PT - JOURNAL ARTICLE AU - Satish K. Chitneni AU - Gerald T. Bida AU - Hong Yuan AU - Gregory M. Palmer AU - Michael P. Hay AU - Thorsten Melcher AU - William R. Wilson AU - Michael R. Zalutsky AU - Mark W. Dewhirst TI - <sup>18</sup>F-EF5 PET Imaging as an Early Response Biomarker for the Hypoxia-Activated Prodrug SN30000 Combined with Radiation Treatment in a Non–Small Cell Lung Cancer Xenograft Model AID - 10.2967/jnumed.112.116293 DP - 2013 Aug 01 TA - Journal of Nuclear Medicine PG - 1339--1346 VI - 54 IP - 8 4099 - http://jnm.snmjournals.org/content/54/8/1339.short 4100 - http://jnm.snmjournals.org/content/54/8/1339.full SO - J Nucl Med2013 Aug 01; 54 AB - Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-18F-pentafluoropropyl)-acetamide (18F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). Methods: Human non–small cell lung cancer xenografts (H460) in athymic rats were imaged with 18F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by 18F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. Results: The uptake of 18F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P &lt; 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in 18F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased 18F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased 18F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in 18F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. Conclusion: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of 18F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.