FLUORINE-18-FPH FOR PET IMAGING OF NICOTINIC ACETYLCHOLINE-RECEPTORS

Visualization of central nicotinic acetylcholine receptors (nAChRs) wi th modern PET or SPECT imaging techniques has been hampered by the tac k of a radioligand with suitable in vivo binding characteristics (i.e. , high target-to-nontarget ratios and kinetics appropriate for the hal f-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent F-18-lab eled analog of epibatidine, (+/-)-exo-2-(2-[18 F]fluoro-5-pyridyl)-7-a zabicyclo[2.2.1]heptane ([F-18]FPH), in the mouse brain with the view towards application of this tracer for PET imaging of nAChR in human b rain. Methods: Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the b rain and other organs. Saturation and pharmacology of [F-18]FPH bindin g was demonstrated in vivo by preinjecting unlabeled FPH or other drug s with known pharmacological action before [F-18]FPH was injected. The effect of the drugs on [F-18]FPH accumulation was evaluated. Results: [F-18]FPH was rapidly incorporated into the mouse brain; peak activit y (2.4% of the injected dose) was measured at 5 min after intravenous administration, followed by washout to 1.1% injected dose (ID) at 60 m in. Highest concentrations of F-18 occurred at 15 min in areas known t o contain high densities of nAChR {e.g., thalamus [9.7% of injected do se per gram tissue (ID/g)] and superior colliculus (8.3% ID/g)}. Accum ulation of the F-18 tracer in hippocampus, striatum, hypothalamus and cortical areas was intermediate (5.0, 5.6, 4.2 and 5.6% ID/g, respecti vely) and low in the cerebellum (2.8% ID/g). The distribution of [F-18 ]FPH in the mouse brain matched that of other in vivo nAChR probes suc h as H-3-labeled epibatidine or norchloroepibatidine, [H-3](-)-nicotin e and [H-3]cytisine and that of nAChR densities determined in postmort em autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine, (-)-nicotine, lobeline and cytisine signifi cantly inhibited [F-18]FPH binding in thalamus and superior colliculus , but not in cerebellum, whereas drugs that interact with binding site s other than acetylcholine recognition sites of nAChR (e.g., mecamylam ine, scopolamine, N-methylspiperone and ketanserin) had no effect on [ F-18]FPH accumulation in any of the brain regions examined. Conclusion : Fluorine-18-FPH labels nAChR in vivo in the mouse brain. Because of its high uptake into the brain and high ratios of specific-to-nonspeci fic binding, this radioligand appears to be ideally suited for PET ima ging of nAChR in the mammalian brain.