane (H 6 phospa); Y is an optional linker; Xaa 1 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (Ii) An alpha-amino acid that increases stability of Xaa 1 —Xaa 2 peptide bond in serum or plasma compared to when Xaa 1 is Gln and Xaa 2 is Trp in an otherwise identical compound; Xaa 2 is Trp or an alpha-amino acid that increases the stability of Xaa 1 —Xaa 2 peptide bond in serum or plasma compared to an otherwise identical compound in which Xaa 1 is Gln and Xaa 2 is Trp; provided that Xaa 1 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and that Xaa 2 is also not Trp; xaa 5 is Gly, N-Me-Gly, D-Ala, beta-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, and T is an optional end group.
  2. 2. The compound according to claim 1, wherein Xaa 1 is L-Gln, D-Gln or L-His; xaa 2 is α -Me-Trp; Xaa 5 is Gly, N-Me-Gly, D-Ala or beta-Ala, and T is Sta-Leu-NH 2 、Leu-ψ(CH 2 N)-Pro-NH 2 , leu-NHEt or NH-CH [ CH 2 -CH(CH 3 ) 2 ] 2 , Wherein Sta is (3S, 4S) -4-amino-3-hydroxy-6-methylheptanoic acid.
  3. 3. The compound of claim 1 or 2, wherein Xaa 1 is L-Gln.
  4. 4. The compound of claim 1 or 2, wherein Xaa 5 is Gly.
  5. 5. A compound of formula (II) S — Y — Xaa 3 — Xaa 4 — L-Ala — L-Val — Xaa 5 — L-His — T (II) Wherein the method comprises the steps of S is a moiety capable of producing a detectable signal, which is a metal ion chelator selected from the group consisting of bis (carboxymethyl) -1,4,8, 11-tetraazabicyclo [6.6.2] hexadecane (CBTE a), cyclohexyl-1, 2-diamine tetraacetic acid (CDTA), 4- (1, 4,8, 11-tetraazacyclotetradec-1-yl) -methylbenzoic acid (CPTA), N' - [5- [ acetyl (hydroxy) amino ] pentyl ] -N- [5- [ [4- [ 5-aminopentyl- (hydroxy) amino ] -4-oxobutanoyl ] amino ] pentyl ] -N-hydroxysuccinamide (DFO), 4, 11-bis (carboxymethyl) -1,4,8, 11-tetraazabicyclo [6.6.2] hexadecane (DO 2A), 1,4,7, 10-tetraazacyclododecane-N, N ', N' ', N' '' -tetraacetic acid (DOTA), alpha- (2-carboxyethyl) -1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid or 2- [1,4,7, 10-tetraazacyclododecane-4, 7, 10-triacetic acid ] -glutaric acid (DOTAGA), N '-bipyridyloxyethylenediamine-N, N' -diacetate-5, 5 '-bis (phosphate) (DPDP), diethylenetriamine pentaacetic 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), hydroxyethylenediamine triacetic acid (HEDTA), 1- (p-nitrobenzyl) -1,4,7, 10-tetraazacyclodecane-4, 7, 10-triacetate (HP-DOA 3), 6-hydrazino-N-methylpyridine-3-carboxamide (HYNIC), 1,4, 7-triazacyclononane-1-succinic acid-4, 7-diacetic acid (NODASA), 1- (1-carboxy-3-carboxypropyl) -4,7- (carboxy) -1,4, 7-triazacyclononane (NODAGA), 1,4, 7-triazacyclononane triacetic acid (NOTA), 4, 11-bis (carboxymethyl) -1,4,8, 11-tetraazabicyclo [6.6.2] hexadecane (TE 2A), 1,4,8, 11-tetraazacyclododecane-1, 4,8, 11-tetraacetic acid (TETA), terpyridyl-bis (methylenetetraacetic acid) (TMT), 1,4,7, 10-tetraazacyclotridecane-N, N ', N ' ', N ' ' ' -tetraacetic acid (TRITA), triethylenetetramine hexaacetic acid (TTHA), N ' -bis [ (6-carboxy-2-pyridinyl) methyl ] -4, 13-diaza-18-crown-6 (H 2 macropa), 4-amino-4- {2- [ (3-hydroxy-1, 6-dimethyl-4-oxo-1, 4-dihydro-pyridin-2-ylmethyl) -carbamoyl ] -ethyl } pimelic acid bis- [ (3-hydroxy-1, 6-dimethyl-4-oxo-1, 4-dihydro-pyridin-2-ylmethyl) -amide ] (THP), 6-carboxy-1, 4,8, 11-tetraazaundecane (N4), 6- { p [ (carboxymethoxy) acetyl ] -aminobenzyl } -1,4,8, 11-tetraazaundecane (N4'), 1,4,7, 10-tetraazadodecane-1, 4, 7-triacetic acid (DO 3A), S-acetylmercaptoacetyl-trisserine (MAS 3), mercaptoacetyl-trisglycine (MAG 3), 1, 4-bis (hydroxycarbonylmethyl) -6- [ bis (hydroxycarbonylmethyl) ] amino-6-methylperfhydro-1, 4-diaza-ne (AAZTA), 3,6,9,15-tetraazabicyclo [9.3.1] pentadecano-1 (15), 11, 13-triene-2, 10-dione (TBPD), 9-oxa-3,6,12,15,21-pentaazatricyclo [15,3,2,1] eicosa-1 (21), 17, 19-triene-2,7,11,16-tetradione (OPTT), 2- [ bis (carboxymethyl) aminomethyl ] -2- [ (4-isothiocyanatobenzyl) oxy-methyl ] propene-1, 3-dinitrosotetraacetic 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-oxobutanoic acid (Me-3, 2-HOPO), 2,20- (6- ((carboxymethyl) amino) -1, 4-diazacycloheptane-1, 4-diyl) diacetic acid (DATA), 1,4, 7-triazacyclononane-1, 4, 7-tris [ methyl (2-carboxyethyl) phosphinic acid ] (TRAP) and functional derivatives thereof, for example NOPO (1, 4, 7-triazacyclononane-1, 4-bis [ methylene (hydroxymethyl) phosphinic acid ] -7- [ methylene (2-carboxyethyl) phosphinic acid ]), 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetrakis [ methylene (2-carboxyethyl) phosphinic acid ] (DOTPI), 6' - ({ 9-hydroxy-1, 5-bis (methoxycarbonyl) -2, 4-bis (pyridin-2-yl) -3, 7-diazabicyclo [3.3.1] nonane-3, 7-diyl } bis (methylene)) pyridinedicarboxylic acid (H2 bispa), 1,4,7,10, 13-pentaazacyclopentadecane-N, N ', N' ', N' '', N '' '' -pentaacetic acid (PEPA), 1,4,7,10,13, 16-hexaazahexadecane-N, N ', N' ', N' '', N '' '' -hexaacetic acid (HEHA), 1,2- [ {6- (carboxy) -pyridin-2-yl } -methylamino ] ethane (H 2 dedpa), N '-bis { 6-carboxy-2-pyridylmethyl } -ethylenediamine-N, N' -diacetic acid (H 4 octapa), and, 4, 10-bis (carboxymethyl) -1,4,7, 10-tetraazabicyclo [5.5.2] tetradecane (CB-DO 2A), 1,4,7, 10-tetra (carbamoylmethyl) -l,4,7, 10-Tetraazacyclododecane (TCMC), 1, 8-diamino-3,6,10,13,16,19-hexaazabicyclo [6.6.6] eicosane (sar) and functional derivatives thereof, {4- [2- (bis-carboxymethyl-amino) -ethyl ] -7-carboxymethyl- [1,4,7] triazolin-1-yl } -acetic acid (NETA), N ', N ' ' -tris (2-mercaptoethyl) -1,4, 7-triazacyclononane (TACN-TM), 2- (p-isothiocyanate-benzyl) -cyclohexyldiethylenetriamine pentaacetic acid (CHX-A "-DTPA), N '- [ 1-benzyl-1, 2, 3-triazol-4-yl ] methyl-N, N' - [6- (carboxy) pyridin-2-yl ] -1, 2-diaminoethane (H 2 azapa), N '- [ [6- (carboxy) pyridin-2-yl ] methyl ] diethylenetriamine-N, N', N" -triacetic acid (H 5 decapa), N, N '-bis (2-hydroxy-5-sulfobenzyl) ethylenediamine-N, N' -diacetic acid (SHBED), 3,6,9,15-tetraazabicyclo [9.3.1] pentadec-1 (15), 11, 13-triene-3, 6,9, -triacetic acid (PCTA), and N, N '- (methylenephosphonate) -N, N' - [6- (methoxycarbonyl) pyridin-2-yl ] methyl-1, 2-diaminoethane (H 6 phospa); Y is an optional linker; xaa 3 is (i) L-Gln, D-Gln, L-His, D-His or Gly, preferably L-Gln, or (Ii) An alpha-amino acid that reduces stability of Xaa 3 —Xaa 4 peptide bond in serum or plasma compared to when Xaa 3 is Gln and Xaa 4 is Trp in an otherwise identical compound; Xaa 4 is Trp or an alpha-amino acid that reduces the stability of Xaa 3 —Xaa 4 peptide bond in serum or plasma compared to an otherwise identical compound in which Xaa 3 is Gln and Xaa 4 is Trp; Wherein the alpha-amino acid at the Xaa 4 position that reduces the stability of Xaa 3 —Xaa 4 peptide bond in serum or plasma is not a proteinogenic amino acid; Provided that Xaa 3 is not any of L-Gln, D-Gln, L-His, D-His, and Gly, and that Xaa 4 is also not Trp; xaa 5 is Gly, N-Me-Gly, beta-Ala or 2-aminoisobutyric acid (Aib), preferably Gly, and T is an optional end group.
