Closing the gap between (19)F and (18)F chemistry

Positron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to (18)F-labelled radiotracers can make a direct impact in medicine. For many years, access to (18)F-labelled radiotracers was limited by the paucity of methodologies available, and the poor diversity of precursors amenable to (18)F-incorporation. During the last two decades, (18)F-radiochemistry has progressed at a fast pace with the appearance of numerous methodologies for late-stage (18)F-incorporation onto complex molecules from a range of readily available precursors including those that do not require pre-functionalisation. Key to these advances is the inclusion of new activation modes to facilitate (18)F-incorporation. Specifically, new advances in late-stage (19)F-fluorination under transition metal catalysis, photoredox catalysis, and organocatalysis combined with the availability of novel (18)F-labelled fluorination reagents have enabled the invention of novel processes for (18)F-incorporation onto complex (bio)molecules. This review describes these major breakthroughs with a focus on methodologies for C–(18)F bond formation. This reinvigorated interest in (18)F-radiochemistry that we have witnessed in recent years has made a direct impact on (19)F-chemistry with many laboratories refocusing their efforts on the development of methods using nucleophilic fluoride instead of fluorination reagents derived from molecular fluorine gas.