[F]-3-Fluoro-2-(4-((2-nitro-1-imidazol-1-yl)methyl)-1-1,2,3-triazol-1-yl)propan-1-ol

The presence of hypoxia is a characteristic feature of solid neoplastic tumors, and it is believed to be related to the aggressive metastasis nature and the development of chemo- and radiotherapy resistance by the tumor (1, 2). In addition, tumor hypoxia is considered to be an important prognostic factor and indicates a poor outcome for the patient (1). Therefore, the hypoxia characterization of tumors is an important diagnostic method for planning cancer treatment(s). Although several invasive and noninvasive methods are available for the detection of hypoxic tumors, these methods have limitations because of the complex blood supply, tumor structure, and oxygen utilization by the tumor cells (3). The invasive method involves placement of oxygen-sensing electrodes and is known to have significant operator variability (1). Among the noninvasive approaches, magnetic resonance imaging with or without contrast agents has been used for the detection of hypoxic tumors, but even this approach does not yield optimal results due to the aberrant blood flow known to exist in different areas of the solid tumors (1). As an alternative, several small molecule tracers or their derivatives (labeled with F or various copper isotopes) have been developed for use with positron emission tomography (PET) imaging to screen for tumor hypoxia. However, because of their lypophilic nature, these agents produce either low signal/noise ratios due to low uptake by hypoxic lesions and slow clearance from normal tissues (e.g., F-fluoromisonidazole ([F]FMISO), a 2-nitroimidazole derivative that is frequently used to characterize hypoxic tumors. The mechanisms of activation, biochemistry, and pharmacology of nitroimidazoles are described by Krohn et al. (4)) or do not detect hypoxia in all tumor types (e.g., Cu-labeled diacetyl-bis(-methylthiosemicarbazone) (4). In an effort to develop a nitroimidazole derivative with superior water solubility and tissue clearance compared to that of [F]-FMISO, a new F-labeled 2-nitroimidazole derivative, [F]-3-fluoro-2-(4-((2-nitro-1-imidazol-1-yl)methyl)-1-1,2,3-triazol-1-yl)propan-1-ol ([F]-HX4), was produced and evaluated for PET imaging of hypoxic tumors in a phase I clinical trial involving six cancer patients (5). Preclinical data for this imaging agent have not been published.