  6. 6. The compound according to claim 5, wherein Xaa 3 is L-Gln, D-Gln or L-His; xaa 4 is Bta; Xaa 5 is Gly, N-Me-Gly or beta-Ala, and T is Sta-Leu-NH 2 、Leu-ψ(CH 2 N)-Pro-NH 2 , leu-NHEt or NH-CH [ CH 2 -CH(CH 3 ) 2 ] 2 , Wherein Sta is (3S, 4S) -4-amino-3-hydroxy-6-methylheptanoic acid.
  7. 7. The compound of claim 6, wherein Xaa 3 is L-Gln.
  8. 8. The compound of claim 6, wherein Xaa 5 is Gly.
  9. 9. The compound of any one of claims 1 to 8, wherein the metal ion chelating agent is selected from DOTA or dotga.
  10. 10. The compound according to any one of claims 1 to 9, wherein Y (A) Comprising one, two, three, four, five or six positive and/or negative charges; (b) Comprising one, two, three, four, five or six amino acids or consisting of one two, three, four, five or six amino acids; (c) Comprises or consists of PEG n or PEG n , n is an integer selected from 1,2, 3,4, 5, 6, 7, 8, 9 and 10, and/or (D) Comprising a moiety capable of producing a detectable signal.
  11. 11. The compound of claim 10, wherein the amino acid in (b) is a D-amino acid.
  12. 12. The compound of claim 10, wherein the amino acid in (b) is a D-a-amino acid.
  13. 13. The compound of any one of claims 11 to 12, wherein the linker Y comprises or consists of: (i) D-Glu-urea-D-Glu; (ii) One or two 2, 3-diaminopropionic acid moieties, optionally substituted with moieties capable of generating a detectable signal; (iii) One, two, three, four, five or six consecutive amino acids comprising or consisting of one or more amino acids selected from the group consisting of D-/L-aspartic acid, D-/L-ornithine, 4-amino-1-carboxymethyl-piperidine (Pip), D-/L-2, 3-diaminopropionic acid, D-/L-serine, D-/L-citrulline moiety, L-sulfoalanine (Ala (SO 3 H)), aminopentanoic acid (Ava), 4-aminobenzoic acid (PABA) and D-Phe, and/or (Iv) Para-aminomethylaniline diglycolic acid (pABza-DIG, AMA-DGA) and/or diglycolic acid salts (DIG, DGA).
  14. 14. A pharmaceutical composition, in the form of a capsule, comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, excipient a diluent or any combination thereof or consisting of a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, excipient, diluent or any combination thereof.
  15. 15. A diagnostic composition comprising a therapeutically effective amount of a compound, comprising a compound according to any one of claims 1 to 13 and a diagnostically acceptable carrier an excipient and/or diluent or any combination thereof or consisting of a compound according to any one of claims 1 to 13 and a diagnostically acceptable carrier, excipient and/or diluent or any combination thereof.
  16. 16. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of cancer.
  17. 17. The use of a compound according to claim 16, wherein the cancer is selected from prostate cancer, breast cancer, neuroendocrine tumor, non-small cell lung cancer (NSCLC), small Cell Lung Cancer (SCLC), pancreatic cancer, head/neck squamous cell carcinoma, neuroglioblastoma, colorectal cancer, and thyroid medullary cancer (MTC) where the receptor is CCK-2R.

