Development of <sup>18</sup>F-Labeled Radiotracers for PET Imaging of the Adenosine A<sub>2A</sub> Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation
The adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A...
Main Authors: | , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-02-01
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Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/22/5/2285 |
Summary: | The adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A<sub>2A</sub>R-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (<b>PPY</b>). Among those, the highly affine 4-fluorobenzyl derivate (<b>PPY1</b>; <i>K</i><sub>i</sub>(<i>h</i>A<sub>2A</sub>R) = 5.3 nM) and the 2-fluorobenzyl derivate (<b>PPY2</b>; <i>K</i><sub>i</sub>(<i>h</i>A<sub>2A</sub>R) = 2.1 nM) were chosen for <sup>18</sup>F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [<sup>18</sup>F]<b>PPY</b><b>1</b> and [18F]<b>PPY2</b> in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [<sup>18</sup>F]<b>PPY</b><b>2</b> on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance. |
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ISSN: | 1661-6596 1422-0067 |