Fluorescent Tools for the Imaging of Dopamine D2‐Like Receptors

The family of dopamine D2‐like receptors represents an interesting target for a variety of neurological diseases, e. g. Parkinson's disease (PD), addiction, or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D2‐li...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2024-01, Vol.25 (2), p.e202300659-n/a
Main Authors: Nagl, Martin, Mönnich, Denise, Rosier, Niklas, Schihada, Hannes, Sirbu, Alexei, Konar, Nergis, Reyes‐Resina, Irene, Navarro, Gemma, Franco, Rafael, Kolb, Peter, Annibale, Paolo, Pockes, Steffen
Format: Article
Language:English
Subjects:
Addictions
Affinity
Binding
Chemical compounds
Confocal microscopy
D2-like receptors
Dopamine
Dopamine D1 receptors
Dopamine D2 receptors
Dopamine D3 receptors
Dopamine D4 receptors
dopamine receptors
Fluorescence
Fluorescence microscopy
fluorescent ligands
Ligands
Mental disorders
Microscopy
molecular brightness
Movement disorders
Neurodegenerative diseases
Neurological diseases
Parkinson's disease
Receptors
Schizophrenia
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Summary:The family of dopamine D2‐like receptors represents an interesting target for a variety of neurological diseases, e. g. Parkinson's disease (PD), addiction, or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D2‐like receptors. Pharmacological characterization in radioligand binding studies identified UR‐MN212 (20) as a high‐affinity ligand for D2‐like receptors (pKi (D2longR)=8.24, pKi (D3R)=8.58, pKi (D4R)=7.78) with decent selectivity towards D1‐like receptors. Compound 20 is a neutral antagonist in a Go1 activation assay at the D2longR, D3R, and D4R, which is an important feature for studies using whole cells. The neutral antagonist 20, equipped with a 5‐TAMRA dye, displayed rapid association to the D2longR in binding studies using confocal microscopy demonstrating its suitability for fluorescence microscopy. Furthermore, in molecular brightness studies, the ligand's binding affinity could be determined in a single‐digit nanomolar range that was in good agreement with radioligand binding data. Therefore, the fluorescent compound can be used for quantitative characterization of native D2‐like receptors in a broad variety of experimental setups. In this study, we have identified UR‐MN212 (20), a spiperone‐based fluorescent ligand bearing a 5‐TAMRA dye, as suitable for fluorescence microscopy at the D2R. The binding affinity in the single‐digit nanomolar range could be determined in radioligand competition binding and molecular brightness studies at D2‐like receptors.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.202300659