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 α4β2 nicotinic acetylcholine receptor and wide range of lipophilicity:: Potential probes for imaging with positron emission tomography

被引：51

作者：

Zhang, Y ^{[1
]}

Pavlova, OA ^{[1
]}

Chefer, SI ^{[1
]}

Hall, AW ^{[1
]}

Kurian, V ^{[1
]}

Brown, LL ^{[1
]}

Kimes, AS ^{[1
]}

Mukhin, AG ^{[1
]}

Horti, AG ^{[1
]}

机构：

[1] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 10期

关键词：

D O I：

10.1021/jm030432v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) 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 alpha4beta2-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-[F-18]-fluoro-5-(pyridin-3-yl)-A-85380 ([F-18]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2- [F-18]-fluoropyridin-5-yl)pyridine) ([F-18]35), were radiolabeled with F-18. Comparison of PET data for [F-18]31 and 2-[F-18]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [F-18]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[F-18]FA. Therefore, [F-18]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs.

引用

页码：2453 / 2465

页数：13

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