<sup>18</sup> F‐Radiopharmaceutical Diversification Enabled by Deaminative Cross‐Electrophile Couplings
Abstract
Abstract The development of 18 F‐labelled radiotracers is of vital importance for (pre)clinical positron emission tomography (PET) imaging and to guide drug discovery campaigns. State‐of‐the‐art approaches often require labour‐intensive preparation of highly functionalised radiolabelling precursors. This bottleneck impedes analogue generation for optimal imaging and exploration of radiochemical space. To this end, we disclose a nickel‐mediated aryl (C) sp 2 ‐(C) sp 3 cross‐coupling with amine‐derived alkyl 2,4,6‐triphenylpyridinium salts as coupling partners amenable to radiosynthesis. The method was applied to primary and secondary 2,4,6‐triphenylpyridinium salts in radiochemical conversion (RCC) up to 86% and a high‐throughput experimentation (HTE) assay proved crucial for expedient ligand evaluation. A late‐stage diversification case study from a sole precursor achieved six 18 F‐labelled GSK‐3 kinase inhibitor analogues, one being prepared in up to gigabecquerel (GBq) quantities in a (semi)automated two‐step protocol applied across three commercial radiosynthesis platforms.
Article Details
Authors (14)
Isabella F. Ogilvy
Department of Chemistry, University of Oxford Chemistry Research Laboratory 12 Mansfield Road Oxford OX1 3TA UK
Joseph Ford
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Sebastiano Ortalli
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Evelien Renders
Global Discovery Chemistry Johnson & Johnson Turnhoutseweg 30 Beerse 2340 Belgium
Thomas R. Hayes
Global Discovery Chemistry Johnson & Johnson La Jolla California 92121 USA
Shuanglong Liu
Department of Physics
Inne Mortiers
Global Discovery Chemistry Johnson & Johnson Turnhoutseweg 30 Beerse 2340 Belgium
Anastasia Nikolopoulou
Global Discovery Chemistry Johnson & Johnson Spring House Pennsylvania 19477 USA
Alexandre M. Sorlin
Global Discovery Chemistry Johnson & Johnson Spring House Pennsylvania 19477 USA
Andrés A. Trabanco
Global Discovery Chemistry Johnson & Johnson Janssen‐Cilag S.A. Toledo E‐45007 Spain
Matthew Tredwell
Wales Research and Diagnostic PET Imaging Centre, Cardiff University, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, U.K.
Peter J. J. A. Buijnsters
Global Discovery Chemistry Johnson & Johnson Turnhoutseweg 30 Beerse 2340 Belgium
Rhys Salter
Global Discovery Chemistry Johnson & Johnson Spring House Pennsylvania 19477 USA
Véronique Gouverneur