The 18 F-Difluoromethyl Group: Challenges, Impact and Outlook.

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 18 F-difluoromethyl-containing radiotracers. Two distinct approaches have prevailed, the first of which relies on 18 F-fluorination. A second approach consists of a 18 F-difluoromethylation process, which uses 18 F-labelled reagents capable of releasing key reactive intermediates such as the [ 18 F]CF 2 H radical or [ 18 F]difluorocarbene. Finally, we provide an outlook for future directions in the radiosynthesis of [ 18 F]CF 2 H compounds and their application in tracer radiosynthesis.