Development of new 18F-labelled small molecules for the detection of oxidative stress using positron emission tomography: SI:Abstracts ISHR-ES Amsterdam

Background: Reactive oxygen species are endogenously generated as by-products of the mitochondrial electron transport chain, and play important roles in the regulation of cell growth, neurotransmission, and the immune system. In elevated levels however, ROS ultimately lead to oxidation of DNA, proteins, and cell membranes. The resulting oxidative stress underlies the pathogenesis of numerous disease states, including cardiovascular disease, and chemotherapy-induced cardiotoxicity. Despite their widespread pathological importance, there is currently no means of non-invasively detecting elevated ROS levels in humans.

Methods and results: ROS detection in vitro and in small animals in vivo using fluorescent probes such as Dihydroethidium (DHE) is common practice, but of limited translational potential due to their lack of selectivity, susceptibility to radiolysis, and ability to intercalate DNA.

We are exploring new chemical entities as potential tracers for direct detection of ROS in vivo using PET. Our 18F-tracers were designed to be cell membrane permeable, but susceptible to oxidation by ROS, leading to changes in physicochemical properties that favour prolonged intracellular retention.

Conclusion: Preliminary studies in small animals show our lead tracer has low baseline retention in the heart, and fast blood clearance. The newly developed tracers will be used to investigate the timeline of ROS generation in models of cardiac injury and toxicity in vivo.