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

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

Research output: Contribution to journalArticle

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Abstract

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-HT1A, 5-HT2A, and 5-HT2C 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.

Original languageEnglish
Pages (from-to)7344-7355
Number of pages12
JournalJournal of Medicinal Chemistry
Volume53
Issue number20
DOIs
StatePublished - 28 Oct 2010

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    Lacivita, E., De Giorgio, P., Lee, I. T., Rodeheaver, S. I., Weiss, B. A., Fracasso, C., Caccia, S., Berardi, F., Perrone, R., Zhang, M. R., Maeda, J., Higuchi, M., Suhara, T., Schetz, J. A., & Leopoldo, M. (2010). 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. Journal of Medicinal Chemistry, 53(20), 7344-7355. https://doi.org/10.1021/jm100925m