[11C]GR103545: novel one-pot radiosynthesis with high specific activity

Introduction: 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.

Conclusion: 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.