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 Cā18F bonds through direct halide/18F conversion in electron-rich halo(hetero)arenes. [18F]Fā 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
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 /Ā 30Ā days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
Ametamey, S. M., Honer, M. & Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 108, 1501ā1516 (2008).
Pike, V. W. PET radiotracers: crossing the blood-brain barrier and surviving metabolism. Trends Pharmacol. Sci. 30, 431ā440 (2009).
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, 2580ā2605 (2019).
Aldeghi, M., Malhotra, S., Selwood, D. L. & Chan, A. W. Two- and three-dimensional rings in drugs. Chem. Biol. Drug Des. 83, 450ā461 (2014).
Taylor, R. D., MacCoss, M. & Lawson, A. D. Rings in drugs. J. Med. Chem. 57, 5845ā5859 (2014).
Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 61, 5822ā5880 (2018).
Zhou, Y. et al. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase IIāIII clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 116, 422ā518 (2016).
Jacobson, O., Kiesewetter, D. O. & Chen, X. Y. Fluorine-18 radiochemistry, labeling strategies and synthetic routes. Bioconjug. Chem. 26, 1ā18 (2015).
Preshlock, S., Tredwell, M. & Gouverneur, V. 18F-Labeling of arenes and heteroarenes for applications in positron emission tomography. Chem. Rev. 116, 719ā766 (2016).
van der Born, D. et al. Fluorine-18 labelled building blocks for PET tracer synthesis. Chem. Soc. Rev. 46, 4709ā4773 (2017).
Krishnan, H. S., Ma, L. L., Vasdev, N. & Liang, S. H. 18F-Labeling of sensitive biomolecules for positron emission tomography. Chem. Eur. J. 23, 15553ā15577 (2017).
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, 861ā863 (1991).
Cai, L. S., Lu, S. Y. & Pike, V. W. Chemistry with [18F]fluoride ion. Eur. J. Org. Chem. 2008, 2853ā2873 (2008).
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, 875ā900 (2014).
Adams, D. J. & Clark, J. H. Nucleophilic routes to selectively fluorinated aromatics. Chem. Soc. Rev. 28, 225ā231 (1999).
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, 4545ā4553 (2014).
Lee, E. et al. A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging. Science 334, 639ā642 (2011).
Lee, E., Hooker, J. M. & Ritter, T. Nickel-mediated oxidative fluorination for PET with aqueous [18F] fluoride. J. Am. Chem. Soc. 134, 17456ā17458 (2012).
Tredwell, M. et al. A general copper-mediated nucleophilic 18F fluorination of arenes. Angew. Chem. Int. Ed. 53, 7751ā7755 (2014).
Taylor, N. J. et al. Derisking the Cu-mediated 18F-fluorination of heterocyclic positron emission tomography radioligands. J. Am. Chem. Soc. 139, 8267ā8276 (2017).
Guibbal, F. et al. Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [18F]olaparib. Nat. Protoc. 15, 1525ā1541 (2020).
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, 3332ā3338 (2010).
Ichiishi, N. et al. Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts. Org. Lett. 16, 3224ā3227 (2014).
Mossine, A. V. et al. Synthesis of [18F]arenes via the copper-mediated [18F]fluorination of boronic acids. Org. Lett. 17, 5780ā5783 (2015).
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, 5440ā5443 (2016).
McCammant, M. S. et al. Cu-mediated CāH 18F-fluorination of electron-rich (hetero)arenes. Org. Lett. 19, 3939ā3942 (2017).
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).
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, 1530ā1545 (2019).
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, 11125ā11132 (2018).
Neumann, C. N., Hooker, J. M. & Ritter, T. Concerted nucleophilic aromatic substitution with 19Fā and 18Fā. Nature 534, 369ā373 (2016).
Xu, P. et al. Site-selective late-stage aromatic [18F]fluorination via aryl sulfonium salts. Angew. Chem. Int. Ed. 59, 1956ā1960 (2020).
Tay, N. E. S. et al. 19F- and 18F-arene deoxyfluorination via organic photoredox-catalysed polarity-reversed nucleophilic aromatic substitution. Nat. Catal. 3, 734ā742 (2020).
Hoover, A. J. et al. A transmetalation reaction enables the synthesis of [18F]5-fluorouracil from [18F]fluoride for human PET imaging. Organometallics 35, 1008ā1014 (2016).
