科研之友
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摘要
Thalamic and extrathalamic nicotinic alpha 4 beta 2 receptors found in the brain have been implicated in Alzheimer's disease, Parkinson's disease, substance abuse and other disorders. We report here the development of 3-(2-(S)-azetidinylmethoxy)-5-(3'-fluoropropyl)pyridine (nifzetidine) as a new putative high-affinity antagonist for nicotinic alpha 4 beta 2 receptors. Nifzetidine in rat brain homogenate assays containing alpha 4 beta 2 sites labeled with H-3-cytisine exhibited a binding affinity: Ki=0.67 nM. The fluorine-18 analog, 3-(2-(5)-azetidinylmethoxy)-5-(3'-F-18-fluoropropyl)pyridine (F-18-nifzetidine), was synthesized in 20%-40% yield, and apparent specific activity was estimated to be above 2 Ci/mu mol. Rat brain slices indicated selective binding of F-18-nifzetidine to thalamus, subiculum, striata, cortex and other regions consistent with alpha 4 beta 2 receptor distribution. This selective binding was displaced >85% by 150 mu M nicotine. Positron emission tomography (PET) imaging studies of F-18-nifzetidine in anesthetized rhesus monkey showed slow uptake in the various brain regions. Retention of (1)8(F)-nifzetidine was maximal in the thalamus and lateral geniculate followed by regions of the temporal and frontal cortex. Cerebellum showed the least uptake. Thalamus to cerebellum ratio was about 2.3 at 180 min postinjection and continued to rise. F-18-Nifzetidine shows promise as a new PET imaging agent for alpha 4 beta 2 nAChR. However, the slow kinetics suggests a need for >3-h PET scans for quantitative studies of the alpha 4 beta 2 nAChRs.
- 出版日期2011-11
