Towards the preparation of radiolabeled 1-aryl-3-benzyl ureas: Radiosynthesis of [(11)C-carbonyl] AR-A014418 by [(11)C]CO(2) 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 ((11)C; half-life=20.4min) at the urea moiety via [(11)C]CO(2) fixation. Reaction of [(11)C]CO(2) with 4-methoxybenzylamine in the presence of a CO(2) fixating base was followed by dehydration with POCl(3) and addition of 2-amino-5-nitrothiazole to prepare [(11)C-carbonyl] AR-A014418. This reaction resulted in an 8% uncorrected radiochemical yield, based on [(11)C]CO(2), with high specific activity (4Ci/μmol) within 30min. An in vitro GSK-3β enzyme activity assay revealed that AR-A014418 (K(i)=770nM) is not as potent as previously claimed. The [(11)C]CO(2) fixation methodology described herein should prove generally applicable to preparing 1-aryl-3-benzyl-[(11)C-carbonyl] ureas as radiotracers for positron emission tomography.
PET Centre, Centre for Addiction and Mental Health, Department of Psychiatry, Institute of Medical Science, University of Toronto, 250 College St., Toronto, ON, Canada M5T 1R8.
Justin W
JW
Hicks
Alan A
AA
Wilson
Elizabeth A
EA
Rubie
James R
JR
Woodgett
Sylvain
S
Houle
Neil
N
Vasdev
D002245:Carbon Dioxide / Q000737:chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D013844:Thiazoles; D002245:Carbon Dioxide; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D038362:Glycogen Synthase Kinase 3