Products Cited in Publications Worldwide Synthesis and preclinical evaluation of gastrin releasing peptide receptor antagonist [18F] MeTz-PEG2-RM26 for positron emission tomography

Synthesis and preclinical evaluation of gastrin releasing peptide receptor antagonist [18F] MeTz-PEG2-RM26 for positron emission tomography

Kanellopoulos, Panagiotis; Lundmark, Fanny; Abouzayed, Ayman; Balestri, Lorenzo Jacopo Ilic; Håkansson, Esther Olaniran; Obeid, Karim; Odell, Luke R; Tolmachev, Vladimir; Rosenström, Ulrika; Eriksson, Jonas

DOI:

Abstract

Background: The gastrin-releasing peptide receptor (GRPR) is overexpressed in the majority of primary prostate cancer lesions, with persistent expression in lymph nodes and bone metastases, making it a legitimate molecular target for diagnostic imaging and staging. This study presents the synthesis and preclinical evaluation of [18F]MeTz-PEG2-RM26, a GRPR antagonist which utilises the Inverse Electron Demand Diels-Alder (IEDDA) reaction for 18F-labelling. This click-chemistry approach allows for site-specific incorporation of fluorine-18 under mild conditions, preserving the peptide's structural integrity and biological activity. Receptor specificity and affinity of [18F]MeTz-PEG2-RM26 were evaluated in vitro using GRPR-expressing PC-3 cells. Furthermore, the biodistribution profile of [18F]MeTz-PEG2-RM26 was assessed in NMRI mice and its tumour-targeting capability was investigated in mice bearing PC-3 xenografts. Results: The labelling of TCO-PEG2-RM26 precursor involved three steps: (1) synthesis of an 18F-labelled activated ester on a quaternary methyl ammonium (QMA) cartridge, (2) conjugation of the labelled ester to a tetrazine amine, and (3) attachment to TCO-PEG2-RM26 via an IEDDA click reaction. This production method of [18F] MeTz-PEG2-RM26 afforded a high apparent molar activity of 3.5–4.3 GBq/µmol and radiochemical purity exceeding 98%, with 43–70 MBq activity incorporation, while the entire synthesis was completed within 75 min. Both in vitro and in vivo studies confirmed the specific binding of [18F]MeTz-PEG2-RM26 to GRPR, with a significant reduction in activity uptake observed upon receptor saturation. The radioligand exhibited rapid blood clearance and minimal bone uptake, confirming the stability of the fluorine-carbon bond. However, high hepatic uptake (12–13% IA/g at 1 h postinjection) indicated predominant hepatobiliary excretion. Receptor-mediated uptake was observed in the tumours and pancreatic tissue, although the overall activity uptake in tumours was low, likely due to the rapid hepatobiliary clearance of [18F] MeTz-PEG2-RM26. Conclusions: These findings demonstrate the effectiveness of the IEDDA click reaction for fluorine-18 labelling of GRPR-targeting PET tracers. Future studies should focus on increasing the hydrophilicity of the imaging probe to improve the targeting properties and biodistribution profile of the radioligand.

Keywords

Fluorine-18 ; TCO ; Tetrazine ; IEDDA click chemistry ; GRPR ; Bombesin ; PET ; Prostate cancer

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