Design synthesis radiolabeling and in vivo evaluation of carbon-11 labeled N-2-4-(3-cyanopyridin-2-yl)piperazin-1-ylethyl-3-methoxybenzamide a potential Positron Emission Tomography tracer for the dopamine D4 receptors

摘要

Here we describe the design, synthesis, physicochemical, and pharmacological evaluation of D4 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 D2 and sigma1 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 D4 receptor, > 100-fold selectivity over D2 and D3 dopamine receptor 5-HT1A, 5-HT2A and 5-HT2C serotonin receptors and sigma1 receptors, and logP = 2.37–2.55. Following intraperitoneal administration, 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 radiolabelled with carbon-11 and subjected to PET analysis in non-human primate. [¹¹C]>7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D4 receptors.