The Chemistry and Radiochemistry of Hypoxia-Speci fi c, Radiohalogenated Nitroaromatic Imaging Probes Piyush Kumar, PhD, Veena Bacchu, PhD, and Leonard Irving Wiebe, PhD, DSc Hypoxia is prevalent in many solid tumors. Hypoxic tumors tend to exhibit rapid growth and aberrant vasculature, which lead to oxygen (O 2 ) 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, resist- ance 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, O 2 -mimetic radioactive drugs that bioreduc- tively 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 nitro- aromatics that directly exploit the bioreductive environment in hypoxic cells. Both experimental and calculated single-electron reduction potentials of electron-affinic compounds, nitro- imidazoles 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 (O 2 -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 trans- formation to effective molecular theranostics, leading to improved multimodal management of cancer. Semin Nucl Med 45:122-135 C 2015 Elsevier Inc. All rights reserved. Introduction H ypoxia occurs when oxygen (O 2 ) demand exceeds its supply; it can be a systemic (whole body) or regional or focal phenomenon. The regional ischemia associated with many pathologies creates long-standing or transient 1 focal hypoxic microenvironments that are characterized by anaero- bic metabolism. In cancer, hypoxia induces metabolic and molecular changes that create an aggressive phenotype, promoting metastasis and inducing resistance to chemother- apy and radiotherapy. 2,3 The detection of focal hypoxia 122 http://dx.doi.org/10.1053/j.semnuclmed.2014.10.005 0001-2998/& 2015 Elsevier Inc. All rights reserved. The authors sincerely acknowledge Alberta Innovates - Health Solutions, Canada for providing CRIO Program award (PK#201201164) and CRIO Cancer Project award (PK#201300709) to support our hypoxia research program. Financial support from Alberta Cancer Foundation, Canada (Grants PK#791926 and PK#22125) and ACF-Canadian Institutes of Health Research, Canada Partner Grant (PK#25966) is also greatly appreciated. Department of Oncology, University of Alberta, Edmonton, Alberta, Canada. Address reprint requests to Piyush Kumar, PhD, Oncologic Imaging, Depart- ment of Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta, Canada T6G 1Z2. E-mail: pkumar@ualberta.ca