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PET imaging of mitochondrial complex I expression


Deficiency or dysfunction in mitochondrial complex-I (MC-I) is common to many genetic, muscular, endocrine, psychiatric, and neurological diseases. Furthermore, myocardial ischemia and infarction cause moderate to severe reductions in MC-I with implications for tissue viability and treatment options. Currently, there is no method by which to assess mitochondrial expression non-invasively. [18F]Flurpiridaz is an analog of pyridaben, a potent MC-I inhibitor, and a new PET tracer currently in clinical trials to measure myocardial blood flow. It's mechanism of action as a flow tracer is that of a chemical microsphere, appearing to be irreversibly bound to MC-I over short time scales such as the duration of a myocardial perfusion study. Although in vitro experiments confirm that the binding of this ligand at MC-I is indeed saturable and reversible, the potential of [18F]flurpiridaz for imaging MC-I expression has not yet been explored. Our preliminary data suggest that the first few minutes of the [18F]flurpiridaz concentration history is determined solely by blood flow; whereas, its later time course is determined by reversible binding to MC-I, permitting the estimation of its binding potential with PET imaging and tracer kinetic modeling. In this proposal, we will non-invasively map blood flow and MC-I expression using dynamic PET imaging with specific application to a porcine model of myocardial infarction and validate PET- derived estimates of perfusion and MC-I binding using microspheres and Western blotting, respectively. We anticipate that our methods for quantifying myocardial MC-I with PET will be applicable to other conditions in which mitochondrial dysregulation is implicated. MC-I imaging with PET could obviate the need for muscle biopsies to diagnose neuromuscular disease and permit MC-I assay where biopsy is not feasible, such as in the brain where mitochondrial pathology has been implicated in Parkinson's disease, Huntington's disease, and schizophrenia.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.