11C-NS14492 as a Novel PET Radioligand for Imaging Cerebral alpha 7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Small-molecule alpha 7 nicotinic acetylcholine receptor ( alpha 7nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled alpha 7nAChR PET tracer would be important for in vivo quantification of alpha 7nAChR binding in humans and to measure alpha 7nAChR occupancy of alpha 7nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of 11C-NS14492 as a selective alpha 7nAChR PET radioligand. METHODS: The high-affinity alpha 7nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using 11C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the alpha 7nAChR partial agonist SSR180711 or the unlabeled NS14492. 11C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; 11C-NS14492 regional distribution volumes were calculated, and alpha 7nAChR occupancy was determined using an occupancy plot. RESULTS: 11C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with alpha 7nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of 11C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to alpha 7nAChR in vivo. CONCLUSION: We report here that 11C-NS14492 is the first, to our knowledge, PET radioligand for alpha 7nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of alpha 7nAChR binding in the human brain.