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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and evaluation of N-[C-11]methylated analogues of epibatidine as tracers for positron emission tomographic studies of nicotinic acetylcholine receptors
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Synthesis and evaluation of N-[C-11]methylated analogues of epibatidine as tracers for positron emission tomographic studies of nicotinic acetylcholine receptors

机译：依巴替丁的N- [C-11]甲基化类似物作为示踪剂的合成和评价，用于烟碱乙酰胆碱受体的正电子发射断层扫描

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摘要

Four halogen-substituted analogues of N-methylepibatidine, a nicotinic acetylcholine receptor (nAChR) ligand, were synthesized. They were (+)-exo-N-methyl-2-(2-halogeno-5-pyridyl)-7- azabicyclo[2.2.1]heptanes, where halogeno = F (1a), Cl (2a), Br (3a), I (4a). (+/-)-N-Ethylepibatidine (2b) also was synthesized. The compounds 1a, 2a, 3a, and 4a and their corresponding normethyl analogues 1, 2, 3, and 4 inhibited the in vitro binding of [H-3]epibatidine to nAChRs to a similar degree, with affinities in the 27-50 pM range. The binding affinity of N-ethylepibatidine (2b), however, was substantially lower. The N-[C-11]methyl derivatives of 1, 2, and 3 were synthesized from high-specific radioactivity [C-11]methyl iodide using a high-temperature/high-pressure technique. The corresponding radiolabeled compounds [C-11]1a, [C-11]2a, and [C-11]3a were administrated to mice intravenously. The pattern of regional distribution of the three tracers in the mouse brain following intravenous administration matched those of [H-3]epibatidine, [H-3]norchloroepibatidine, and (+/-)-exo-2-(2-[F-18]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([F-18]FPH), which are highly specific nAChR probes. The initial brain uptake of the C-11 analogues and the acute toxicity of the corresponding authentic nonlabeled compounds appeared to be related to their lipophilicity. [References: 41]
机译：合成了N-甲基表巴替丁的四个卤素取代的类似物（一种烟碱乙酰胆碱受体（nAChR）配体）。它们是（+）-exo-N-甲基-2-（2-卤代-5-吡啶基）-7-氮杂双环[2.2.1]庚烷，其中卤代= F（1a），Cl（2a），Br（3a ），我（4a）。还合成了（+/-）-N-乙基哌丁啶（2b）。化合物1a，2a，3a和4a及其相应的正甲基类似物1、2、3和4在27-50 pM中具有相似程度的抑制[H-3] epibatidine与nAChR的体外结合的能力。范围。然而，N-乙基表巴替丁（2b）的结合亲和力明显较低。使用高温/高压技术由高比活度[C-11]甲基碘化物合成1、2和3的N- [C-11]甲基衍生物。将相应的放射性标记的化合物[C-11] 1a，[C-11] 2a和[C-11] 3a静脉内给予小鼠。静脉内给药后，小鼠脑中三种示踪剂的区域分布模式与[H-3]依巴替丁，[H-3]去氯依巴替丁和（+/-）-exo-2-（2- [F- 18]氟-5-吡啶基）-7-氮杂双环[2.2.1]庚烷（[F-18] FPH），它们是高度特异性的nAChR探针。 C-11类似物的最初大脑摄取以及相应的真实未标记化合物的急性毒性似乎与其亲脂性有关。 [参考：41]

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