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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB016315-02
Application #
8554770
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Sastre, Antonio
Project Start
2012-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$204,223
Indirect Cost
$86,348
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Andreyev, Andriy; Sitek, Arkadiusz; Celler, Anna (2014) EM reconstruction of dual isotope PET using staggered injections and prompt gamma positron emitters. Med Phys 41:022501