title: [11C]GR103545: novel one-pot radiosynthesis with high specific activity.
abstract: BACKGROUND
  GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [(11)C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [(11)C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [(11)C]GR103545 with higher SA and radiochemical yields.
  
  
  METHODS
  The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [(11)C]methyl trifluoromethanesulfonate to give [(11)C]GR103545.
  
  
  RESULTS
  This novel synthesis produced [(11)C]GR103545 with ≥90% chemical and radiochemical purities and an SA of 290.45±99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961±814 GBq/μmol with 43 min of average synthesis time from the end of beam.
  
  
  CONCLUSIONS
  We have developed a practical one-pot method for the routine production of [(11)C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans.
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048, USA. nabeel.nabulsi@yale.edu
authors.forename: Nabeel B
authors.initials: NB
authors.lastname: Nabulsi
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Laura
authors.initials: L
authors.lastname: Blumberg
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D002219:Carbamates / Q000737:chemistry; D002245:Carbon Dioxide / Q000737:chemistry; D002250:Carbon Radioisotopes; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011854:Radiochemistry / Q000379:methods*; D017473:Receptors, Opioid, kappa / Q000819:agonists
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002219:Carbamates; D002250:Carbon Radioisotopes; D010879:Piperazines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C071609:GR 89696; D002245:Carbon Dioxide; C031033:1,8-diazabicyclo(5.4.0)undec-7-ene; C070766:carbamic acid