Radiosynthesis of a Bruton's tyrosine kinase inhibitor, [11C]Tolebrutinib, via palladium-NiXantphos-mediated carbonylation

Bruton's tyrosine kinase (BTK) is a key component in the B-cell receptor signaling pathway and is consequently a target for in vivo imaging of B-cell malignancies as well as in multiple sclerosis (MS) with positron emission tomography (PET). A recent Phase 2b study with Sanofi's BTK inhibitor, Tolebrutinib (also known as [a.k.a.] SAR442168, PRN2246, or BTK'168) showed significantly reduced disease activity associated with MS. Herein, we report the radiosynthesis of [C-11]Tolebrutinib ([C-11]5) as a potential PET imaging agent for BTK. TheN-[C-11]acrylamide moiety of [C-11]5was labeled by(11)C-carbonylation starting from [C-11]CO, iodoethylene, and the secondary amine precursor via a novel palladium-NiXantphos-mediated carbonylation protocol, and the synthesis was fully automated using a commercial carbon-11 synthesis platform (TracerMaker (TM), Scansys Laboratorieteknik). [C-11]5was obtained in a decay-corrected radiochemical yield of 37 +/- 2% (n= 5, relative to starting [C-11]CO activity) in >99% radiochemical purity, with an average molar activity of 45 GBq/mu mol (1200 mCi/mu mol). We envision that this methodology will be generally applicable for the syntheses of labeledN-acrylamides.