5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for alpha4beta2 nicotinic acetylcholine receptor and wide range of lipophilicity: potential pr
5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for alpha4beta2 nicotinic acetylcholine receptor and wide range of lipophilicity: potential pr
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6-卤代-3-((2-(S)-氮杂环丁基)甲氧基)吡啶和6-卤代-3-((2-(S)-吡咯烷基)甲氧基)吡啶的5-取代衍生物，对 alpha4beta2 具有低皮摩尔亲和力
DOI：
10.1021/jm030432v
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发表时间：
2004
影响因子：
7.3
通讯作者：
Horti,AndrewG
中科院分区：
文献类型：
--
作者：
Zhang,Yi;Pavlova,OlgaA;Chefer,SvetlanaI;Hall,AndrewW;Kurian,Varughese;Brown,LaVerneL;Kimes,AlaneS;Mukhin,AlexeyG;Horti,AndrewG
已经合成了潜在的正电子发射断层扫描（PET）配体，其对烟碱乙酰胆碱受体（nAChR）具有低皮摩尔亲和力，亲脂性（logD）范围为−1.6至+1.5。该系列的大多数成员是5-取代-6-卤代-A-85380的衍生物，与地棘蛙素相比，对α4β2-nAChR表现出更高的结合亲和力。通过分子建模的分析揭示了额外的杂环的取向对配体与nAChRs的结合亲和力的重要作用。现有的烟碱药效团模型不适应这一发现。用18F放射性标记该系列的两种化合物6-[18F]氟-5-（吡啶-3-基）-A-85380（[18F]31）和6-氯-3-（（2-（S）-氮杂环丁烷基）甲氧基）-5-（2-[18F]氟吡啶-5-基）吡啶）（[18F]35）。[18 F] 31和2-[18 F]FA的PET数据比较显示亲脂性对结合潜力的影响。我们最近用[18F] 35进行的PET研究表明，其在恒河猴脑中的结合电位值约为1.25。2.5 2-[18F]FA的倍数。因此，[18 F] 35和该系列的其他几个成员，当放射性标记时，将适用于丘脑外nAChRs的定量成像。
Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (logD) ranging from −1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at α4β2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[18F]fluoro-5-(pyridin-3-yl)-A-85380 ([18F]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-[18F]fluoropyridin-5-yl)pyridine) ([18F]35), were radiolabeled with18F. Comparison of PET data for [18F]31and 2-[18F]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [18F]35demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[18F]FA. Therefore, [18F]35and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.