{"entity": "publication", "iuid": "4d692659a42e4fa889d513b147537734", "timestamp": "2026-09-30T22:58:43.846Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/4d692659a42e4fa889d513b147537734.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/4d692659a42e4fa889d513b147537734"}}, "title": "Improving GRPR-targeting peptides for radiotheranostics application: insights from chelator modifications and \u03b1-methyl-L tryptophan substitution.", "authors": [{"family": "Obeid", "given": "Karim", "initials": "K"}, {"family": "Bezverkhniaia", "given": "Ekaterina", "initials": "E"}, {"family": "Tolmachev", "given": "Vladimir", "initials": "V"}, {"family": "Orlova", "given": "Anna", "initials": "A"}, {"family": "Kanellopoulos", "given": "Panagiotis", "initials": "P", "orcid": "0000-0002-0617-3936", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/85ce3df2ffae4754946f11bb2e98ef97.json"}}], "type": "journal article", "published": "2025-11-13", "journal": {"title": "EJNMMI Radiopharm Chem", "issn": "2365-421X", "volume": "10", "issue": "1", "pages": "74", "issn-l": null}, "abstract": "Targeting the gastrin-releasing peptide receptor (GRPR) is a promising approach for radionuclide therapy in prostate and breast cancers. GRPR-targeting peptides often have limited metabolic stability, which can compromise their clinical efficacy due to rapid degradation in the bloodstream, leading to reduced tumor uptake. We previously reported the GRPR-targeting peptide AU-RM26-M2 (DOTAGA-PEG2-Pip-[Sar11]RM26), which demonstrated promising pharmacokinetics in GRPR-expressing xenografts. In this study, we aimed to enhance the metabolic stability and targeting properties of AU-RM26-M2 by incorporating \u03b1-methyl-L-tryptophan (MetTrp) at position 8 in the pharmacophore, and to investigate the influence of chelator choice (DOTAGA vs. DOTA) for labeling with Lu-177, a \u03b2-emitting therapeutic nuclide.\n\nTherefore, we designed two peptides: PKB2 (DOTAGA-PEG2-Pip-[MetTrp8, Sar11]RM26) and PKB3 (DOTA-PEG2-Pip-[MetTrp8, Sar11]RM26). For comparison, we also evaluated the DOTA-bearing analogue of AU-RM26-M2, PKB1 (DOTA-PEG2-Pip-[Sar11]RM26). PKB1, PKB2, and PKB3 were labeled with Lu-177, achieving high radiochemical yields (> 97%) and purities (> 93%). In PC-3 cells, [177Lu]Lu-PKB1, [177Lu]Lu-PKB2, and [177Lu]Lu-PKB3 showed affinity in the sub-nanomolar range and high specificity for GRPR, with a slow internalization rate. The radiopeptides with MetTrp8 modification had high metabolic stability against peptidases in vivo. In PC-3 xenografts, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3 demonstrated rapid background clearance and high GRPR-mediated tumor activity uptake at 2 h pi, exceeding activity uptake in the kidneys. Activity uptake in the tumor was highly retained at 24 h pi.\n\nThis study led to the development of two metabolically stable GRPR-targeting radiopeptides, [177Lu]Lu-PKB2 and [177Lu]Lu-PKB3, with a high potential for targeted radionuclide therapy.", "doi": "10.1186/s41181-025-00402-2", "pmid": "41231375", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12615863"}, {"db": "pii", "key": "10.1186/s41181-025-00402-2"}], "notes": [], "created": "2026-09-23T12:36:09.803Z", "modified": "2026-09-23T12:36:09.848Z"}