Towards the preparation of radiolabeled 1-aryl-3-benzyl ureas: Radiosynthesis of [(11)C-carbonyl] AR-A014418 by [(11)C]CO(2) fixation.

Abstract

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.

• Authors: Justin W Hicks, Alan A Wilson, Elizabeth A Rubie, James R Woodgett, Sylvain Houle, Neil Vasdev
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 5 Pg. 2099-101 (Mar 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22321216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Carbon Radioisotopes
• Radiopharmaceuticals
• Thiazoles
• Carbon Dioxide
• N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
• Urea
• Glycogen Synthase Kinase 3

Topics

• Carbon Dioxide (chemistry)
• Carbon Radioisotopes (chemistry)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Humans
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacology)
• Thiazoles (chemical synthesis, chemistry, pharmacology)
• Urea (analogs & derivatives, chemical synthesis, chemistry, pharmacology)