Non-invasive PET and SPECT imaging of tissue hypoxia using isotopically labeled 2-nitroimidazoles

The measurement of pathologically low levels of tissue pO2 is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. A class of bioreductively activated drugs, typified by the 2-nitroimidazoles, has excellent potential for application to this goal. Such drugs bind to cells at a rate which is maximal under conditions of severe hypoxia (e.g. less than 0.05% oxygen) and is inhibited, with Michaelis-Menten kinetics, as a function of increasing oxygen concentration. A number of detection possibilities exist for the drug adducts, including invasive assays which can measure drug adducts in tissue sections at cell-to-cell resolution. Use of such agents in non-invasive assays is important and, to this end, a number of drugs have been conjugated with radioactive isotopes suitable for detection by Nuclear Medicine techniques. In contrast with the invasive assays, resolution and contrast is much more limited with the non-invasive assays. Thus, there are many factors contributing to the balance of pros and cons for the non-invasive vs. invasive use of 2-nitroimidazole drugs as hypoxia detectors. These factors will be summarized in this review, with emphasis on compounds suitable for clinical use. PET (positron emission tomography) imaging with 18F-labeled EF5 (a drug in current clinical trials using invasive assays) will be described.