Radiosynthesis of a Bruton's tyrosine kinase inhibitor, [11 C]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 [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.