Nitroimidazoles and imaging hypoxia

Abstract

Decreased tissue oxygen tension is a component of many diseases. Although hypoxia can be secondary to a low inspired pO2 or a variety of lung disorders, the commonest cause is ischemia due to an oxygen demand greater than the local oxygen supply. In tumors, low tissue pO2 is often observed, most often due to a blood supply inadequate to meet the tumor's demands. Hypoxic tumor tissue is associated with increased resistance to therapy. In the heart tissue hypoxia is often observed in persistent low-flow states, such as hibernating myocardium. In patients with stroke, hypoxia has been associated with the penumbral region, where an intervention could preserve function. Despite the potential importance of oxygen levels in tissue, difficulty in making this measurement in vivo has limited its role in clinical decision making. A class of compounds known to undergo different intracellular metabolism depending on the availability of oxygen in tissue, the nitroimidazoles, have been advocated for imaging hypoxic tissue. When a nitroimidazole enters a viable cell the molecule undergoes a single electron reduction, to form a potentially reactive species. In the presence of normal oxygen levels the molecule is immediately reoxidized. This futile shuttling takes place for some time, before the molecule diffuses out of the cell. In hypoxic tissue the low oxygen concentration is not able to effectively compete to reoxidize the molecule and further reduction appears to take place, culminating in the association of the reduced nitroimidazole with various intracellular components. The association is not irreversible, since these agents clear from hypoxic tissue over time. Initial development of nitroimidazoles for in vivo imaging used radiohalogenated derivatives of misonidazole, such as fluoromisonidazole, some of which have recently been employed in patients. 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 min after injection). Even with high-resolution positron emission tomographic imaging, this combination of circumstances makes successful evaluation of hypoxic lesions a challenge.(ABSTRACT TRUNCATED AT 400 WORDS)

PET imaging of cardiac hypoxia: Opportunities and challenges

“…It must rapidly localize in the tissue of interest with a target to background ratio ideally greater than 3 to 1, and it should clear quickly from the blood pool and normoxic tissues to allow rapid imaging of hypoxic tissue [36]. This requirement is amplified in the case of ischemia because of the potential for poor delivery of tracer to the affected region.…”

PET imaging of hypoxia using [18F]HX4: a phase I trial

“…[ 18 F]Fluoromisonidazole ([ 18 F]FMISO) is the first radiolabelled 2-nitroimidazole derivative proposed for hypoxia imaging with PET [3,4]. The relatively low uptake of [ 18 F]FMISO observed in hypoxic lesions coupled with its slow clearance from normoxic tissue, however, limits the clinical potential of this agent [5]. A number of other 18 F-labelled nitroimidazole derivatives have been identified, investigated and reported to overcome these problems [6,7].…”

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

“…Instead of using enzymatically induced pH changes (3,8), for the first time to our knowledge, we have taken advantage of the local generation of hypoxia due to the consumption of oxygen in the enzymatic reaction as a trigger for rapid insulin release in response to hyperglycemia. To achieve hypoxia-responsive transduction, 2-nitroimidazole (NI), a hydrophobic component that has often been applied in cancer imaging due to its high sensitivity to the hypoxic condition in tumor sites, was used (24,25). NI can be converted to hydrophilic 2-aminoimidazoles under a hypoxic environment via a single-electron reduction catalyzed by a series of nitroreductases coupled to bioreducing agents, such as NADPH, a plentiful coenzyme in tissues (24)(25)(26)(27).…”