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

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 (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.