IMAGING NICOTINIC ACETYLCHOLINE-RECEPTORS WITH FLUORINE-18-FPH, AN EPIBATIDINE ANALOG

Nicotinic acetylcholine receptors (nAChRs) have been implicated in a v ariety of central processes, such as learning and memory and analgesia . These receptors also mediate the reinforcing properties of nicotine in tobacco products and are increased in postmortem samples of brains of smokers, On the other hand, brains of individuals who have died fro m dementia of the Alzheimer type show abnormally low densities of nACh Rs. In this study, the distribution and kinetics of [(+/-)-exo-2-(2-[F -18] fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (F-18-FPH), a high-a ffinity nAChR agonist, was evaluated in a baboon using PET. Methods: A fter intravenous injection of 5 mCi [185 MBq] F-18-FPH into a 25-kg an esthetized baboon, sequential quantitative tomographic data were acqui red over a period of 150 min. Regions of interest were placed and time -activity curves were generated, Brain kinetics of the radiotracer wer e calculated, and the in vivo regional binding in the baboon brain was compared with the known in vitro regional distribution of nAChRs in t he rat and human brain. Results: Brain activity reached a plateau with in 60 min after injection of the tracer, and the binding was reversibl e. Elimination of F-18-FPH was relatively rapid from the cerebellum (c learance t(1/2) = 3 hr), intermediate from the hypothalamus/midbrain ( t(1/2) = 7 hr) and slow from the thalamus (t(1/2) = 16 hr). Radioactiv ity due to F-18-FPH at 130 min postinjection was highest in the thalam us and hypothalamus/midbrain, intermediate in the neocortex and hippoc ampus and lowest in the cerebellum. Subcutaneous injection of 1 mg/kg cytisine 45 min after injection of the radiotracer reduced brain activ ity at 130 min by 67%, 64%, 56% and 52% of control values in the thala mus, hypothalamus/midbrain, hippocampus and cerebellum, respectively. The regional binding of F-18-FPH at 130 min was highly correlated with the known densities of nAChR measured in vitro in human (r = 0.81) an d rat brain (r = 0.90). Conclusion: These results demonstrate the feas ibility of imaging nAChRs in vivo. Fluorine-18-FPH appears to be a sui table tracer to study nAChRs in the human brain.