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., [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., S_NAr, S_N2 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.

Figure 1

Utility of [¹¹C]PiB positron emission tomography in human clinical trials toward the development of Alzheimer’s therapeutics.

Scheme 1. Electrophilic C–H Radiofluorination. 1-18F

Scheme 2. Mechanism of Decatungstate-Mediated Electrophilic C–H Radiofluorination

Scheme 3. Direct sp² C–H Fluorine-18 Labeling Reactions

Scheme 4. Direct sp² C–H Electrochemical Radiofluorination

Scheme 5. Photochemical C–H Radiofluorination Mediated by 9, with Plausible Mechanism

O₂ may induce rearomatization.

Scheme 6. Photochemical C–H Radiofluoroalkylation Starting from 11, with Plausible Mechanism

Sulfinate byproduct may be produced.

Scheme 7. Sequential C–H Radiofluorination Protocols

Scheme 8. Multistep sp² C–H Radiofluorination Methodologies

Scheme 9. Directed Radiofluorination of sp³ C–H Bonds

Scheme 10. Manganese-Mediated Radiofluorination of sp³ C–H Bonds

Scheme 11. Directed Radiofluorination of sp³ C–H Bonds

Scheme 12. Electrochemical sp³ C–H Radiofluorination