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Arene radiofluorination enabled by photoredox-mediated halide interconversion

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Abstract

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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Fig. 1: Nucleophilic arene 18F-fluorination.
Fig. 2: Chemo- and regioselectivity study of photoredox-mediated aryl halide/18F interconversion.
Fig. 3: Radiofluorination of potential bioactive compounds through halide/18F interconversion.
Fig. 4: Exploration of 18F-labelled O-methyl tyrosines as PET agents in an MCF-7 tumour model.
Fig. 5: Synthesis of [18F]FDOPA.

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Data availability

All data generated or analysed during this study are included in this Article (and its Supplementary Information files). The PET imaging data of the animal study have been deposited to the public repository Zenodo61.

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Acknowledgements

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.

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Authors and Affiliations

  1. Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Wei Chen, Hui Wang, Kang-Po Li, Tao Zhang, Zhanhong Wu & Zibo Li

  2. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Nicholas E. S. Tay, Vincent A. Pistritto & David A. Nicewicz

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  1. Wei Chen
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  2. Hui Wang
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  3. Nicholas E. S. Tay
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Contributions

W.C. originated the halides/18F conversion project, prepared the substrates and 19F-standards and performed the radiolabelling reactions. H.W. conducted the animal imaging studies and performed PET imaging data collection and analysis. N.E.S.T. was involved in the discovery of the 19F/18F exchange reaction. V.A.P. and K.-P.L. assisted in the synthesis and analysis of substrates. T.Z. assisted in the animal studies. Z.W. contributed to the initial discussion. D.A.N. and Z.L. conceived and supervised the project and experiments. W.C., D.A.N. and Z.L. wrote the manuscript. N.E.S.T. and V.A.P. assisted in editing the manuscript.

Corresponding authors

Correspondence to David A. Nicewicz or Zibo Li.

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Competing interests

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.

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Supplementary Information

Substrates and standards preparation, general experiment procedures, Supplementary Figs. 1–140, Tables 1–83 and NMR spectra.

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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

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