Grant: Operating Grant

When cellular antioxidant regulatory mechanisms become overwhelmed oxidative stress can result. A number of diseases are thought to be the result of acute and/or chronic oxidative stress, but to date there is no means by which to non-invasively monitor this condition in vivo during the onset and progression of disease. This proposal seeks to demonstrate the utility of a new positron emission tomography (PET) tracer that is taken up by the cystine transporter. Cystine is the rate-limiting substrate in cellular glutathione biosynthesis, the predominant cellular antioxidant, thus playing a critical role in the cellular defensive response to oxidative stress by neutralizing free radicals and reactive oxygen and nitrogen species. Thus, the cystine/glutamate transporter (system xc-) represents a potentially attractive biomarker for PET to enable in vivo quantification of transporter activity and its response to oxidative stress associated to disease. We have developed a novel F-18 labeled amino acid tracer, fluoroaminosuberic acid (FASu) that binds xc-. This study seeks to 1) FASu is a specific in vivo binder of the xc- cystine transporter; 2) FASu and PET can be used to non-invasively correlate tracer uptake to xc- transporter activity in vivo; and 3) FASu can be used (by targeting xc-) as a novel amino acid biomarker for imaging tumors outside of the enhanced glycolysis paradigm as established with FDG-PET. A PET agent that can monitor a cellular response outside of the current tradition of assessing enhanced glucose metabolism could allow for earlier diagnoses and a better gauge of post-treatment response for a range of conditions. The results from this study will lay the groundwork for future in vivo specificity and sensitivity studies within specific disease types, with a long term goal of understanding the utility of the cystine transporter as a diagnostic tool to assess the role of ROS in oncology, cardiovascular disease and neurodegeneration.