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.
Deficiency or dysfunction in mitochondrial complex-I (MC-I) is common to many genetic, muscular, endocrine, psychiatric, neurological, and cardiac diseases. Our aim in this project is to validate imaging methodology for non-invasive and quantitative mapping of MC-I expression. Here we apply the technique in myocardial infarction, but envision that the imaging techniques we develop will have general utility in other applications where tissue biopsy is impossible or undesirable.
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