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

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.