A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers

The presence of regions of low tumor oxygen partial pressure (pO2) have long been associated with resistance to radio- and chemotherapy and increased incidence of metastasis and rates of disease recurrence. This phenomenon was attributed to a direct effect of pO2 on the efficacy of external-beam radiation (termed the oxygen enhancement effect) (1). Recent studies have also highlighted the role of the cellular oxygen-sensing mechanisms, in particular the hypoxia-inducible factor (HIF) transcription factors, in governing tumor phenotype and response to therapy (2). Although the influence of tumor hypoxia on disease progression and treatment response is becoming increasing clear, there is no widespread clinical utility for the determination of pO2 in solid tumors. This is in part due to the methods currently available to measure pO2, none of which are completely appropriate as universal biomarkers of tumor hypoxia. Polarographic electrodes inserted directly into tumors can provide absolute pO2 measurements but can only practically be performed on easily accessible tumor sites. The systemic administration of 2-nitroimidazole–based hypoxia tracers such as pimonidazole and EF5, followed by immunohistochemical detection, has also been previously used (3). These compounds are reduced and specifically retained in hypoxic tumor cells, allowing detection and quantitation of hypoxic regions at the microscopic level. However, in common with polarographic electrode measurements, the method is invasive and subject to potential sampling errors. The employment of endogenous histologic biomarkers of tumor hypoxia has also been widely examined, with the markers carbonic anhydrase 9 (Ca9) and lysyl oxidase showing the most promise (4). Employment of such markers can be complicated by cell-type–specific expression and nonuniform response to changes in the underlying pO2, nonhypoxic regulation of expression, and a temporal mismatch between changes in pO2 and the corresponding change in marker expression (5). When compared with these methods, PET imaging using hypoxia-selective tracers is an attractive option for tumor pO2 assessment. Several hypoxia PET tracers have been developed, based mainly on radiochemical derivatives of the 2-nitroimidazole and (bis) thiosemicarbazone structures (6). PET imaging is generally conducted soon after tracer administration (reducing temporal mismatch) and allows quantitative imaging of the whole tumor (reducing sampling error). Although cellular uptake of these tracers is passive, an enzyme-mediated reduction step is crucial to their hypoxia selectivity. However, in the case of 2-nitroimidazole compounds, bio reductive enzyme expression is rarely rate-limiting, and pO2 is the primary determinant of tracer retention (7). Significant efforts have been made to optimize hypoxia PET image contrast, primarily by modifications to the chemical structures of the radiotracers resulting in altered pharmacokinetics (8). In general, the more lipophilic compounds display rapid tissue equilibration and higher first-pass tumor uptake rates but slower background clearance and higher liver accumulation. The hydrophilic compounds display the reverse characteristics: rapid renal clearance, lower liver uptake, and reduced production of metabolites, at the cost of lower absolute uptake and more heterogeneous tumor distribution. There are few published studies that directly compare the performance of the PET hypoxia tracers relative to each other under controlled conditions. Those that have been conducted have used sequential tracer administration to the same patient or animal, separated by periods of up to 3 d. However, acute changes in tumor hypoxia can potentially introduce uncertainly into studies using sequential tracer administration. The aim of this study was to compare the imaging characteristics and hypoxia specificity of 4 hypoxia PET tracers under standardized conditions in the same animal xenograft model.