Ettrup_2011_J.Nucl.Med_52_1449

Small-molecule alpha(7) nicotinic acetylcholine receptor (alpha(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled alpha(7)nAChR PET tracer would be important for in vivo quantification of alpha(7)nAChR binding in humans and to measure alpha(7)nAChR occupancy of alpha(7)nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of (11)C-NS14492 as a selective alpha(7)nAChR PET radioligand.
METHODS: The high-affinity alpha(7)nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using (11)C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the alpha(7)nAChR partial agonist SSR180711 or the unlabeled NS14492. (11)C-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; (11)C-NS14492 regional distribution volumes were calculated, and alpha(7)nAChR occupancy was determined using an occupancy plot.
RESULTS: (11)C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with alpha(7)nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of (11)C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to alpha(7)nAChR in vivo. CONCLUSION: We report here that (11)C-NS14492 is the first, to our knowledge, PET radioligand for alpha(7)nAChR 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(7)nAChR binding in the human brain.