Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Arene radiofluorination enabled by photoredox-mediated halide interconversion

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

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.

References

  1. Ametamey, S. M., Honer, M. & Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 108, 1501–1516 (2008).

    CAS  PubMed  Google Scholar 

  2. Pike, V. W. PET radiotracers: crossing the blood-brain barrier and surviving metabolism. Trends Pharmacol. Sci. 30, 431–440 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Deng, X. Y. et al. Chemistry for positron emission tomography: recent advances in 11C-, 18F-, 13N- and 15O-labeling reactions. Angew. Chem. Int. Ed. 58, 2580–2605 (2019).

    CAS  Google Scholar 

  4. Aldeghi, M., Malhotra, S., Selwood, D. L. & Chan, A. W. Two- and three-dimensional rings in drugs. Chem. Biol. Drug Des. 83, 450–461 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Taylor, R. D., MacCoss, M. & Lawson, A. D. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).

    CAS  PubMed  Google Scholar 

  6. Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 61, 5822–5880 (2018).

    CAS  PubMed  Google Scholar 

  7. Zhou, Y. et al. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 116, 422–518 (2016).

    CAS  PubMed  Google Scholar 

  8. Jacobson, O., Kiesewetter, D. O. & Chen, X. Y. Fluorine-18 radiochemistry, labeling strategies and synthetic routes. Bioconjug. Chem. 26, 1–18 (2015).

    CAS  PubMed  Google Scholar 

  9. Preshlock, S., Tredwell, M. & Gouverneur, V. 18F-Labeling of arenes and heteroarenes for applications in positron emission tomography. Chem. Rev. 116, 719–766 (2016).

    CAS  PubMed  Google Scholar 

  10. van der Born, D. et al. Fluorine-18 labelled building blocks for PET tracer synthesis. Chem. Soc. Rev. 46, 4709–4773 (2017).

    PubMed  Google Scholar 

  11. Krishnan, H. S., Ma, L. L., Vasdev, N. & Liang, S. H. 18F-Labeling of sensitive biomolecules for positron emission tomography. Chem. Eur. J. 23, 15553–15577 (2017).

    CAS  PubMed  Google Scholar 

  12. Ding, Y. S. et al. Synthesis of high specific activity 6-[18F]fluorodopamine for positron emission tomography studies of sympathetic nervous-tissue. J. Med. Chem. 34, 861–863 (1991).

    CAS  PubMed  Google Scholar 

  13. Cai, L. S., Lu, S. Y. & Pike, V. W. Chemistry with [18F]fluoride ion. Eur. J. Org. Chem. 2008, 2853–2873 (2008).

    Google Scholar 

  14. Cole, E. L., Stewart, M. N., Littich, R., Hoareau, R. & Scott, P. J. H. Radiosyntheses using fluorine-18: the art and science of late stage fluorination. Curr. Top. Med. Chem. 14, 875–900 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Adams, D. J. & Clark, J. H. Nucleophilic routes to selectively fluorinated aromatics. Chem. Soc. Rev. 28, 225–231 (1999).

    CAS  Google Scholar 

  16. Brooks, A. F., Topczewski, J. J., Ichiishi, N., Sanford, M. S. & Scott, P. J. Late-stage [18F]fluorination: new solutions to old problems. Chem. Sci. 5, 4545–4553 (2014).

    CAS  PubMed  Google Scholar 

  17. Lee, E. et al. A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging. Science 334, 639–642 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee, E., Hooker, J. M. & Ritter, T. Nickel-mediated oxidative fluorination for PET with aqueous [18F] fluoride. J. Am. Chem. Soc. 134, 17456–17458 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Tredwell, M. et al. A general copper-mediated nucleophilic 18F fluorination of arenes. Angew. Chem. Int. Ed. 53, 7751–7755 (2014).

    CAS  Google Scholar 

  20. Taylor, N. J. et al. Derisking the Cu-mediated 18F-fluorination of heterocyclic positron emission tomography radioligands. J. Am. Chem. Soc. 139, 8267–8276 (2017).

    CAS  PubMed  Google Scholar 

  21. Guibbal, F. et al. Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [18F]olaparib. Nat. Protoc. 15, 1525–1541 (2020).

