Discovery of (−)-7-Methyl-2-exo-[3′-(6-[18F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcho

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• 作者：Yongjun Gao ; Hiroto Kuwabara ; Charles E. Spivak ; Yingxian Xiao ; Kenneth Kellar ; Hayden T. Ravert ; Anil Kumar ; Mohab Alexander ; John Hilton ; Dean F. Wong ; Robert F. Dannals ; Andrew G. Horti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：August 14, 2008
• 年：2008
• 卷：51
• 期：15
• 页码：4751-4764
• 全文大小：339K
• 年卷期：v.51,no.15(August 14, 2008)
• ISSN：1520-4804

文摘

Several isomers of 7-methyl-2-exo-([¹⁸F]fluoropyridinyl-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are β-nAChR selective ligands with K_i = 0.02−0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D_7.4= 0.67−0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (K_i = 0.3 nM) ((−)-7-methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, [¹⁸F](−)-6c) and greatest lipophilicity (log D_7.4 = 0.99) exhibited optimal brain kinetics. [¹⁸F](−)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (−)-6c is an α4β2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [¹⁸F]-(−)-6c is a potentially superior replacement for 2-[¹⁸F]fluoro-A-85380 and 6-[¹⁸F]fluoro-A-85380, the only available nAChR PET radioligands for humans.