Syntheses and pharmacological evaluation of two potent antagonists for dopamine D4 receptors:[11C]YM-50001 and N-[2-[4-(4-Chlorophenyl)-piperizin-l-yl]ethyl]-3-[11C]methoxybenzamide

Two benzamide derivatives as dopamine D4 receptor antagonists, YM-50001(4) and N-[2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide(9),were labeled by positron-emitter(11C),and their pharmacological specificities to dopamine D4 receptor were examined by quanitative autoradiography and positron emission tomography(PET). Radiosyntheses were accomplished by O-methylation of corresponding phenol precursors (5 and 10) with [11C]CH3I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [11C]4 showed the highest binding in the striatum,which was inhibited not only by 10muM4 but also by 10muM raclopride, a selective dopamine D2 receptor antagonist. In contrast,[11C]9 showed the highest binding in the cerebral cortex, which was inhibited by several D4 receptor antagonists (9,RBI-254,L-745,870),but not by any other receptor ligands(D1"/"D5,D2"/"D3,5-HT1A,5-HT2A,sigma1 and alpha1) tested. In vivo brain distribution of [11C]9 in rat showed the highest uptake in the frontal cortex,a region that has a high density of D4 receptors. These results indicate that the pharmacological property of [11C]9 matches the rat brain D4 receptors, but that of [11C]4 rather appears to match the rat brain D2 receptors. The results for the benzamide [11C]9 prompted us to further evaluate its potential as a PET radioligand for D4 receptors by employing PET on monkey brain. Unfortunately,in contrst to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous [11C]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only family expressed in the brain,[11C]9 with an extremely high specific activity (1810GBq"/"mumol) was used for PET study. However,the effort to determine the specific binding for D4 failed. These results indicate that both of the benzamide derivatives would not be suitable radioligands for D4 receptors with PET. (C)2002 Elsevier Science Inc. All rights reserved.\nKeywords;DopamineD4receptors; Schizophrenia;Carbon-11;Autoradiography;PE