Coronary artery disease (CAD) is the greatest cause of morbidity and mortality in the USA and the greatest health care cost. Currently, myocardial perfusion scintigraphy (MPS) is the most widely applied noninvasive imaging method for the diagnosis, localization and risk stratification of patients with known or suspected CAD. Thallium-201 and technetium-99m labeled compounds are most widely used. The uptake of these agents is not completely linear with the blood flow. The deviation from linearity at high flow rates limits the ability to image regions of less severe disease and distinguish these regions from normally perfused tissue. This, in turn, reduces diagnostic sensitivity and leads to the underestimation of disease, prejudicing risk assessment and related management decisions. Iodorotenone, a compound that binds to complex I of the electron transport chain in mitochondria, has been found to have distribution, extraction and retention characteristics in heart tissue, superior to thallium and the technetium perfusion agents. Iodorotenone is extracted 80-90% in heart tissue, is more linear with flow than Tc-sestamibi and has limited lung accumulation giving better heart-to-lung contrast. The goal of the present research is to validate our hypothesis that iodorotenone is a superior perfusion tracer that will be a more beneficial clinical agent by improving the sensitivity and specificity of lesion detection. The approach involves gathering the requisite biological, toxicological and radiation dosimetry data to prove the safety of the tracer and gaining approvals to evaluate the efficacy of the new tracer in humans. To this end toxicological and pharmacokinetic studies will be performed to GLP standards. Blood binding and sub-cellular distribution of the tracer will be evaluated. The radiation dosimetry will be performed in normal canines. Models of ischemic coronary disease and low flow in canines will be used to further validate the tracer kinetics. Finally, human subject studies will offer a direct comparison of [123I]iodorotenone to 99mTc-sestamibi thereby providing initial evidence of the clinical value of iodorotenone as a perfusion tracer. The potential clinical impact of an improved flow tracer such as [123I]iodorotenone is far-reaching.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000482-03
Application #
6865412
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Zhang, Yantian
Project Start
2003-03-10
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2008-02-29
Support Year
3
Fiscal Year
2005
Total Cost
$587,244
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
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