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[18F]Difluorocarbene for positron emission tomography


The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O–H, S–H and N–H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

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Fig. 1: Difluorocarbene chemistry, radiosynthesis and divergent reactivity of [18F]1.
Fig. 2: Scope of [18F]OCF2H, [18F]SCF2H and [18F]NCF2H from (thio)phenols and N-heterocycles.
Fig. 3: Scope of [18F]OCF2H and [18F]NCF2H.
Fig. 4: Scope of [18F]ArCF2H.

Data availability

Materials and methods, optimization studies, experimental procedures, mechanistic studies, 1H NMR, 13C NMR and 19F NMR spectra, and high-resolution mass spectrometry, infrared and HPLC data are available in the Supplementary Information.


  1. Reardon, S. Whole-body PET scanner produces 3D images in seconds. Nature 570, 285–287 (2019).

    Article  CAS  PubMed  ADS  Google Scholar 

  2. Ajenjo, J., Destro, G., Cornelissen, B. & Gouverneur, V. Closing the gap between 19F and 18F chemistry. EJNMMI Radiopharm. Chem. 6, 33 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sap, J. B. et al. Late-stage difluoromethylation: concepts, developments and perspective. Chem. Soc. Rev. 50, 8214–8247 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Buchner, E. & Curtius, T. Ueber die Einwirkung von Diazoessigäther auf aromatische Kohlenwasserstoffe. Ber. Dtsch. Chem. Ges. 18, 2377–2379 (1885).

    Article  Google Scholar 

  5. Staudinger, H. & Kupfer, O. Über reaktionen des methylens. III. Diazomethan. Ber. Dtsch. Chem. Ges. 45, 501–509 (1912).

    Article  CAS  Google Scholar 

  6. Hopkinson, M. N., Richter, C., Schedler, M. & Glorius, F. An overview of N-heterocyclic carbenes. Nature 510, 485–496 (2014).

    Article  CAS  PubMed  ADS  Google Scholar 

  7. Geri, J. B. et al. Microenvironment mapping via Dexter energy transfer on immune cells. Science 367, 1091–1097 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  8. Marinelli, M., Santini, C. & Pellei, M. Recent advances in medicinal applications of coinage-metal (Cu and Ag) N-heterocyclic carbene complexes. Curr. Top. Med. Chem. 16, 2995–3017 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Smith, C. A. et al. N-heterocyclic carbenes in materials chemistry. Chem. Rev. 119, 4986–5056 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Campbell, M. G. et al. Bridging the gaps in 18F PET tracer development. Nat. Chem. 9, 1–3 (2017).

    Article  CAS  Google Scholar 

  11. Deng, X. 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).

    Article  CAS  Google Scholar 

  12. McCluskey, S. P., Plisson, C., Rabiner, E. A. & Howes, O. Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development. Eur. J. Nucl. Med. Mol. Imaging 47, 451–489 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Prchalová, E., Štěpánek, O., Smrček, S. & Kotora, M. Medicinal applications of perfluoroalkylated chain-containing compounds. Future Med. Chem. 6, 1201–1229 (2014).

    Article  PubMed  CAS  Google Scholar 

  14. Huiban, M. et al. A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. Nat. Chem. 5, 941–944 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Levin, M. D. et al. A catalytic fluoride-rebound mechanism for C(sp3)–CF3 bond formation. Science 356, 1272–1276 (2017).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  16. van der Born, D. et al. A universal procedure for the [18F]trifluoromethylation of aryl iodides and aryl boronic acids with highly improved specific activity. Angew. Chem. Int. Ed. 53, 11046–11050 (2014).

    Article  CAS  Google Scholar 

  17. Mizuta, S. et al. Catalytic decarboxylative fluorination for the synthesis of tri-and difluoromethyl arenes. Org. Lett. 15, 2648–2651 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Verhoog, S. et al. Silver-mediated 18F-labeling of aryl–CF3 and aryl–CHF2 with 18F-fluoride. Synlett 27, 25–28 (2016).

    CAS  Google Scholar 

  19. Shi, H. et al. Synthesis of 18F‐difluoromethylarenes from aryl (pseudo) halides. Angew. Chem. Int. Ed. 55, 10786–10790 (2016).

    Article  CAS  Google Scholar 

  20. Yuan, G. et al. Metal-free 18F-labeling of aryl–CF2H via nucleophilic radiofluorination and oxidative C–H activation. Chem. Commun. 53, 126–129 (2017).

    Article  CAS  Google Scholar 

  21. Sap, J. B. et al. Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride. Chem. Sci. 10, 3237–3241 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhao, Q. et al. Radiosynthesis of [18F]arylSCF2H using aryl boronic acids, S-(chlorofluoromethyl) benzenesulfonothioate and [18F]fluoride. CCS Chem. 3, 1921–1928 (2021).

    Article  CAS  Google Scholar 

  23. Trump, L. et al. Late‐stage 18F‐difluoromethyl labeling of N‐heteroaromatics with high molar activity for PET imaging. Angew. Chem. Int. Ed. 58, 13149–13154 (2019).

    Article  CAS  Google Scholar 

  24. Ni, C. & Hu, J. Recent advances in the synthetic application of difluorocarbene. Synthesis 46, 842–863 (2014).

    Article  CAS  Google Scholar 

  25. Fier, P. S. & Hartwig, J. F. Synthesis of difluoromethyl ethers with difluoromethyltriflate. Angew. Chem. Int. Ed. 52, 2092–2095 (2013).

    Article  CAS  Google Scholar 

  26. Xie, Q. et al. Efficient difluoromethylation of alcohols using TMSCF2Br as a unique and practical difluorocarbene reagent under mild conditions. Angew. Chem. Int. Ed. 56, 3206–3210 (2017).

    Article  CAS  Google Scholar 

  27. Birchall, J. M., Haszeldine, R. N. & Roberts, D. W. Cyclopropane chemistry. Part II. Cyclopropanes as sources of difluorocarbene. J. Chem. Soc. Perkin Trans. I 1071–1078 (1973).

  28. Jia, Y., Yuan, Y., Huang, J., Jiang, Z. & Yang, Z. Synthesis of difluorinated heterocyclics through metal-free [8+1] and [4+1] cycloaddition of difluorocarbene. Org. Lett. 23, 2670–2675 (2021).

    Article  PubMed  CAS  Google Scholar 

  29. Feng, Z., Min, Q. & Zhang, X. Access to difluoromethylated arenes by Pd-catalyzed reaction of arylboronic acids with bromodifluoroacetate. Org. Lett. 18, 44–47 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Deng, X., Lin, J. & Xiao, J. Pd-catalyzed transfer of difluorocarbene. Org. Lett. 18, 4384–4387 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Feng, Z., Min, Q., Fu, X., An, L. & Zhang, X. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nat. Chem. 9, 918–923 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Fu, X. et al. Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes. Nat. Chem. 11, 948–956 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Smail, T. & Rowland, F. S. Insertion reactions of mono-and difluorocarbene with hydrogen halides. J. Phys. Chem. 74, 1866–1871 (1970).

    Article  CAS  Google Scholar 

  34. Prakash, G. S. et al. Long‐lived trifluoromethanide anion: a key intermediate in nucleophilic trifluoromethylations. Angew. Chem. Int. Ed. 53, 11575–11578 (2014).

    Article  CAS  Google Scholar 

  35. Hine, J. & Porter, J. J. The formation of difluoromethylene from difluoromethyl phenyl sulfone and sodium methoxide. J. Am. Chem. Soc. 82, 6178–6181 (1960).

    Article  CAS  Google Scholar 

  36. Xing, L. et al. Fluorine in drug design: a case study with fluoroanisoles. ChemMedChem 10, 715–726 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Khotavivattana, T. et al. 18F‐labeling of aryl–SCF3, –OCF3 and –OCHF2 with [18F]fluoride. Angew. Chem. Int. Ed. 54, 9991–9995 (2015).

    Article  CAS  Google Scholar 

  38. Dahl, K., Halldin, C. & Schou, M. New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals. Clin. Transl. Imaging 5, 275–289 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Pipal, R. W. et al. Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery. Nature 589, 542–547 (2021).

    Article  CAS  PubMed  ADS  Google Scholar 

  40. Mullard, A. Deuterated drugs draw heavier backing. Nat. Rev. Drug Discov. 15, 219–222 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Cai, Z. et al. Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). Eur. J. Nucl. Med. Mol. Imaging 46, 1952–1965 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Zheng, J., Winkeler, A., Peyronneau, M.-A., Dollé, F. & Boisgard, R. Evaluation of PET imaging performance of the TSPO radioligand [18F]DPA-714 in mouse and rat models of cancer and inflammation. Mol. Imaging Biol. 18, 127–134 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Keller, T. et al. Radiosynthesis and preclinical evaluation of [18F]F-DPA, a novel pyrazolo[1,5a]pyrimidine acetamide TSPO radioligand, in healthy Sprague Dawley rats. Mol. Imaging Biol. 19, 736–745 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lelos, M. J. & Dunnett, S. B. Generating Excitotoxic Lesion Models of Huntington’s Disease 209–220 (Springer, 2018).

  46. Zhou, W. et al. Transition-metal difluorocarbene complexes. Chem. Commun. 57, 9316–9329 (2021).

    Article  CAS  Google Scholar 

  47. Li, X. et al. Copper-mediated aerobic (phenylsulfonyl)difluoromethylation of arylboronic acids with difluoromethyl phenyl sulfone. Chem. Commun. 52, 3657–3660 (2016).

    Article  CAS  Google Scholar 

  48. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Quality guidelines. ICH (2019).

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This research has received funding from the Engineering and Physical Sciences Research Council (EP/V013041/1, J.B.I.S.), Pfizer, Janssen, UCB, the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 721902 (C.F.M., S.M.H. and T.A.M.). J.F. is grateful to the Centre for Doctoral Training in Synthesis for Biology and Medicine for a studentship, generously supported by GlaxoSmithKline, MSD, Syngenta and Vertex. J.B.I.S. acknowledges financial support from an EPSRC Doctoral Prize (EP/T517811/1). R.S.P. acknowledges the RMACC Summit supercomputer at the University of Colorado Boulder and Colorado State University, the Extreme Science and Engineering Discovery Environment (XSEDE) through allocation TG-CHE180056, and support from the National Science Foundation (NSF CHE-1955876). We thank B. G. Davis, S. Verhoog and T. C. Wilson for comments, and T. Khotavivattana for preliminary experiments.

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Authors and Affiliations



J.B.I.S. and C.F.M. labelled the tBu-substituted difluorocarbene reagent and performed all insertions and cycloadditions with this reagent. J.B.I.S., C.F.M. and J.F. prepared the substrates and performed all automation experiments. J.B.I.S. and J.F. performed the cross-coupling reactions, one-pot procedures, the synthesis of the radiotracer for the imaging study, the radiosynthesis of all difluorocarbene reagents, and the experiments with the Cl-substituted difluorocarbene reagent, and developed the NMR assay to probe isotopic dilution. J.B.I.S. and N.J.W.S. performed preliminary studies for the radiosynthesis of the tBu-substituted difluorocarbene reagent. A.B.D. and R.S.P. performed and analysed the computational studies. T.A.M. and C.F.M. did an initial metabolic stability study. J.B.I.S., J.F., M.J.L. and S.J.P. performed all the in vivo experiments. S.M.H. prepared selected substrates. J.B.I.S., J.F. and V.G. conducted the revisions. J.B.I.S., R.S.P. and V.G. wrote the manuscript. All authors read and commented on the paper. V.G. conceived and supervised the project.

Corresponding author

Correspondence to Véronique Gouverneur.

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Competing interests

C.G. is an employee of UCB Pharma. C.W.a.E. is an employee of Pfizer Inc. A patent application (no. GB2113561.1; Difluorocarbene radiosynthesis) has been filed, from which V.G., J.B.I.S., C.F.M., M.T., N.J.W.S., S.M.H. and A.A.T. may benefit from royalties. The other authors declare no competing interests.

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Nature thanks John Groves and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

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This file contains: Materials and methods, Supplementary Text, Figs. 1–69, Tables 1–14, NMR spectra and References.

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Sap, J.B.I., Meyer, C.F., Ford, J. et al. [18F]Difluorocarbene for positron emission tomography. Nature 606, 102–108 (2022).

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