PET imaging of high-affinity a4b2 nicotinic acetylcholine receptors in humans with ¹⁸F-AZAN, a radioligand with optimal brain kinetics

We evaluated (2)-2-(6-[¹⁸F]fluoro-2,39-bipyridin-59-yl)-7- methyl- 7-aza-bicyclo[2.2.1]heptane (¹⁸F-AZAN), a novel radiotracer that binds to a4b2 nicotinic acetylcholine receptors (a4b2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. Methods: We tested safety tolerability and test-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 a4b2-nAChR- 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 (BP_ND) using plasma reference graphical analysis, which showed excellent reproducibility of BP_ND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP_ND 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: ¹⁸FAZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity a4b2-nAChR in the living human brain. COPYRIGHT