Imaging central nicotinic acetylcholine receptors in baboons with [F-18]fluoro-A-85380

Central nicotinic acetylcholine receptors (nAChRs) have been implicated in learning-memory processes. Postmortem brain tissue of patients who suffered senile dementia or Parkinson's disease shows low density of nAChRs. In thi s study, we used PET to evaluate the distribution and kinetics of the fluor o derivative of the high-affinity and alpha 4 beta 2-subtype-selective, nic otinic ligand 3-[2(S)-2-azetidinylmethoxy]pyridine (A-85380) in baboons. Me thods: After intravenous injection of 37 MBq (1 mCi, 1-1.5 nmol) [F-18]fluo ro-A-85380 into isoflurane-anesthetized baboons, dynamic PET data were acqu ired for 180 min. Time-activity curves were generated from regions of inter est. Displacement experiments (80 min after injection of the radiotracer) w ere performed using cytisine (1 mg/kg subcutaneously) and unlabeled fluoro- A-85380 (0.1 and 0.3 mg/kg intravenously). Toxicological studies were perfo rmed in mice. Results: Brain radioactivity reached a plateau within 40-50 m in of injection of the tracer. In the thalamic area, radioactivity remained constant for 180 min, while clearance from the cerebellum was slow (t(1/2) = 145-190 min). Cytisine and unlabeled fIuoro-A-85380 reduced brain radioa ctivity at 180 min by 50%-60%, 30%-35% and 20%-35% of control values in the thalamus, cerebellum and frontal cortex, respectively. A slight, transient increase (20 mm Hg) in blood pressure was observed with the highest displa cing dose of unlabeled fluoro-A-85380. Lethal dose in mice was found to be 2.2 mg/kg intravenously. Conclusion: These results demonstrate the feasibil ity and the safety of imaging nAChRs in vivo using labeled or unlabeled fIu oro-A-85380.