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

## TL;DR

A new nickel-mediated chemical method enables efficient creation of 18F-labeled radiotracers for PET imaging and drug discovery.

## Contribution

A nickel-mediated cross-coupling method for late-stage diversification of 18F-radiopharmaceuticals is introduced.

## Key findings

- The method achieved up to 86% radiochemical conversion using amine-derived alkyl salts.
- Six 18F-labeled GSK-3 kinase inhibitor analogues were produced in sufficient quantities for imaging.
- The approach was successfully applied across three commercial radiosynthesis platforms.

## Abstract

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)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 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.

A general Ni‐mediated (C)sp2
–(C)sp3
cross‐coupling expedites access to 18F‐radiopharmaceuticals, essential for positron emission tomography imaging and drug discovery. This late‐stage diversification approach was implemented across three user‐friendly automated protocols affording 18F‐radiotracers in sufficient quantities for imaging. Tailored high‐throughput experimentation rapidly discovers radiochemically applicable reaction conditions.