Radiosynthesis of a Bruton's tyrosine kinase inhibitor, [<sup>11</sup>C]Tolebrutinib, via palladium‐NiXantphos‐mediated carbonylation
Kenneth Dahl, Timothy J. Turner, Neil Vasdev
Abstract
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 [ 11 C]Tolebrutinib ([ 11 C] 5 ) as a potential PET imaging agent for BTK. The N ‐[ 11 C]acrylamide moiety of [ 11 C] 5 was labeled by 11 C‐carbonylation starting from [ 11 C]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™, Scansys Laboratorieteknik). [ 11 C] 5 was obtained in a decay‐corrected radiochemical yield of 37 ± 2% ( n = 5, relative to starting [ 11 C]CO activity) in >99% radiochemical purity, with an average molar activity of 45 GBq/μmol (1200 mCi/μmol). We envision that this methodology will be generally applicable for the syntheses of labeled N ‐acrylamides.