Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor 7 subtype.


INTRODUCTION: The nicotinic acetylcholine receptor (nAChR) 7 subtype (7 nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled 7 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 7 nAChR in the brain was evaluated in mice and monkeys.
METHODS: The binding affinity for 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.
RESULTS: The affinity for 7 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 (7 nAChR-rich region) but was rapid in the cerebellum (7 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 (7 nAChR antagonist) treatment. In monkeys, 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 [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 7 nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain 7 nAChRs in vivo.