The chemistry and radiochemistry of hypoxia-specific, radiohalogenated nitroaromatic imaging probes

Abstract

Hypoxia is prevalent in many solid tumors. Hypoxic tumors tend to exhibit rapid growth and aberrant vasculature, which lead to oxygen (O2) depletion and impaired drug delivery. The reductive environment in hypoxic tumors alters cellular metabolism, which can trigger transcriptional responses; induce genetic alterations; promote invasion, metastasis, resistance to radiotherapy and chemotherapy, tumor progression, and recurrence; and leads to poor local control and reduced survival rates. Therefore, exploiting the reductive microenvironment in hypoxic tumors by delivering electron-affinic, O2-mimetic radioactive drugs that bioreductively activate selectively in the hypoxic microenvironment offers a logical approach to molecular imaging of focal hypoxia. Because these agents also radiosensitize hypoxic cells, they provide an innovative approach to the therapy management of such tumors. To date, nuclear imaging of hypoxic tumor has proven to be clinically effective, whereas chemical radiosensitization by these compounds has not been helpful. The current review provides an insight into the chemistry, radiochemistry, and purification strategies for selected nitroaromatics that directly exploit the bioreductive environment in hypoxic cells. Both experimental and calculated single-electron reduction potentials of electron-affinic compounds, nitroimidazoles in particular, correlate with in vitro radiosensitizing properties, making them preferred choices for use as radiopharmaceuticals for diagnostic imaging and as sensitizers to enhance the killing effects of low-energy-transfer x-rays (O2-mimetic radiosensitization). Extensive research and careful drug design have led to the development of several potentially useful hypoxia-targeting drugs, for example, [(18)F]FAZA, [(18)F]FMISO, [(18)F]EF5, and [(123)I]IAZA, that accrue selectively in hypoxic cells. These molecular probes are now globally used in clinical hypoxia imaging, including cancer. Future innovative developments must, however, consider hypoxia-selective molecular processes and the physicochemical properties of the drugs that dictate their biodistribution, hypoxia-selective accumulation, pharmacokinetics, clearance, biochemical behavior, and metabolism. This will facilitate their ultimate transformation to effective molecular theranostics, leading to improved multimodal management of cancer.