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

Bioorg Med Chem Lett. 2012 Mar 1;22(5):2099-101. doi: 10.1016/j.bmcl.2011.12.139. Epub 2012 Jan 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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