2-Phenyl-4-(aminomethyl)imidazoles as Potential Antipsychotic Agents. Synthesis and Dopamine D2 Receptor Binding

The dopamine D2 receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson’s disease. Here, computational methods were used to construct the full models of the dopamine D2 receptor short (D2S) and long (D2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with Gi1 and Gi2 proteins. It was found that the D2L isoform preferentially couples with the Gi2 protein and D2S isoform with the Gi1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D2 receptors and Gi proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.

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Association between striatal and extrastriatal dopamine D2-receptor binding and social desirability

NeuroImage ◽

10.1016/j.neuroimage.2009.12.006 ◽

2010 ◽

Vol 50 (1) ◽

pp. 323-328 ◽

Cited By ~ 33

Author(s):

Simon Cervenka ◽

J. Petter Gustavsson ◽

Christer Halldin ◽

Lars Farde

Keyword(s):

Social Desirability ◽

Receptor Binding ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Dopamine D2

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A Double-Injection Technique for in vivo Measurement of Dopamine D2-Receptor Density in Monkeys with 3-(2'-[18F] Fluoroethyl)Spiperone and Dynamic Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.119 ◽

1989 ◽

Vol 9 (6) ◽

pp. 850-858 ◽

Cited By ~ 31

Author(s):

Sung-Cheng Huang ◽

Mark M. Bahn ◽

Jorge R. Barrio ◽

John M. Hoffman ◽

Nagichettiar Satyamurthy ◽

...

Keyword(s):

Positron Emission Tomography ◽

Receptor Binding ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Emission Tomography ◽

Injection Technique ◽

Receptor Density ◽

Dopamine D2 ◽

Positron Emission ◽

Kinetics Of

Dopamine D2-receptor density in striatum of monkey was measured with 3-(2'-[18F]fluoroethyl)spiperone (FESP) and dynamic positron emission tomography (PET), using a double-injection technique. A first bolus of high specific activity (SA) FESP (5 mCi; ≃ 1 Ci/μmol) was injected i.v.; 90 min later, a second bolus of lower SA FESP (5 mCi; ≃ 0.04 Ci/μmol) was injected. A dynamic PET study was performed to measure the kinetics of FESP in striatum over 180 min, and the metabolite-corrected concentration of FESP in plasma as a function of time was obtained from arterial blood samples. A nonlinear compartmental model that took into account the saturability of the receptor binding was used to describe the kinetics of FESP in striatum. Model parameters were estimated by regression with a constraint based on information about the equilibrium dissociation constant of the ligand–receptor binding. Dopamine D2-receptor density in striatum was estimated to be 25.9 ± 12.7 pmol/g in seven Macaca nemestrina monkeys. The method does not require the use of cerebellum as a reference tissue region and an estimate of dopamine D2-receptor density can be obtained from a single study.

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