C–H Labeling with [18F]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., [18F]F2) are effective for C–H radiolabeling, state-of-the-art methodologies predominantly leverage high molar activity nucleophilic [18F]fluoride sources (e.g., [18F]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., SNAr, SN2 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.