Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors

Visualization of central nicotinic acetylcholine receptors (nAChRs) with modern PET or SPECT imaging techniques has been hampered by the tack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics appropriate for the half-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent F-18-labeled analog of epibatidine, (+/-)-exo-2-(2-[18 F]fluoro-5-pyridyl)-7-azabicyclo[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 brain. Methods: Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the brain and other organs. Saturation and pharmacology of [F-18]FPH binding was demonstrated in vivo by preinjecting unlabeled FPH or other drugs 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 activity (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 min. Highest concentrations of F-18 occurred at 15 min in areas known to contain high densities of nAChR {e.g., thalamus [9.7% of injected dose per gram tissue (ID/g)] and superior colliculus (8.3% ID/g)}. Accumulation 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, respectively) 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 such as H-3-labeled epibatidine or norchloroepibatidine, [H-3](-)-nicotine and [H-3]cytisine and that of nAChR densities determined in postmortem autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine, (-)-nicotine, lobeline and cytisine significantly inhibited [F-18]FPH binding in thalamus and superior colliculus, but not in cerebellum, whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR (e.g., mecamylamine, 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-nonspecific binding, this radioligand appears to be ideally suited for PET imaging of nAChR in the mammalian brain.