Evaluation of a new imaging agent for central nicotinic acetylcholine receptor α7 subtype

Abstract

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Objectives: Nicotinic acetylcholine receptor (nAChR) α7 subtype is one of the major nAChR subtypes in the brain. Recent in vitro autoradiographic investigations have suggested that α7 nAChR is implicated in some brain disorders. However, there is no appropriate ligand for in vivo imaging. Recently, we synthesized a novel α7 nAChR ligand, 2-methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (MeQAA, Ki = 0.17 µM) and radiolabelled this with C-11. In this paper, we evaluated its potential for in vivo imaging of α7 nAChR in the brain with mice and monkeys. Methods: Optically pure isomers of [¹¹C]MeQAA was used in this study. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkey using SHR-7700 (Hamamatsu Photonics K.K.). Arterial blood was sampled throughout the scanning period and unmetabolized fraction in plasma was determined. Distribution volume (DV) was estimated by Logan plot analysis. Results: The initial uptake in the mouse brain was high (r-[¹¹C]MeQAA: 7.68, s-[¹¹C]MeQAA: 6.65 %ID/g at 5 min). The clearance of radioactivity of r-[¹¹C]MeQAA was slow in the hippocampus (α7 nAChR rich region) and was rather rapid in the cerebellum (α7 nAChR poor region). On the other hand, the clearance was faster in s-[¹¹C]MeQAA. The brain uptake of r-[¹¹C]MeQAA was decreased in 32 % in hippocampus by MLA (α7 nAChR ligand) treatment. The ondansetron treatments (5HT-3 ligand) had no effect in all brain regions in both isomers. In monkeys, α7 nAChRs are highly distributed in thalamus and cortex and poor in cerebellum. DV of r-[¹¹C]MeQAA was 16.3, 17.0 and 13.8 mL in thalamus, cortex and cerebellum, respectively. In contrast, DV of s-[¹¹C]MeQAA was low, 4.2 mL for thalamus and 3.8 mL for cortex. However, it was also low in cerebellum (3.1 mL). Conclusions: r-[¹¹C]MeQAA was shown to be a promising candidate for imaging α7 nAChR in vivo. The observed difference in each isomer should come from its binding affinities. Further characterization of these tracers and PET analyses are currently underway.