Dataset Information

Preclinical Evaluation of the First Adenosine A₁ Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

ABSTRACT: Central adenosine A₁ receptor (A₁R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A₁R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A₁R during the sleep-awake cycle. Although several human A₁R PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored non-nucleoside (3,5-dicyanopyridine and 5-cyanopyrimidine) templates for developing an agonist A₁R PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxyphenyl)-6-(2-(6-methylpyridin-2-yl)ethyl)pyridine-3,5-dicarbonitrile (MMPD, 22b), a partial A₁R agonist of sub-nanomolar affinity. [¹¹C]22b showed suitable blood-brain barrier (BBB) permeability and test-retest reproducibility. Regional brain uptake of [¹¹C]22b was consistent with known brain A₁R distribution and was blocked significantly by A₁R but not A_2AR ligands. [¹¹C]22b is the first BBB-permeable A₁R partial agonist PET radiotracer with the promise of detecting endogenous adenosine fluctuations.

SUBMITTER: Guo M

PROVIDER: S-EPMC8327296 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Preclinical Evaluation of the First Adenosine A1 Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

Guo Min M Gao Zhan-Guo ZG Tyler Ryan R Stodden Tyler T Li Yang Y Ramsey Joseph J Zhao Wen-Jing WJ Wang Gene-Jack GJ Wiers Corinde E CE Fowler Joanna S JS Rice Kenner C KC Jacobson Kenneth A KA Kim Sung Won SW Volkow Nora D ND

Journal of medicinal chemistry 20181113 22

Central adenosine A1 receptor (A1R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A1R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A1R during the sleep-awake cycle. Although several human A1R PET tracers have been developed, most are xanthine-based antagonis ...[more]

PMID: 30359014

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Preclinical Evaluation of the First Adenosine A₁ Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

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Preclinical Evaluation of the First Adenosine A<sub>1</sub> Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

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Preclinical Evaluation of the First Adenosine A1 Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

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Preclinical Evaluation of the First Adenosine A&lt;sub&gt;1&lt;/sub&gt; Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

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OmicsDI is part of the ELIXIR infrastructure

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Preclinical Evaluation of the First Adenosine A₁ Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

Preclinical Evaluation of the First Adenosine A<sub>1</sub> Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.