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Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice
A(2A) adenosine receptors (A(2A)-AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [(18)F]FLUDA to non-invasively determine the A(2A)-AR availabi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835051/ https://www.ncbi.nlm.nih.gov/pubmed/35162950 http://dx.doi.org/10.3390/ijms23031025 |
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author | Gündel, Daniel Lai, Thu Hang Dukic-Stefanovic, Sladjana Teodoro, Rodrigo Deuther-Conrad, Winnie Toussaint, Magali Kopka, Klaus Moldovan, Rareş-Petru Boknik, Peter Hofmann, Britt Gergs, Ulrich Neumann, Joachim Brust, Peter |
author_facet | Gündel, Daniel Lai, Thu Hang Dukic-Stefanovic, Sladjana Teodoro, Rodrigo Deuther-Conrad, Winnie Toussaint, Magali Kopka, Klaus Moldovan, Rareş-Petru Boknik, Peter Hofmann, Britt Gergs, Ulrich Neumann, Joachim Brust, Peter |
author_sort | Gündel, Daniel |
collection | PubMed |
description | A(2A) adenosine receptors (A(2A)-AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [(18)F]FLUDA to non-invasively determine the A(2A)-AR availability for diagnosis of the A(2A)R status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A(2A)-AR (A(2A)-AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A(2A)R ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters (B(max and) K(D)) of [(18)F]FLUDA on mouse and human atrial tissue samples by autoradiographic studies, and (3) investigated the in vivo uptake of the radiotracer by dynamic PET imaging in A(2A)-AR TG and WT. After A(2A)-AR stimulation by the A(2A)-AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A(2A)-AR-TG animals but not in WT. Radiolabelled [(18)F]FLUDA exhibited a K(D) of 5.9 ± 1.6 nM and a B(max) of 455 ± 78 fmol/mg protein in cardiac samples of A(2A)-AR TG, whereas in WT, as well as in human atrial preparations, only low specific binding was found. Dynamic PET studies revealed a significantly higher initial uptake of [(18)F]FLUDA into the myocardium of A(2A)-AR TG compared to WT. The hA(2A)-AR-specific binding of [(18)F]FLUDA in vivo was verified by pre-administration of the highly affine A(2A)AR-specific antagonist istradefylline. Conclusion: [(18)F]FLUDA is a promising PET probe for the non-invasive assessment of the A(2A)-AR as a marker for pathologies linked to an increased A(2A)-AR density in the heart, as shown in patients with heart failure. |
format | Online Article Text |
id | pubmed-8835051 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88350512022-02-12 Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice Gündel, Daniel Lai, Thu Hang Dukic-Stefanovic, Sladjana Teodoro, Rodrigo Deuther-Conrad, Winnie Toussaint, Magali Kopka, Klaus Moldovan, Rareş-Petru Boknik, Peter Hofmann, Britt Gergs, Ulrich Neumann, Joachim Brust, Peter Int J Mol Sci Article A(2A) adenosine receptors (A(2A)-AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [(18)F]FLUDA to non-invasively determine the A(2A)-AR availability for diagnosis of the A(2A)R status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A(2A)-AR (A(2A)-AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A(2A)R ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters (B(max and) K(D)) of [(18)F]FLUDA on mouse and human atrial tissue samples by autoradiographic studies, and (3) investigated the in vivo uptake of the radiotracer by dynamic PET imaging in A(2A)-AR TG and WT. After A(2A)-AR stimulation by the A(2A)-AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A(2A)-AR-TG animals but not in WT. Radiolabelled [(18)F]FLUDA exhibited a K(D) of 5.9 ± 1.6 nM and a B(max) of 455 ± 78 fmol/mg protein in cardiac samples of A(2A)-AR TG, whereas in WT, as well as in human atrial preparations, only low specific binding was found. Dynamic PET studies revealed a significantly higher initial uptake of [(18)F]FLUDA into the myocardium of A(2A)-AR TG compared to WT. The hA(2A)-AR-specific binding of [(18)F]FLUDA in vivo was verified by pre-administration of the highly affine A(2A)AR-specific antagonist istradefylline. Conclusion: [(18)F]FLUDA is a promising PET probe for the non-invasive assessment of the A(2A)-AR as a marker for pathologies linked to an increased A(2A)-AR density in the heart, as shown in patients with heart failure. MDPI 2022-01-18 /pmc/articles/PMC8835051/ /pubmed/35162950 http://dx.doi.org/10.3390/ijms23031025 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gündel, Daniel Lai, Thu Hang Dukic-Stefanovic, Sladjana Teodoro, Rodrigo Deuther-Conrad, Winnie Toussaint, Magali Kopka, Klaus Moldovan, Rareş-Petru Boknik, Peter Hofmann, Britt Gergs, Ulrich Neumann, Joachim Brust, Peter Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice |
title | Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice |
title_full | Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice |
title_fullStr | Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice |
title_full_unstemmed | Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice |
title_short | Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice |
title_sort | non-invasive assessment of locally overexpressed human adenosine 2a receptors in the heart of transgenic mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835051/ https://www.ncbi.nlm.nih.gov/pubmed/35162950 http://dx.doi.org/10.3390/ijms23031025 |
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