    CAS  PubMed  Google Scholar 

  22. Chun, J. H., Lu, S. Y., Lee, Y. S. & Pike, V. W. Fast and high-yield microreactor syntheses of ortho-substituted [18F]fluoroarenes from reactions of [18F]fluoride ion with diaryliodonium salts.J. Org. Chem. 75, 3332–3338 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ichiishi, N. et al. Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts. Org. Lett. 16, 3224–3227 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mossine, A. V. et al. Synthesis of [18F]arenes via the copper-mediated [18F]fluorination of boronic acids. Org. Lett. 17, 5780–5783 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Makaravage, K. J., Brooks, A. F., Mossine, A. V., Sanford, M. S. & Scott, P. J. H. Copper-mediated radiofluorination of arylstannanes with [18F]KF. Org. Lett. 18, 5440–5443 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. McCammant, M. S. et al. Cu-mediated C–H 18F-fluorination of electron-rich (hetero)arenes. Org. Lett. 19, 3939–3942 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rotstein, B. H., Stephenson, N. A., Vasdev, N. & Liang, S. H. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat. Commun. 5, 4365 (2014).

    CAS  PubMed  Google Scholar 

  28. Liang, S. H., Wang, L., Stephenson, N. A., Rotstein, B. H. & Vasdev, N. Facile 18F labeling of non-activated arenes via a spirocyclic iodonium(III) ylide method and its application in the synthesis of the mGluR5 PET radiopharmaceutical [18F] FPEB. Nat. Protoc. 14, 1530–1545 (2019).

    CAS  PubMed  Google Scholar 

  29. Gendron, T. et al. Ring-closing synthesis of dibenzothiophene sulfonium salts and their use as leaving groups for aromatic 18F-fluorination. J. Am. Chem. Soc. 140, 11125–11132 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Neumann, C. N., Hooker, J. M. & Ritter, T. Concerted nucleophilic aromatic substitution with 19F and 18F. Nature 534, 369–373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Xu, P. et al. Site-selective late-stage aromatic [18F]fluorination via aryl sulfonium salts. Angew. Chem. Int. Ed. 59, 1956–1960 (2020).

    CAS  Google Scholar 

  32. Tay, N. E. S. et al. 19F- and 18F-arene deoxyfluorination via organic photoredox-catalysed polarity-reversed nucleophilic aromatic substitution. Nat. Catal. 3, 734–742 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hoover, A. J. et al. A transmetalation reaction enables the synthesis of [18F]5-fluorouracil from [18F]fluoride for human PET imaging. Organometallics 35, 1008–1014 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sharninghausen, L. S. et al. NHC-copper mediated ligand-directed radiofluorination of aryl halides. J. Am. Chem. Soc. 142, 7362–7367 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Fang, W. Y. et al. Synthetic approaches and pharmaceutical applications of chloro-containing molecules for drug discovery: a critical review. Eur. J. Med. Chem. 173, 117–153 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Langer, O. et al. Synthesis of fluorine-18-labeled ciprofloxacin for PET studies in humans. Nucl. Med. Biol. 30, 285–291 (2003).

    CAS  PubMed  Google Scholar 

  37. Rokka, J. et al. 19F/18F exchange synthesis for a novel [18F]S1P3-radiopharmaceutical. J. Labelled Compd Radiopharm. 56, 385–391 (2013).

    CAS  Google Scholar 

  38. Chen, W. et al. Direct arene C–H fluorination with 18F via organic photoredox catalysis. Science 364, 1170–1174 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zweig, A., Hodgson, W. G. & Jura, W. H. The oxidation of methoxybenzenes. J. Am. Chem. Soc. 86, 4124–4129 (1964).

    CAS  Google Scholar 

  40. Blom, E., Karimi, F. & Langstrom, B. [18F]/19F exchange in fluorine containing compounds for potential use in 18F-labelling strategies. J. Labelled Compd Radiopharm. 52, 504–511 (2009).

    CAS  Google Scholar 

  41. Wagner, F. M., Ermert, J. & Coenen, H. H. Three-step, ‘one-pot’ radiosynthesis of 6-fluoro-3,4-dihydroxy-l-phenylalanine by isotopic exchange. J. Nucl. Med. 50, 1724–1729 (2009).

    CAS  PubMed  Google Scholar 

  42. Weiss, P. S., Ermert, J., Melean, J. C., Schafer, D. & Coenen, H. H. Radiosynthesis of 4-[18F]fluoro-l-tryptophan by isotopic exchange on carbonyl-activated precursors. Bioorg. Med. Chem. 23, 5856–5869 (2015).

