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Background <p>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 [<sup>18</sup>F]MeTz-PEG<sub>2</sub>-RM26, a GRPR antagonist which utilises the Inverse Electron Demand Diels-Alder (IEDDA) reaction for <sup>18</sup>F-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 [<sup>18</sup>F]MeTz-PEG<sub>2</sub>-RM26 were evaluated in vitro using GRPR-expressing PC-3 cells. Furthermore, the biodistribution profile of [<sup>18</sup>F]MeTz-PEG<sub>2</sub>-RM26 was assessed in NMRI mice and its tumour-targeting capability was investigated in mice bearing PC-3 xenografts.</p> Results <p>The labelling of TCO-PEG<sub>2</sub>-RM26 precursor involved three steps: (1) synthesis of an <sup>18</sup>F-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-PEG<sub>2</sub>-RM26 via an IEDDA click reaction. This production method of [<sup>18</sup>F]MeTz-PEG<sub>2</sub>-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&#xa0;min. Both in vitro and in vivo studies confirmed the specific binding of [<sup>18</sup>F]MeTz-PEG<sub>2</sub>-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&#xa0;h post-injection) 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 [<sup>18</sup>F]MeTz-PEG<sub>2</sub>-RM26.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月26日

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

摘要

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 post-injection) 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.