Work

Improving GRPR-targeting peptides for radiotheranostics application: insights from chelator modifications and α-methyl-L tryptophan substitution

Year: 2025

Type: article

Abstract: Background 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-PEG 2 -Pip-[Sar 11 ]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 α-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 β-emitting therapeutic nuclide. Results Therefore, we designed two peptides: PKB2 (DOTAGA-PEG 2 -Pip-[MetTrp 8 , Sar 11 ]RM26) and PKB3 (DOTA-PEG 2 -Pip-[MetTrp 8 , Sar 11 ]RM26). For comparison, we also evaluated the DOTA-bearing analogue of AU-RM26-M2, PKB1 (DOTA-PEG 2 -Pip-[Sar 11 ]RM26). PKB1, PKB2, and PKB3 were labeled with Lu-177, achieving high radiochemical yields (> 97%) and purities (> 93%). In PC-3 cells, [ 177 Lu]Lu-PKB1, [ 177 Lu]Lu-PKB2, and [ 177 Lu]Lu-PKB3 showed affinity in the sub-nanomolar range and high specificity for GRPR, with a slow internalization rate. The radiopeptides with MetTrp 8 modification had high metabolic stability against peptidases in vivo. In PC-3 xenografts, [ 177 Lu]Lu-PKB2 and [ 177 Lu]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. Conclusions This study led to the development of two metabolically stable GRPR-targeting radiopeptides, [ 177 Lu]Lu-PKB2 and [ 177 Lu]Lu-PKB3, with a high potential for targeted radionuclide therapy.

Source: EJNMMI Radiopharmacy and Chemistry

DOI: 10.1186/s41181-025-00402-2

Authors: Karim Obeid, Ekaterina Bezverkhniaia, Vladimir Tolmachev, Anna Orlova, Panagiotis Kanellopoulos

Institutions: Uppsala University, Science for Life Laboratory

Language: English

Topic: Radiopharmaceutical Chemistry and Applications

Subfield: Radiology, Nuclear Medicine and Imaging

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,290