PET Imaging of High-Affinity [alpha]4[Beta]2 Nicotinic Acetylcholine Receptors in Humans with ^sup 18^F-AZAN, a Radioligand with Optimal Brain Kinetics

We evaluated (...)-2-(6-[...F]fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane (...F-AZAN), a novel radiotracer that binds to α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of ...F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the α4β2-nAChR-selective partial agonist varenicline. Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for ...F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BP...) using plasma reference graphical analysis, which showed excellent reproducibility of BP... (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP... values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of ...F-AZAN brain uptake in smokers and varenicline-treated subjects. ...F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity α4β2-nAChR in the living human brain. (ProQuest: ... denotes formulae/symbols omitted.)