Detecting Validated Intracellular ROS Generation with (18)F-dihydroethidine-Based PET

PURPOSE: To determine the sensitivity of the (18)F-radiolabelled dihydroethidine analogue ([(18)F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. PROCEDURES: The sensitivity of [(18)F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [(18)F]DHE (50–150 kBq.min(−1)) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. RESULTS: [(18)F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [(18)F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. CONCLUSION: [(18)F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11307-021-01683-0.