Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an 11C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone.

Abstract

(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer s disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[11C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc)3 as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40 v/v) at 100\u202f°C for 10\u202fmin gave (R,S)-[11C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield. HPLC separation using a strong cation exchange column, followed by pharmaceutical formulation in the presence of d/l-tartaric acid, afforded (R,S)-[11C]isoproterenol with a total radioactivity of 2.0\u202f±\u202f0.2\u202fGBq, a decay-corrected radiochemical yield of 19\u202f±\u202f2%, chemical and radiochemical purities of 71% and >99%, respectively, and a molar activity of 100\u202f±\u202f13\u202fGBq/μmol (n\u202f=\u202f3). The overall synthesis time from the end of the bombardment to pharmaceutical formulation was 48\u202fmin. A preliminary preclinical PET study in a rat demonstrated the potential of the radioligand for the evaluation of the penetration of (R,S)-isoproterenol in human brain.