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...
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doaj-76b84321f4d2489c95d5100f3eac0c6c2021-02-26T00:05:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01222285228510.3390/ijms22052285Development of <sup>18</sup>F-Labeled Radiotracers for PET Imaging of the Adenosine A<sub>2A</sub> Receptor: Synthesis, Radiolabeling and Preliminary Biological EvaluationThu Hang Lai0Susann Schröder1Magali Toussaint2Sladjana Dukić-Stefanović3Mathias Kranz4Friedrich-Alexander Ludwig5Steffen Fischer6Jörg Steinbach7Winnie Deuther-Conrad8Peter Brust9Rareş-Petru Moldovan10Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyDepartment of Research and Development, ROTOP Pharmaka Ltd., Dresden 01328, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyHelmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, GermanyThe 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.https://www.mdpi.com/1422-0067/22/5/2285adenosine receptorsA2A receptorfluorine-18positron emission tomographyvipadenant |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thu Hang Lai Susann Schröder Magali Toussaint Sladjana Dukić-Stefanović Mathias Kranz Friedrich-Alexander Ludwig Steffen Fischer Jörg Steinbach Winnie Deuther-Conrad Peter Brust Rareş-Petru Moldovan |
spellingShingle |
Thu Hang Lai Susann Schröder Magali Toussaint Sladjana Dukić-Stefanović Mathias Kranz Friedrich-Alexander Ludwig Steffen Fischer Jörg Steinbach Winnie Deuther-Conrad Peter Brust Rareş-Petru Moldovan 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 International Journal of Molecular Sciences adenosine receptors A2A receptor fluorine-18 positron emission tomography vipadenant |
author_facet |
Thu Hang Lai Susann Schröder Magali Toussaint Sladjana Dukić-Stefanović Mathias Kranz Friedrich-Alexander Ludwig Steffen Fischer Jörg Steinbach Winnie Deuther-Conrad Peter Brust Rareş-Petru Moldovan |
author_sort |
Thu Hang Lai |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-02-01 |
description |
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. |
topic |
adenosine receptors A2A receptor fluorine-18 positron emission tomography vipadenant |
url |
https://www.mdpi.com/1422-0067/22/5/2285 |
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