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

Journal article

The development of 18F‐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)sp2‐(C)sp3 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 18F‐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.

Authors: Ogilvy, IF; Ford, J; Ortalli, S; Renders, E; Hayes, TR

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie
• Article number: e22650
• Publication date: 2025-12-04
• Acceptance date: 2025-11-25
• DOI: 10.1002/ange.202522650
• EISSN: 1521-3757
• ISSN: 0044-8249
• Language: English
• Keywords: Fluorine; Radiochemistry; High‐throughput screening; Synthetic methods; Cross‐coupling