title: Synthesis and pharmacological evaluation of fluorine-containing D₃ dopamine receptor ligands.
abstract: A series of fluorine-containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized, and their affinities for human dopamine D(2), D(3), and D(4) receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e, and 21e, which bind with high affinity at D(3) (K(i) = 0.17-5 nM) and moderate to high selectivity for D(3) vs D(2) receptors (ranging from ∼25- to 163-fold). These compounds were also evaluated for intrinsic activity at D(2) and D(3) receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D(2) vs D(3) receptors. These compounds may be useful for behavioral pharmacology studies on the role of D(2)-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D(3) receptor (K(i) = 0.17 nM for D(3), 163-fold selectivity for D(3) vs D(2) receptors), represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D(3) receptor expression.
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cui
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Michelle
authors.initials: M
authors.lastname: Taylor
authors.forename: David
authors.initials: D
authors.lastname: Ho
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D005461:Fluorine; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017480:Receptors, sigma; D050638:Receptors, Dopamine D4; D005461:Fluorine; D000242:Cyclic AMP