Neuropharmacological assessment of potential dopamine D4 receptor-selective radioligands

Radiolabeled dopamine D-4 receptor-selective agents ([H-3]1-benzyl-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine maleate; [H-3]PNU-101958, and [I-125]-[4-iodobenzyl]-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine; [I-125]RBI-257) were prepared and characterized. With D-4.2- and D-2L receptor-transfected cell membranes, [H-3]PNU-101958 showed high dopamine D-4 receptor affinity and selectivity, and potent inhibition by dopamine D-4 receptor-selective compounds. However, its binding with rat brain homogenates showed little regional selectivity, and pharmacology inconsistent with selective dopamine D-4 receptor labeling. Autoradiography indicated partial displacement of [H-3]PNU-101958 by unlabeled dopamine D-4 receptor ligands without regional selectivity, and lack of selective labeling with [I-125]RBI-257. The results encourage further efforts to develop better dopamine D-4 receptor-selective radioligands. (C) 1999 Elsevier Science B.V. All rights reserved.