Sharninghausen, L. S. et al. NHC-copper mediated ligand-directed radiofluorination of aryl halides. J. Am. Chem. Soc. 142, 7362ā7367 (2020).
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, 117ā153 (2019).
Langer, O. et al. Synthesis of fluorine-18-labeled ciprofloxacin for PET studies in humans. Nucl. Med. Biol. 30, 285ā291 (2003).
Rokka, J. et al. 19F/18F exchange synthesis for a novel [18F]S1P3-radiopharmaceutical. J. Labelled Compd Radiopharm. 56, 385ā391 (2013).
Chen, W. et al. Direct arene CāH fluorination with 18Fā via organic photoredox catalysis. Science 364, 1170ā1174 (2019).
Zweig, A., Hodgson, W. G. & Jura, W. H. The oxidation of methoxybenzenes. J. Am. Chem. Soc. 86, 4124ā4129 (1964).
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, 504ā511 (2009).
Wagner, F. M., Ermert, J. & Coenen, H. H. Three-step, āone-potā radiosynthesis of 6-fluoro-3,4-dihydroxy-l-phenylalanine by isotopic exchange. J. Nucl. Med. 50, 1724ā1729 (2009).
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, 5856ā5869 (2015).
Tay, N. E. S. & Nicewicz, D. A. Cation radical accelerated nucleophilic aromatic substitution via organic photoredox catalysis. J. Am. Chem. Soc. 139, 16100ā16104 (2017).
Holmberg-Douglas, N. & Nicewicz, D. A. Arene cyanation via cation-radical accelerated-nucleophilic aromatic substitution. Org. Lett. 21, 7114ā7118 (2019).
Venditto, N. J. & Nicewicz, D. A. Cation radical-accelerated nucleophilic aromatic substitution for amination of alkoxyarenes. Org. Lett. 22, 4817ā4822 (2020).
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, 133ā138 (2000).
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).
Wang, Q. & Holst, J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am. J. Cancer Res. 5, 1281ā1294 (2015).
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, 60581ā60588 (2017).
Kuchar, M. & Mamat, C. Methods to increase the metabolic stability of 18F-radiotracers. Molecules 20, 16186ā16220 (2015).
Lee, S. L. Radioactive iodine therapy. Curr. Opin. Endocrinol. Diabetes Obes. 19, 420ā428 (2012).
Barth, R. F., Mi, P. & Yang, W. Boron delivery agents for neutron capture therapy of cancer. Cancer Commun. 38, 35 (2018).
Garnett, E. S., Firnau, G. & Nahmias, C. Dopamine visualized in the basal ganglia of living man. Nature 305, 137ā138 (1983).
Pretze, M., WƤngler, C. & WƤngler, B. 6-[18F]fluoro-L-DOPA: a well-established neurotracer with expanding application spectrum and strongly improved radiosyntheses. BioMed. Res. Int. 2014, e674063 (2014).
Libert, L. C. et al. Production at the Curie level of no-carrier-added 6-18F-fluoro-l-DOPA. J. Nucl. Med. 54, 1154ā1161 (2013).
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).
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, 1742ā1759 (2020).
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, 7079ā7086 (2020).
Krasikova, R. N. Nucleophilic synthesis of 6-l-[18F]FDOPA. Is copper-mediated radiofluorination the answer? Molecules 25, 4365 (2020).
Luxen, A. et al. Production of 6-[18F]fluoro-l-DOPA and its metabolism in vivoāa critical-review. Int. J. Rad. Appl. Instrum. B 19, 149ā158 (1992).
Chen, W. et al. Arene Radiofluorination Enabled by Photoredox-Mediated Halide Interconversion (Zenodo, 2021); https://doi.org/10.5281/zenodo.5220725
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 Carolinaās Department of Chemistry Mass Spectrometry Core Laboratory, especially D. Weatherspoon, for their assistance with mass spectrometry analysis.
Author information
Authors and Affiliations
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
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.
Publisherās 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. 1ā140, Tables 1ā83 and NMR spectra.
Rights and permissions
About this article
Cite this article
Chen, W., Wang, H., Tay, N.E.S. et al. Arene radiofluorination enabled by photoredox-mediated halide interconversion. Nat. Chem. 14, 216ā223 (2022). https://doi.org/10.1038/s41557-021-00835-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41557-021-00835-7
This article is cited by
-
Radiochemistry for positron emission tomography
Nature Communications (2023)
