Abstract
[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.
Highlights
Positron emission tomography (PET) is an in vivo, molecular imaging technique capable of providing information on the disease-associated alteration of neurotransmitter function in the living human brain
Fallypride has a sub-nM affinity for the D3 R and is able to compete with synaptic dopamine for binding to the receptor because its primary contacts are located within the orthosteric binding site
This was confirmed by its low root-mean-square distancedistance (RMSD) in the molecular dynamics simulation (MDS) studies, low free energy of binding in the orthosteric binding site, and strong interaction with ASP110
Summary
Positron emission tomography (PET) is an in vivo, molecular imaging technique capable of providing information on the disease-associated alteration of neurotransmitter function in the living human brain. A neurotransmitter system that has drawn attention in PET imaging studies is the dopaminergic (DAergic) system, and numerous studies can be found in the literature on PET imaging studies of both presynaptic and postsynaptic. DAergic function [1,2,3] This can be attributed to the widely recognized role of the DAergic system in a variety of neurological and neuropsychiatric disorders, including schizophrenia, substance abuse, and Parkinson’s disease (PD) [4,5]. D2-family of receptors have been studied in great detail. Members of this receptor family include the D2 (D2 R; both long and short isoforms), D3 (D3 R), and D4 (D4 R) receptors.
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