Nitroimidazoles for imaging hypoxic myocardium

Abstract

A series of radiopharmaceuticals that incorporate nitroimidazole moieties have been synthesized to detect decreased local tissue pO2. In contrast to agents that localize in proportion to perfusion, these agents concentrate in hypoxic tissue. Myocardium with an intracellular pO2 < 3 mm Hg (about 25% of normal), which has lost its contractile ability but has maintained its ability to catabolize glucose, can be localized with this imaging technique. When a nitroimidazole enters a viable cell, the molecule undergoes a series of reactions: Initially, the molecule gains a single electron by an enzymatic process in the cytoplasm to form a potentially reactive species, then in the presence of adequate intracellular oxygen levels the molecule is reoxidized. These reactions are repeated until the intact molecule diffuses back out of the cell. In myocytes with reduced oxygen concentration, the reoxidation does not take place, the reactive species appears to undergo additional reduction reactions and remains in the cell. The association of the reduced nitroimidazole and other cellular elements is not irreversible, since these agents clear from hypoxic tissue with a half-life of 4 to 8 hours. In one of the first nitroimidazoles used for in vivo imaging, fluoromisonidazole was the radiopharmaceutical. Two major problems with fluoromisonidazole are its relatively low concentration within the lesion and the need to wait several hours to permit clearance of the agent from the normoxic background tissue (contrast between lesion and background typically < 2:1 at about 90 minutes after injection). Even with high resolution positron emission tomography imaging, this combination of circumstances makes successful evaluation of hypoxic lesions a challenge. The development of single photon agents with longer physical half-lives and comparable biologic properties offer a greater opportunity for successful imaging. In 1992 technetium 99m-labeled nitroimidazoles were described that had in vivo kinetics that were potentially suitable for detection of hypoxic myocardium. Laboratory studies showed preferential binding of these agents to hypoxic myocytes and isolated hearts in vitro and to ischemic myocardial tissue in laboratory animals. Patient studies are planned to determine whether the promise of these agents in laboratory studies can be realized in clinical practice.