Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

Abstract

The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB.