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

Date

2021-04-02

Authors

Hsieh, Chia-JI
Riad, Aladdin
Lee, Ji Youn
Sahlholm, Kristoffer
Xu, Kuiying
Luedtke, Robert R.
Mach, Robert H.

ORCID

0000-0001-8469-2371 (Luedtke, Robert R.)

Journal Title

Journal ISSN

Volume Title

Publisher

MDPI

Abstract

[(18)F]Fallypride and [(18)F]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: [(18)F]Fallypride is capable of binding to D3R under "baseline" conditions, whereas [(18)F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [(18)F]Fallypride is able to compete with synaptic dopamine for binding to the D3R, whereas [(18)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 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 beta-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 beta-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.

Description

Citation

Hsieh, C. J., Riad, A., Lee, J. Y., Sahlholm, K., Xu, K., Luedtke, R. R., & Mach, R. H. (2021). Interaction of Ligands for PET with the Dopamine D3 Receptor: In Silico and In Vitro Methods. Biomolecules, 11(4), 529. https://doi.org/10.3390/biom11040529

Rights

© 2021 by the authors.

License

Attribution 4.0 International (CC BY 4.0)