Interaction of Ligands for PET with the Dopamine D3 Receptor: In Silico and In Vitro Methods.

[F]Fallypride and [F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (DR). In spite of their similar D affinities, the two PET ligands display very different properties for labeling the DR in vivo: [F]Fallypride is capable of binding to DR under "baseline" conditions, whereas [F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [F]Fallypride is able to compete with synaptic dopamine for binding to the DR, whereas [F]FTP is not. The goal of this study was to conduct a series of docking and molecular dynamic simulation studies to identify differences in the ability of each molecule to interact with the DR that could explain these differences with respect to competition with synaptic dopamine. Competition studies measuring the ability of each ligand to compete with dopamine in the β-arrestin assay were also conducted. The results of the in silico studies indicate that FTP has a weaker interaction with the orthosteric binding site of the DR versus that of Fallypride. The results of the in silico studies were also consistent with the IC50 values of each compound in the dopamine β-arrestin competition assays. The results of this study indicate that in silico methods may be able to predict the ability of a small molecule to compete with synaptic dopamine for binding to the DR.