[3H]4-(dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl)benzamide: A selective radioligand for dopamine D3receptors. II. Quantitative analysis of dopamine D3and D2receptor density ratio in the caudate-putamen

Abstract

4‐(Dimethylamino)‐N‐(4‐(4‐(2‐methoxyphenyl)piperazin‐1‐yl)butyl)benzamide (WC‐10), a N‐phenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D₃ receptors versus dopamine D₂ receptors (Chu et al. [ 2005 ] Bioorg Med Chem 13:77–87). In this study, WC‐10 was radiolabeled with tritium (specific activity = 80 Ci/mmol), and quantitative autoradiography studies were conducted using rhesus monkey and Sprague‐Dawley rat brain sections. K_d values for the binding of [³H]WC‐10 to D₃ receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with K_d values obtained from cloned human and rat receptors (Xu et al. [ 2009 ] Synapse 63:717‐728). The D₂ selective antagonist [³H]raclopride binds with 11‐fold higher affinity to human HEK D_2L (K_d = 1.6 nM) than HEK D₃ (K_d = 18 nM) receptors; [³H]raclopride binds to rat Sf9 rD_2L receptors with a K_d of 6.79 nM, a value that is 4‐fold lower than binding to human HEK D_2L receptors and 2.5‐fold higher than binding to rat Sf9 rD₃ receptors. In vitro quantitative autoradiography studies with [³H]WC‐10 and [³H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D₂ and D₃ receptors based on the in vitro receptor binding data of [³H]WC‐10 and [³H]raclopride was developed. Synapse 64:449–459, 2010.