PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with 18F-AZAN, a Radioligand with Optimal Brain Kinetics

摘要

We evaluated (a?’)-2-(6-[18F]fluoro-2,3a€2-bipyridin-5a€2-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane (18F-AZAN), a novel radiotracer that binds to ?±4?22 nicotinic acetylcholine receptors (?±4?22-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. Methods: We tested safety tolerability and testa€“retest reliability (n = 5) and proposed initial quantification of 18F-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 ?±4?22-nAChRa€“selective partial agonist varenicline. Results: 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 18F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (testa€“retest variability 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BPND 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 18F-AZAN brain uptake in smokers and varenicline-treated subjects. Conclusion: 18F-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 ?±4?22-nAChR in the living human brain.