Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor α₇ subtype

Introduction: The nicotinic acetylcholine receptor (nAChR) α7 subtype (α₇ nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled α₇ nAChR ligands, (R)-2-[¹¹C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([¹¹C](R)-MeQAA) and its isomer (S)-[¹¹C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[¹¹C]MeQAA for in vivo imaging of α₇ nAChR in the brain was evaluated in mice and monkeys. Methods: The binding affinity for α₇ nAChR was measured using rat brain. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkeys. Results: The affinity for α₇ nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([¹¹C](R)-MeQAA: 7.68 and [¹¹C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [¹¹C](R)-MeQAA was slow in the hippocampus (α₇ nAChR-rich region) but was rapid in the cerebellum (α₇ nAChR-poor region). On the other hand, the clearance was fast for [¹¹C](S)-MeQAA in all regions. The brain uptake of [¹¹C](R)-MeQAA was decreased by methyllycaconitine (α₇ nAChR antagonist) treatment. In monkeys, α₇ nAChRs were highly distributed in the thalamus and cortex but poorly distributed in the cerebellum. The high accumulation was observed in the cortex and thalamus for [¹¹C](R)-MeQAA, while the uptake was rather homogeneous for [¹¹C](S)-MeQAA. Conclusions: [¹¹C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for α₇ nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain α₇ nAChRs in vivo.