Synthesis and Pharmacological Evaluation of Fluorine-Containing D3 Dopamine Receptor Ligands

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• 作者：Zhude Tu ; Shihong Li ; Jinquan Cui ; Jinbin Xu ; Michelle Taylor ; David Ho ; Robert R. Luedtke ; Robert H. Mach
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1555-1564
• 全文大小：938K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

A series of fluorine-containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized, and their affinities for human dopamine D₂, D₃, and D₄ receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e, and 21e, which bind with high affinity at D₃ (K_i = 0.17鈭? nM) and moderate to high selectivity for D₃ vs D₂ receptors (ranging from 25- to 163-fold). These compounds were also evaluated for intrinsic activity at D₂ and D₃ receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D₂ vs D₃ receptors. These compounds may be useful for behavioral pharmacology studies on the role of D₂-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D₃ receptor (K_i = 0.17 nM for D₃, 163-fold selectivity for D₃ vs D₂ receptors), represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D₃ receptor expression.