Description

Modified GRPR antagonist peptides for cancer imaging and treatment The present application is a divisional application of chinese patent application 202080087499.8 "modified GRPR antagonist peptide for cancer imaging and treatment", filing date 2020, 10, 21. Background Prostate cancer (PCa), one of the most common malignancies in men in the western world, remains a difficult medical task due to the low survival rate of the disease progression stage. Studies have shown that the earlier it is diagnosed, the higher the success rate of treatment, and thus new methods are needed. Over the past few decades, nuclear medicine diagnosis and treatment of cancer based on radiotracers that accumulate rapidly and almost completely at the tumor site has attracted increasing attention. Prostate Specific Membrane Antigen (PSMA) tracers are often used for in vivo radiotherapy and imaging of PCa due to several excellent properties such as overexpression in prostate cancer and low expression in healthy tissue, rapid clearance and high incidence (92% of all prostate cancers). However, the use of PSMA also has some drawbacks, such as rather low expression in the early stages of the disease, and high uptake in the kidneys and salivary glands. As an interesting alternative, the Gastrin Releasing Peptide Receptor (GRPR) also showed good incidence in PCa (early up to 100%, late up to 60%), over-expression in malignant tissue, and high expression in only one healthy tissue (pancreas). This is an advantage over PSMA because metastases in the kidney region cannot be detected correctly by using PSMA tracers due to high kidney uptake. Furthermore, an increasingly alarming problem with the use of high therapeutic doses appears to be damage to salivary glands and kidneys due to the high accumulation of PSMA tracer. GRPR was found to exhibit higher expression in the early stages of PCa, while PSMA overexpression was observed more in the late stages of the disease. In addition, GRPR overexpression is also found in breast cancer (breast cancer) that is rich in Estrogen Receptor (ER), which allows the use of the same tracer for different cancers and sexes. Thus, GRPR tracers are a useful tool as a surrogate for patients with low PSMA expression or better diagnosis of renal zone metastases. Conditional treatment (contingent therapy) of prostate cancer (early stage) benefits from GRPR tracers rather than PSMA tracers due to higher expression rates and lower side effects (salivary gland damage). Furthermore, the GRPR antagonist enables use for different sexes because it is overexpressed in prostate and breast cancers. To date, both GRPR agonists and antagonists have been and are currently used in clinical settings. The development of antagonists is increasing because, on the one hand, agonists exhibit some painful side effects after application to patients and, due to the much slower clearance from non-tumour tissues, have poorer pharmacokinetics. The GRPR derivative is significantly less than PSMA ligand in clinical use. However, there is a clinical benefit since only 92% of all PCa tumors express PSMA, while GRPR is also overexpressed in about 85% of all Estrogen Receptor (ER) -rich breast cancers. The generally necessary structure of antagonistic GRPR molecules contains a binding unit based on the C-terminal portion of native bombesin or Gastrin Releasing Peptide (GRP) due to its second nanomolar affinity. The linker moiety between the pharmacodynamic moiety and the N-terminal chelator is not necessarily necessary, as there are many reports demonstrating the pharmacokinetic benefit of using the linker unit despite the presence of a tracer that exhibits good performance. Among GRPR antagonists, the derivative RM2 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2) is the most commonly used agent for selective GRPR imaging and therapy. It is marked mainly with 68Ga (88.9% β+, Eβ+, Maximum value = 1.89 MeV, t½ =68 minutes) for imaging and 177Lu (78.6% β-, Eβ, Maximum value = 0.498 MeV, t½ =6.7 d) for in vivo radiotherapy and can be applied to PCa and ER-rich breast cancer, so it has so far been considered as the gold standard in GRPR antagonists. 68 Both Ga-and 177 Lu-RM2 show favourable pharmacokinetics, because of high tumor accumulation, rapid clearing from non-tumor tissue and good retention in tumors over a long time span in humans, leading to high contrast and good therapeutic results, respectively. Nevertheless, certain bombesin analogs are metabolically unstable in animals, which limits the desired accumulation in tumor tissue. On the other hand, it has to be mentioned that more stable GRPR derivatives show a slower clearance from the GRPR-rich pancreas, which has to be taken into account before use in human therapy due to possible pancreatitis. Among other malignant indications, there are more markers and targets of interest. These include the neuromodulation peptide-B receptor (bombesin-1 receptor, NMBR), bombesin receptor subt