Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way. Here we disclose a method for constructing C–18F bonds through direct halide/18F conversion in electron-rich halo(hetero)arenes. [18F]F− is introduced into a broad spectrum of readily available aryl halide precursors in a site-selective manner under mild photoredox conditions. Notably, our direct 19F/18F exchange method enables rapid PET probe diversification through the preparation and evaluation of an [18F]-labelled O-methyl tyrosine library. This strategy also results in the high-yielding synthesis of the widely used PET agent l-[18F]FDOPA from a readily available l-FDOPA analogue.
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This work was supported in part by the National Institutes of Health (NIBIB) grants R01EB029451 (Z.L. and D.A.N.) and 5R01CA233904 (Z.L.), UNC LCCC pilot grant (Z.L. and D.A.N.), grant 1S10OD023611 (Z.L.) and the startup fund from UNC Department of Radiology, Biomedical Research Imaging Center, and UNC Lineberger Comprehensive Cancer Center (Z.L.). N.E.S.T. and V.A.P are grateful for NSF Graduate Research Fellowships. We thank G. T. Bida for assistance with cyclotron operation, X. Wu for NMR data collection and the University of North Carolina’s Department of Chemistry Mass Spectrometry Core Laboratory, especially D. Weatherspoon, for their assistance with mass spectrometry analysis.
The authors Z.L., D.A.N. and W.C. have filed a WO patent (patent applicant, The University of North Carolina at Chapel Hill, USA; inventors, Z. Li, D. Nicewicz and W. Chen; patent no. WO 2020176804) related to the labelling methodology in this manuscript and is under review. The remaining authors declare no competing interests.
Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.
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Chen, W., Wang, H., Tay, N.E.S. et al. Arene radiofluorination enabled by photoredox-mediated halide interconversion. Nat. Chem. 14, 216–223 (2022). https://doi.org/10.1038/s41557-021-00835-7