C-H Labeling with [F]Fluoride: An Emerging Methodology in Radiochemistry.

Fluorine-18 is the most routinely employed radioisotope for positron emission tomography, a dynamic nuclear imaging modality. The radiolabeling of C-H bonds is an attractive method for installing fluorine-18 into organic molecules since it can preclude the cumbersome prefunctionalization of requisite precursors. Although electrophilic "F" reagents (e.g., [F]F) are effective for C-H radiolabeling, state-of-the-art methodologies predominantly leverage high molar activity nucleophilic [F]fluoride sources (e.g., [F]KF) with substantial (pre)clinical advantages. Reflecting this, multiple nucleophilic C-H radiolabeling techniques of high utility have been disclosed over the past decade. However, the adoption of (pre)clinical C-H radiolabeling has been slow, and PET imaging agents are still routinely prepared via methods that, despite a high level of practicality, are limited in scope (e.g., SAr, S2 radiofluorinations). By addressing the drawbacks inherent to these strategies, C-H radiofluorination and radiofluoroalkylation carry the potential to complement and supersede state-of-the-art labeling methods, facilitating the expedited production of PET agents used in disease staging and drug development. In this Outlook, we showcase recent C-H labeling developments with fluorine-18 and discuss the merits, potential, and barriers to adoption in (pre)clinical settings. In addition, we highlight trends, challenges, and directions in this emerging field of study.