Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice.

Abstract

A2A adenosine receptors (A2A-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 [18F]FLUDA to non-invasively determine the A2A-AR availability for diagnosis of the A2AR status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A2A-AR (A2A-AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A2AR ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters (Bmax and KD) of [18F]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 A2A-AR TG and WT. After A2A-AR stimulation by the A2A-AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A2A-AR-TG animals but not in WT. Radiolabelled [18F]FLUDA exhibited a KD of 5.9 ± 1.6 nM and a Bmax of 455 ± 78 fmol/mg protein in cardiac samples of A2A-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 [18F]FLUDA into the myocardium of A2A-AR TG compared to WT. The hA2A-AR-specific binding of [18F]FLUDA in vivo was verified by pre-administration of the highly affine A2AAR-specific antagonist istradefylline. Conclusion: [18F]FLUDA is a promising PET probe for the non-invasive assessment of the A2A-AR as a marker for pathologies linked to an increased A2A-AR density in the heart, as shown in patients with heart failure.

• Authors: Daniel Gündel, Thu Hang Lai, Sladjana Dukic-Stefanovic, Rodrigo Teodoro, Winnie Deuther-Conrad, Magali Toussaint, Klaus Kopka, Rareş-Petru Moldovan, Peter Boknik, Britt Hofmann, Ulrich Gergs, Joachim Neumann, Peter Brust
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 3 (Jan 18 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35162950 (Publication Type: Journal Article)

Chemical References

• ADORA2A protein, human
• Fluorine Radioisotopes
• Phenethylamines
• Purines
• Receptor, Adenosine A2A
• 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
• istradefylline
• Vidarabine
• Fluorine-18
• Adenosine
• fludarabine

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Animals
• Fluorine Radioisotopes (chemistry)
• Heart (diagnostic imaging, physiology)
• Humans
• Mice
• Mice, Transgenic
• Myocardium (metabolism)
• Phenethylamines (pharmacology)
• Positron-Emission Tomography (methods)
• Purines (pharmacology)
• Receptor, Adenosine A2A (genetics, metabolism)
• Vidarabine (administration & dosage, analogs & derivatives, chemistry)