Enza Lacivita, Paola De Giorgio, Irene T Lee, Sean I Rodeheaver, Bryan A Weiss, Claudia Fracasso, Silvio Caccia, Francesco Berardi, Roberto Perrone, Ming-Rong Zhang, Jun Maeda, Makoto Higuchi, Tetsuya Suhara, John A Schetz, Marcello Leopoldo
Dipartimento Farmaco-Chimico, Università degli Studi di Bari A Moro, Via Orabona 4, 70125 Bari, Italy.
Journal of medicinal chemistry 2010 Oct 28Here 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 σ(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-HT(1A), 5-HT(2A), and 5-HT(2C) serotonin receptors and σ(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. [(11)C]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.
Enza Lacivita, Paola De Giorgio, Irene T Lee, Sean I Rodeheaver, Bryan A Weiss, Claudia Fracasso, Silvio Caccia, Francesco Berardi, Roberto Perrone, Ming-Rong Zhang, Jun Maeda, Makoto Higuchi, Tetsuya Suhara, John A Schetz, Marcello Leopoldo. 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. Journal of medicinal chemistry. 2010 Oct 28;53(20):7344-55
PMID: 20873719
View Full Text