Molecular modeling of potential new and selective PET radiotracers for the serotonin transporter. Positron Emission Tomography.

Julia Wellsow, Karl-Artur Kovar, Hans-Jürgen Machulla

Index: J. Pharm. Pharm. Sci. 5(3) , 245-57, (2002)

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Abstract

Imaging the serotonin transporter (SERT) with Positron Emission Tomography (PET) provides a useful tool for understanding alterations of the serotonergic system. However, no optimal PET radiotracer for the SERT yet exists. The main purpose of this study was to design potential new and selective PET radiotracers for the SERT and to predict their binding affinity at both the SERT and the norepinephrine transporter.Molecular Modeling was used for ligand design. Predictions of binding affinity were based on models generated by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA).A series of 100 compounds were suggested. As diphenyl sulfide derivatives like [(11)C] DASB have recently proven to be promising PET ligands, rational modification of the diphenyl sulfide scaffold has been performed. The novel compounds were predicted to be selective high affinity SERT ligands. Important new ideas are the introduction of a fluoroethyl-oxycarbonyl group (ester) and a fluorethyl-carbonyl group (ketone), as well as a formyl group (aldehyde), and its corresponding oxime and imine. Another innovative suggestion is the replacement of the sulfur bridge with a cyanamide group and a fluoroethylamino group.The suggested compounds possess features providing new possibilities for carbon-11 or fluorine-18 labeling. Synthesis, biological testing, and screening for PET suitability are reasonable further steps.