Derivatives of (-)-7-Methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane Are Potential Ligands for Positron Emission Tomography Imaging of Extrathalamic Nicotinic Acetylcholine Receptors

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• 作者：Yongjun Gao ; Andrew G. Horti ; Hiroto Kuwabara ; Hayden T. Ravert ; John Hilton ; Daniel P. Holt ; Anil Kumar ; Mohab Alexander ; Christopher J. Endres ; Dean F. Wong ; Robert F. Dannals
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 9, 2007
• 年：2007
• 卷：50
• 期：16
• 页码：3814 - 3824
• 全文大小：319K
• 年卷期：v.50,no.16(August 9, 2007)
• ISSN：1520-4804

文摘

A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives withpicomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and theirenantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greaterin vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best bindingaffinities have been radiolabeled with positron emitting isotopes ¹¹C and ¹⁸F as potential radioligands forpositron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistributionstudies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3'-(2-[¹⁸F]fluoropyridin-5-yl))-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, exhibited good properties as a first practicalPET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for furtherinvestigation for human studies.