11C-GR103545, a radiotracer for imaging kappa-opioid receptors in vivo with PET: synthesis and evaluation in baboons.

Brain kappa-opioid receptors (ORs) may be involved in several pathologic conditions, such as addiction, psychosis, and seizures. (+/-)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a potent and selective kappa-OR agonist. The (-)-isomer, GR103545, is the active enantiomer of GR89696. The aim of this study was to characterize the potential of 11C-GR103545 to image kappa-OR in vivo with PET. Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg intravenously). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution volumes were derived using the arterial input function and a 2-tissue-compartment model. 11C-GR103545 showed excellent brain penetration and uptake kinetics, with significant washout observed within the time frame of the PET experiment. Naloxone pretreatment did not affect cerebellar total distribution volume and reduced total distribution volume in other regions to a level comparable to that in the cerebellum. The regional pattern of 11C-GR103545 binding potential was consistent with the distribution of kappa-OR in primate brain, with highest levels observed in anterior cortical regions (prefrontal cortex and cingulate cortex) and striatum. In most regions, the specific-to-nonspecific equilibrium partition coefficient (V3'') ranged from 1 to 2, predicting reliable quantification. 11C-GR103545 V3'' values were approximately double the 11C-GR89696 V3'' values, whereas (+)-11C-GR89696 V3'' values were negligible, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomer for PET studies. 11C-GR103545 is a promising PET radiotracer for imaging the kappa-OR.