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 D₄ receptors

Here we describe the design, synthesis, and evaluation of physicochemical and pharmacological properties 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 σ₁ 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 receptors, 5-HT_1A, 5-HT_2A, and 5-HT_2C serotonin receptors and σ₁ 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. [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.