Nicotinic α4β2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3′-18F-fluoropropyl)pyridine (18F-nifzetidine)
Nicotinic α4β2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3′-18F-fluoropropyl)pyridine (18F-nifzetidine)
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DOI：
10.1016/j.nucmedbio.2011.05.005
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发表时间：
2011-11-01
影响因子：
3.1
通讯作者：
Mukherjee, Jogeshwar
中科院分区：
文献类型：
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作者：
Pichika, Rama;Easwaramoorthy, Balu;Mukherjee, Jogeshwar
大脑中发现的丘脑和丘脑外烟碱 α4β2 受体与阿尔茨海默病、帕金森病、药物滥用和其他疾病有关。我们在此报告 3-(2-(S)-氮杂环丁基甲氧基)-5-(3'-氟丙基)吡啶 (nifzetidine) 的开发，作为烟碱 α 4 β 2 受体的新推定高亲和力拮抗剂。含有用H-3-金雀花碱标记的α4β2位点的大鼠脑匀浆测定中的硝西替丁表现出结合亲和力：Ki=0.67nM。氟18类似物3-(2-(5)-氮杂环丁烷基甲氧基)-5-(3'-F-18-氟丙基)吡啶(F-18-nifzetidine)的合成收率为20%-40%，表观比活性估计高于2 Ci/mu mol。大鼠脑切片表明 F-18-硝西替丁选择性结合至丘脑、下托、纹状体、皮质和其他与 α4β2 受体分布一致的区域。这种选择性结合被 150 μM 尼古丁取代 >85%。麻醉恒河猴中 F-18-硝西替丁的正电子发射断层扫描 (PET) 成像研究显示，各个脑区的吸收缓慢。 (1)8(F)-硝西替丁的保留在丘脑和外侧膝状体中最多，其次是颞叶和额叶皮层区域。小脑的吸收最少。注射后 180 分钟，丘脑与小脑的比率约为 2.3，并持续上升。 F-18-Nifzetidine 有望成为 α 4 beta 2 nAChR 的新型 PET 成像剂。然而，缓慢的动力学表明需要 >3 小时的 PET 扫描才能对 α 4 β 2 nAChR 进行定量研究。 (C) 2011 Elsevier Inc. 保留所有权利。
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. (C) 2011 Elsevier Inc. All rights reserved.