Design, Synthesis, Radiolabeling, and in Vivo Evaluation of Carbon-11 Labeled N-[2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a Potential Positron Emission Tomography Tracer for the Dopamine D-4 Receptors

[摘要]：Here we describe the design, synthesis, and evaluation of physicochemical and pharmacological properties of D-4 dopamine receptor ligands related to N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (2). Structural features were incorporated to increase affinity for the target receptor, to improve selectivity over D-2 and sigma(1) receptors, to enable labeling with carbon-11 or fluorine-18, and to adjust lipophilicity within the range considered optimal for brain penetration and low nonspecific binding. Compounds 7 and 13 showed the overall best characteristics: nanomolar affinity for the D-4 receptor, >100-fold selectivity over D-2 and D-3 dopamine receptors, 5-HT1A, 5-HT2A, and 5-HT2C serotonin receptors and sigma(1) receptors, and log P = 2.37-2.55. Following intraperitoneal administration in mice, both compounds rapidly entered the central nervous system. The methoxy of N-[2-[4-(3-cyanopyridin-2-yl)piperazin- 1-yl]ethyl]-3-methoxybenzamide (7) was radiolabeled with carbon-11 and subjected to PET analysis in non-human primate. [C-11]7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D-4 receptors.

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