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

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 63; no. 11; pp. 482 - 487
• Main Authors: Dahl, Kenneth, Turner, Timothy, Vasdev, Neil
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.09.2020; Wiley Subscription Services, Inc
• Subjects: Acrylamide; Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; aminocarbonylation; Biochemical Research Methods; Biochemistry & Molecular Biology; Bruton's tyrosine kinase; BTK; Carbon monoxide; Carbon Radioisotopes - chemistry; Carbonyls; carbon‐11; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Analytical; Chemistry, Medicinal; Emission analysis; Enzyme inhibitors; Kinases; Life Sciences & Biomedicine; Medical imaging; Multiple sclerosis; Palladium; Palladium - chemistry; PET; Pharmacology & Pharmacy; Physical Sciences; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Radiochemistry; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Science & Technology; Signal transduction; Synthesis; Target recognition; Tomography; Tyrosine; Tyrosine kinase inhibitors; ACID; C-11-CARBONYLATION; MONOXIDE; BTK; carbon-11; PET; radiochemistry; LABELING CHEMISTRY; aminocarbonylation
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3872

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 [11C]Tolebrutinib ([11C]5) as a potential PET imaging agent for BTK. The N‐[11C]acrylamide moiety of [11C]5 was labeled by 11C‐carbonylation starting from [11C]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). [11C]5 was obtained in a decay‐corrected radiochemical yield of 37 ± 2% (n = 5, relative to starting [11C]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. The N‐[11C]acrylamide moiety of [11C]Tolebrutinib was labeled via reaction from [11C]CO, via a novel palladium‐NiXantphos‐mediated carbonylation protocol, and fully automated using a commercial carbon‐11 synthesis platform.