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.
Highlights
Multiple effects of adenosine in humans and animals have been described for many years
The present work demonstrates the usefulness of the new radiotracer [18F]FLUDA for specific A2A-AR imaging by positron emission tomography (PET) in cardiac tissue
We present evidence that (1) FLUDA is a functional antagonist towards the human A2A-AR and (2) [18F]FLUDA binds and with high binding affinity to the human A2A-AR in a mouse model with transgenic overexpression of the receptor in the cardiac tissue and to A2A-AR in human cardiac tissue in vitro
Summary
Multiple effects of adenosine in humans and animals have been described for many years. Adenosine, potentially released from myocardial ATP, reduces the heart rate and dilates coronary arteries [1]. It elicits negative chronotropic (sinus node), negative dromotropic (AV-node), and negative inotropic (atrial tissue) effects in the hearts of mice and humans [1]. Adenosine binds to different adenosine receptors, which are classified into different subtypes (A1-AR, A2A-AR, A2B-AR, and A3-AR) [1,2] They are located in the outer cell membrane of cardiomyocytes, endothelial cells, fibroblasts, erythrocytes, leucocytes, and smooth muscle cells and coupled to GTP-binding proteins to trigger intracellular signalling pathways. Inotropic effects elicited by β-adrenergic stimulation (cAMP elevation) are antagonised by the A1-AR adenosine signalling in cardiomyocytes in the atrium and the ventricle [5,6].
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