Fluoromisonidazole. A metabolic marker of myocyte hypoxia.

Abstract

Fluoromisonidazole is metabolically trapped in viable hypoxic cells in vitro. This property is the basis for the hypothesis that [18F]fluoromisonidazole can be used to detect hypoxic tissues noninvasively using positron emission tomography. To assess the potential usefulness of this compound as a marker for hypoxic myocardium, we measured the accumulation of [3H]fluoromisonidazole in isolated adult rat myocytes under normoxic, hypoxic (5,000 ppm O2), and anoxic conditions. Both anoxia and hypoxia caused a marked increase in [3H]fluoromisonidazole accumulation. Relative to uptake during normoxia, uptake during anoxia was increased by 8.4-fold at 60 minutes and 26.5-fold at 180 minutes (p less than 0.001). During hypoxia, uptake was increased by 4.4-fold at 60 minutes and by 15.3-fold at 180 minutes (p less than 0.0001) and occurred in the absence of significant cell injury as measured by release of creatine kinase and changes in cell morphology. Additional studies demonstrated a slow oxygen-insensitive efflux of fluoromisonidazole or labeled metabolite(s) from myocytes reincubated in drug-free medium. We conclude that fluoromisonidazole is avidly retained in hypoxic myocytes and thus may be suitable for noninvasive detection of hypoxic myocardium using positron emission tomography.