[18F]Difluorocarbene for positron emission tomography

Jeroen B. I. Sap, Claudio F. Meyer, Joseph Ford, Natan J. W. Straathof, Alexander B. Dürr, Mariah J. Lelos, Stephen J. Paisey, Tim A. Mollner, Sandrine M. Hell, Andrés A. Trabanco, Christophe Genicot, Christopher W. am Ende, Robert S. Paton, Matthew Tredwell and Véronique Gouverneur ()
Additional contact information
Jeroen B. I. Sap: University of Oxford, Chemistry Research Laboratory
Claudio F. Meyer: University of Oxford, Chemistry Research Laboratory
Joseph Ford: University of Oxford, Chemistry Research Laboratory
Natan J. W. Straathof: University of Oxford, Chemistry Research Laboratory
Alexander B. Dürr: University of Oxford, Chemistry Research Laboratory
Mariah J. Lelos: Cardiff University
Stephen J. Paisey: Cardiff University
Tim A. Mollner: University of Oxford, Chemistry Research Laboratory
Sandrine M. Hell: University of Oxford, Chemistry Research Laboratory
Andrés A. Trabanco: Discovery Chemistry Janssen Research and Development
Christophe Genicot: UCB Biopharma Sprl
Christopher W. am Ende: Pfizer Inc., Medicine Design
Robert S. Paton: Colorado State University
Matthew Tredwell: Cardiff University
Véronique Gouverneur: University of Oxford, Chemistry Research Laboratory

Nature, 2022, vol. 606, issue 7912, 102-108

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04669-2

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