C–H Labeling with [¹⁸F]Fluoride: An Emerging Methodology in Radiochemistry

Abstract

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., [ 18 F]F 2 ) are effective for C−H radiolabeling, state-ofthe-art methodologies predominantly leverage high molar activity nucleophilic [ 18 F]fluoride sources (e.g., [ 18 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., S N Ar, S N 2 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.