Synthesis and pharmacological evaluation of fluorine-containing D₃ 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 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.