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

[¹⁸F]Fallypride and [¹⁸F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D₃R). In spite of their similar D₃ affinities, the two PET ligands display very different properties for labeling the D₃R in vivo: [¹⁸F]Fallypride is capable of binding to D₃R under "baseline" conditions, whereas [¹⁸F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [¹⁸F]Fallypride is able to compete with synaptic dopamine for binding to the D₃R, whereas [¹⁸F]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 D₃R 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 D₃R 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 D₃R.