    CAS  PubMed  Google Scholar 

  43. Tay, N. E. S. & Nicewicz, D. A. Cation radical accelerated nucleophilic aromatic substitution via organic photoredox catalysis. J. Am. Chem. Soc. 139, 16100–16104 (2017).

    CAS  PubMed  Google Scholar 

  44. Holmberg-Douglas, N. & Nicewicz, D. A. Arene cyanation via cation-radical accelerated-nucleophilic aromatic substitution. Org. Lett. 21, 7114–7118 (2019).

    CAS  PubMed  Google Scholar 

  45. Venditto, N. J. & Nicewicz, D. A. Cation radical-accelerated nucleophilic aromatic substitution for amination of alkoxyarenes. Org. Lett. 22, 4817–4822 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Shewchuk, L. et al. Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase. J. Med. Chem. 43, 133–138 (2000).

    CAS  PubMed  Google Scholar 

  47. Werry, E. L. et al. Recent developments in TSPO PET imaging as a biomarker of neuroinflammation in neurodegenerative disorders. Int. J. Mol. Sci. 20, 3161 (2019).

    CAS  PubMed Central  Google Scholar 

  48. Wang, Q. & Holst, J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am. J. Cancer Res. 5, 1281–1294 (2015).

    PubMed  PubMed Central  Google Scholar 

  49. Qi, Y. Q., Liu, X. H., Li, J., Yao, H. Q. & Yuan, S. H. Fluorine-18 labeled amino acids for tumor PET/CT imaging. Oncotarget 8, 60581–60588 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Kuchar, M. & Mamat, C. Methods to increase the metabolic stability of 18F-radiotracers. Molecules 20, 16186–16220 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee, S. L. Radioactive iodine therapy. Curr. Opin. Endocrinol. Diabetes Obes. 19, 420–428 (2012).

    CAS  PubMed  Google Scholar 

  52. Barth, R. F., Mi, P. & Yang, W. Boron delivery agents for neutron capture therapy of cancer. Cancer Commun. 38, 35 (2018).

    Google Scholar 

  53. Garnett, E. S., Firnau, G. & Nahmias, C. Dopamine visualized in the basal ganglia of living man. Nature 305, 137–138 (1983).

    CAS  PubMed  Google Scholar 

  54. Pretze, M., Wängler, C. & Wängler, B. 6-[18F]fluoro-L-DOPA: a well-established neurotracer with expanding application spectrum and strongly improved radiosyntheses. BioMed. Res. Int. 2014, e674063 (2014).

    Google Scholar 

  55. Libert, L. C. et al. Production at the Curie level of no-carrier-added 6-18F-fluoro-l-DOPA. J. Nucl. Med. 54, 1154–1161 (2013).

    CAS  PubMed  Google Scholar 

  56. Luurtsema, G. et al. Improved GMP-compliant multi-dose production and quality control of 6-[18F]fluoro-l-DOPA. EJNMMI Radiopharm. Chem. 1, 7 (2017).

    CAS  PubMed  Google Scholar 

  57. Mossine, A. V. et al. Synthesis of high-molar-activity [18F]6-fluoro-l-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor. Nat. Protoc. 15, 1742–1759 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Orlovskaya, V., Fedorova, O., Kuznetsova, O. & Krasikova, R. Cu-mediated radiofluorination of aryl pinacolboronate esters: alcohols as solvents with application to 6-l-[18F]FDOPA synthesis. Eur. J. Org. Chem. 2020, 7079–7086 (2020).

    CAS  Google Scholar 

  59. Krasikova, R. N. Nucleophilic synthesis of 6-l-[18F]FDOPA. Is copper-mediated radiofluorination the answer? Molecules 25, 4365 (2020).

    CAS  PubMed Central  Google Scholar 

  60. Luxen, A. et al. Production of 6-[18F]fluoro-l-DOPA and its metabolism in vivo—a critical-review. Int. J. Rad. Appl. Instrum. B 19, 149–158 (1992).

    CAS  PubMed  Google Scholar 

  61. Chen, W. et al. Arene Radiofluorination Enabled by Photoredox-Mediated Halide Interconversion (Zenodo, 2021); https://doi.org/10.5281/zenodo.5220725

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

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.

Additional information

Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary Information

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

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-021-00835-7

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing