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Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery


Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, neurodegenerative diseases and numerous oncology targets1. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands2, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds [11C]UCB-J and [11C]PHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.

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Fig. 1: General approach to radioligand synthesis.
Fig. 2: Scope of high-molar-activity tritiation.
Fig. 3: Scope of carbon-11 radiolabelling.
Fig. 4: Synthesis of various carbon and hydrogen isotopologues.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information.


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Research reported in this publication was supported by the NIH (under award number R35GM134897-01) and the Princeton Catalysis Initiative. We thank L. Wilson (Lotus Separations) and H. Wang for compound purification; I. Mergelsberg, M. Reibarkh and Y. N. J. Chen for discussions; A. Chaudhary and Z. Zhu (Siemens) for high-activity [11C]UCB-J radiotracer synthesis; and C. Liu for assistance in preparing this manuscript.

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Authors and Affiliations



P.Z.M., S.R., T.J.A.G., D.H., E.D.H., I.W.D. and D.W.C.M. conceived the work. R.W.P., P.Z.M. and S.R. conducted initial optimization. R.W.P., K.T.S. and S.R. synthesized organobromide precursors. R.W.P. and K.T.S. performed and isolated labelling experiments. R.W.P., K.T.S., S.R. and D.H. developed purification conditions. T.J.A.G., S.V. and E.D.H. provided insight into experimental design. L.G. conducted the non-human primate PET imaging study and T.G.L. performed data analysis. A.S. configured and performed the fully automated radiosynthesis and H.S.L. performed data analysis. R.W.P., K.T.S., T.J.A.G. and D.W.C.M. prepared the manuscript with input from all co-authors.

Corresponding author

Correspondence to David W. C. MacMillan.

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The authors declare no competing interests.

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Peer review information Nature thanks Yu-Shin Ding and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

This file contains Supplementary Materials and Methods, Supplementary Text, Supplementary Figures S1–S17, NMR Spectra, and Supplementary References.

Reporting Summary

Supplementary Video 1

: Photoreactor Initiation for Automated Radiosynthesis A brief video demonstrating how the integrated photoreactor is switched on with a Bluetooth-enabled, SwitchBot remote control push button for application to automated carbon-11 radiolabeling.

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Pipal, R.W., Stout, K.T., Musacchio, P.Z. et al. Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery. Nature 589, 542–547 (2021).

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