Synthesis and pharmacological evaluation of fluorine-containing D 3 dopamine receptor ligands

Zhude Tu, Shihong Li, Jinquan Cui, Jinbin Xu, Michelle Taylor, David Ho, Robert R. Luedtke, Robert H. MacH

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 = 0.17-5 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 (Ki = 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.

Original languageEnglish
Pages (from-to)1555-1564
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 24 2011


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