Two benzamide derivatives as dopamine D-4 receptor antagonists, YM-50001(4) and N- [2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide (9), were labeled by positron-emitter (C-11), and their pharmacological specificities to dopamine D-4 receptors were examined by quantitative autoradiography and positron emission tomography (PET). Radiosyntheses were accomplished by O-methylation of corresponding phenol precursors (5 and 10) with [C-11]CH3I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [C-11]4 showed the highest binding in the striatum, which was inhibited not only by 10 muM 4 but also by 10 muM raclopride, a selective dopamine D-4 receptor antagonist. In contrast, [C-11]9 showed the highest binding in the cerebral cortex, which was inhibited by several D-4 receptor antagonists (9, RBI-254. L-745,870), but not by any other receptor ligands (D-1/D-5, D-2/D-3, 5-HT1A, 5-HTA2, sigma(1), and alpha(1)) tested. In vivo brain distribution of [C-11]9 in rat showed the highest uptake in the frontal cortex, a region that has a high density of D-4 receptors. These results indicate that the pharmacological property of [C-11]9 matches the rat brain D-4 receptors, but that of [C-11]4 rather appears to match the rat brain D-2 receptors. The results for the benzamide [C-11]9 prompted us to further evaluate its potential as a PET radioligand for D-4 receptors by employing PET on monkey brain. Unfortunately, in contrast to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous [C-11]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only faintly expressed in the brain, [C-11]9 with an extremely high specific activity (1810 GBq/mumol) was used for PET study. However, the effort to determine the specific binding for D-4 failed. These results indicate that both of the benzamide derivatives would not be suitable radioligands for D-4 receptors with PET. (C) 2002 Elsevier Science Inc. All rights reserved.