The ¹⁸F‐Difluoromethyl Group: Challenges, Impact and Outlook

Abstract

The difluoromethyl functionality has proven useful in drug discovery, as it can modulate the properties of bioactive molecules. For PET imaging, this structural motif has been largely underexploited in (pre)clinical radiotracers due to a lack of user-friendly radiosynthetic routes. This Minireview provides an overview of the challenges facing radiochemists and summarises the efforts made to date to access ¹⁸F-difluoromethyl-containing radiotracers. Two distinct approaches have prevailed, the first of which relies on ¹⁸F-fluorination. A second approach consists of a ¹⁸F-difluoromethylation process, which uses ¹⁸F-labelled reagents capable of releasing key reactive intermediates such as the [¹⁸F]CF₂H radical or [¹⁸F]difluorocarbene. Finally, we provide an outlook for future directions in the radiosynthesis of [¹⁸F]CF₂H compounds and their application in tracer radiosynthesis.