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

The nicotinic acetylcholine receptor (nAChR) alpha7 subtype (alpha(7) nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled alpha(7) nAChR ligands, (R)-2-[(11)C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([(11)C](R)-MeQAA) and its isomer (S)-[(11)C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[(11)C]MeQAA for in vivo imaging of alpha(7) nAChR in the brain was evaluated in mice and monkeys. The binding affinity for alpha(7) 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. The affinity for alpha(7) nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([(11)C](R)-MeQAA: 7.68 and [(11)C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [(11)C](R)-MeQAA was slow in the hippocampus (alpha(7) nAChR-rich region) but was rapid in the cerebellum (alpha(7) nAChR-poor region). On the other hand, the clearance was fast for [(11)C](S)-MeQAA in all regions. The brain uptake of [(11)C](R)-MeQAA was decreased by methyllycaconitine (alpha(7) nAChR antagonist) treatment. In monkeys, alpha(7) 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 [(11)C](R)-MeQAA, while the uptake was rather homogeneous for [(11)C](S)-MeQAA. [(11)C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for alpha(7) nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain alpha(7) nAChRs in vivo.