[3H]4-(Dimethylamino)-N-[4-(4-(2-Methoxyphenyl)Piperazin-1-yl)Butyl]Benzamide, a Selective Radioligand for Dopamine D3 Receptors. I. In Vitro Characterization

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ABSTRACT4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (WC-10), a N-phenyl piperazine analog, has been shown to have high affinity and 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 [3H]WC-10 binding to genetically cloned dopamine D2L and D3 receptors was evaluated in vitro. [3H]WC-10 binds with a 66-fold higher affinity to human HEK D3 than HEK D2L receptors, with a dissociation constant (Kd) of 1.2 nM at HEK D3 receptors. However, [3H]WC-10 binds to rat Sf9 rD3 receptors with a Kd of 3.9 nM, a value that is 3-fold lower than binding to human HEK D3 receptors and 40-fold value higher than binding to rat Sf9 rD2L receptors. The Kd values obtained from saturation binding experiments were consistent with the results determined from kinetic (kon and koff) studies. The pharmacologic profiles of a series of dopaminergic drugs for inhibiting the binding of [3H]WC-10 to D3 receptors was in agreement with previously reported data. In vitro autoradiography studies of rat and monkey brains show that [3H]WC-10 labeled D3 sites in the striatal region.

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