18 F‐Radiopharmaceutical Diversification Enabled by Deaminative Cross‐Electrophile Couplings

作者：Isabella F. Ogilvy, Joseph Ford, Sebastiano Ortalli, Evelien Renders, Thomas R. Hayes, Zibo Li, Inne Mortiers, Anastasia Nikolopoulou, Alexandre M. Sorlin, Andrés A. Trabanco, Matthew Tredwell, Peter Buijnsters, Rhys Salter, Véronique Gouverneur · 发表于：Angewandte Chemie International Edition · 年份：2025 · DOI：10.1002/anie.202522650 · 被引用次数：2 · 研究领域：Radiopharmaceutical Chemistry and Applications、Medical Imaging Techniques and Applications、Click Chemistry and Applications

Abstract The development of 18 F‐labelled radiotracers is of vital importance for (pre)clinical positron emission tomography (PET) imaging and to guide drug discovery campaigns. State‐of‐the‐art approaches often require labour‐intensive preparation of highly functionalised radiolabelling precursors. This bottleneck impedes analogue generation for optimal imaging and exploration of radiochemical space. To this end, we disclose a nickel‐mediated aryl (C) sp 2 ‐(C) sp 3 cross‐coupling with amine‐derived alkyl 2,4,6‐triphenylpyridinium salts as coupling partners amenable to radiosynthesis. The method was applied to primary and secondary 2,4,6‐triphenylpyridinium salts in radiochemical conversion (RCC) up to 86% and a high‐throughput experimentation (HTE) assay proved crucial for expedient ligand evaluation. A late‐stage diversification case study from a sole precursor achieved six 18 F‐labelled GSK‐3 kinase inhibitor analogues, one being prepared in up to gigabecquerel (GBq) quantities in a (semi)automated two‐step protocol applied across three commercial radiosynthesis platforms.