PET imaging of nicotinic acetylcholine receptors in baboons with ¹⁸F-AZAN, a radioligand with improved brain kinetics

There are only 2 currently available radioligands, 2- ¹⁸F-FA and 6- ¹⁸F-FA, for quantitative PET of the main cerebral subtype of nicotinic acetylcholine receptors (α4β2-nAChRs) in humans. Both exhibit slow distribution kinetics in the brain and require several hours for PET imaging. This makes PET of nAChRs with these radioligands logistically difficult and a serious burden for human subjects. The main purpose of this study was to preclinically evaluate (-)-2-(6- ¹⁸F-fluoro-2,3′- bipyridin-5′-yl)-7-methyl- 7-azabicyclo[2.2.1]heptane ( ¹⁸F-AZAN), our new radiolabeled antagonist of α4β2-nAChRs, that has high binding potential and rapid brain kinetics in baboons. Methods: ¹⁸F-AZAN was synthesized using a modified ¹⁸F-FDG synthesis module. The regional distribution of ¹⁸F-AZAN in the brain was evaluated in baseline and cytisine-blocking studies of 4 male Papio anubis baboons. PET modeling procedures were used for calculation of regional distribution volume (V _T), nondisplaceable binding potential (BP _ND), and receptor occupancy. Results: ¹⁸F-AZAN rapidly entered the baboon brain, reached a steady state within 90 min after injection, and specifically labeled cerebral nAChRs. The peak radioactivity in the thalamus was 540 (percentage standardized uptake value) at 18 ± 7 min (n = 4) after bolus injection. Mathematical data analysis demonstrated that scanning for only 90 min is sufficient for determination of PET outcome variables (BP _ND, 3.2 [unitless] and V _T, 32-35 mL/mL in thalamus). The dose-dependent blocking experiments with cytisine demonstrated that ¹⁸F-AZAN binds specifically with β2-containing (predominantly α4β2) nAChRs. Conclusion: ¹⁸F-AZAN specifically labels nAChRs in baboon brains with a high value of BP _ND and it requires only 90 min of PET scanning to produce estimates of V _T and BP _ND in the various brain regions. The blocking of nAChRs with cytisine is dose-dependent and it showed that ¹⁸F-AZAN is suitable for application in nicotinic drug evaluation. In summary, ¹⁸F-AZAN is superior to 2- ¹⁸F-FA and 6- ¹⁸F-FA for imaging cerebral β2-containing nAChRs in baboons. Further evaluations of ¹⁸F-AZAN in the human brain are under way.