Towards the preparation of radiolabeled 1-aryl-3-benzyl ureas: Radiosynthesis of [11C-carbonyl] AR-A014418 by [11C]CO2 fixation

The highly selective glycogen synthase kinase-3 (GSK-3) inhibitor N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl) urea (AR-A014418) was radiolabeled with carbon-11 (C-11; half-life = 20.4 min) at the urea moiety via [C-11]CO2 fixation. Reaction of [C-11]CO2 with 4-methoxybenzylamine in the presence of a CO2 fixating base was followed by dehydration with POCl3 and addition of 2-amino-5-nitrothiazole to prepare [C-11-carbonyl] AR-A014418. This reaction resulted in an 8% uncorrected radiochemical yield, based on [C-11]CO2, with high specific activity (4 Ci/mu mol) within 30 min. An in vitro GSK-3 beta enzyme activity assay revealed that AR-A014418 (K-i = 770 nM) is not as potent as previously claimed. The [C-11]CO2 fixation methodology described herein should prove generally applicable to preparing 1-aryl-3-benzyl-[C-11-carbonyl] ureas as radiotracers for positron emission tomography. (C) 2012 Elsevier Ltd. All rights reserved.