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 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.