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Enhanced Binding of the Hypoxic Cell Marker [³H]Fluoromisonidazole in Ischemic Myocardium

Division of Cardiology, Department of Medicine and the Departments of Radiology, Radiation Oncology and Medicine, Seattle V. A. Medical Center and the University of Washington, Seattle, Washington

Correspondence: For reprints contact: Gary V. Martin, MD, Dept. of Cardiology (111c), Veterans Administration Medical Center, 1660 South Columbian Way, Seattle, WA 98108.

ABSTRACT

The 2-nitroimidazole fluoromisonidazole is metabolically trapped in viable hypoxic cells in inverse proportion to PO₂. This attribute suggests that [¹⁸F]fluoromisonidazole may be useful for imaging hypoxic tissue using positron emission tomography. To examine this potential, we studied the pharmacokinetics and biodistribution of [³H]fluoromisonidazole in six open chest dogs. In two normal dogs, plasma and urine samples were collected over a 4-hr period following i.v. injection of the drug. In four animals, regional myocardial ischemia was produced 2 hr prior to drug injection by occlusion of the circumflex coronary artery and maintained during the 4-hr sampling period. In all animals, postmortem samples of myocardium and other organs were obtained and tissue, plasma, and urine tritium activity were determined by liquid scintillation counting. In areas of reduced flow, [³H]fluoromisonidazole accumulated in myocardium in inverse proportion to myocardial blood flow measured by microspheres, indicating enhanced binding in hypoxic tissues. Maximum tissue concentrations in ischemic myocardium were two- to three-fold greater than in normal myocardium and plasma. Plasma clearance data indicate the drug is rapidly distributed into the total-body water, clears from the body with a half-life of 275 ± 50 min, and undergoes minimal metabolism by 4 hr. We conclude [¹⁸F]fluoromisonidazole may be a suitable agent for radionuclide imaging of hypoxic myocardium.

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