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Noninvasive Detection of Tumor Hypoxia Using the 2-Nitroimidazole [¹⁸F]EF1

Schools of Medicine and Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Department of Chemistry, University of Florida, Gainesville, Florida
Cancer Center, University of Rochester, Rochester, New York

Correspondence: For correspondence or reprints contact: Sydney M. Evans, VMD, University of Pennsylvania School of Medicine, Division of Oncology Research, 195 John Morgan Bldg., Philadelphia, PA 19104.

ABSTRACT

The noninvasive assessment of tumor hypoxia in vivo is under active investigation because hypoxia has been shown to be an important prognostic factor for therapy resistance. Various nuclear medicine imaging modalities are being used, including PET imaging of ¹⁸F-containing compounds. In this study, we report the development of ¹⁸F-labeled EF1 for noninvasive imaging of hypoxia. EF1 is a 3-monofluoro analog of the well-characterized hypoxia marker EF5, 2(2-nitro-1H-imidazol-1-yl)-N(2,2,3,3,3-pentafluoropropyl)acetamide, which has been used to detect hypoxia in tumor and nontumor systems using immunohistochemical methods. Methods: We have studied 2 rat tumor types: the hypoxic Morris 7777 (Q7) hepatoma and the oxic 9LF glioma tumor, each grown in subcutaneous sites. PET studies were performed using a pharmacological dose of nonradioactive carrier in addition to [¹⁸F]EF1 to optimize and assess drug biodistribution. After PET imaging of the tumor-bearing rats, tissues were obtained for -counting of the ¹⁸F in various tissues and immunohistochemical detection of intracellular drug adducts in tumors. In one pair of tumors, Eppendorf needle electrode studies were performed. Results: [¹⁸F]EF1 was excreted dominantly through the urinary tract. The tumor-to-muscle (T/M) ratio of [¹⁸F]EF1 in the Q7 tumors was 2.7 and 2.4 based on PET studies and 2.1, 2.5, and 3.0 based on -counting of the tissues (n = 3). In contrast, the T/M ratio of [¹⁸F]EF1 in the 9LF glioma tumor was 0.8 and 0.5 based on PET studies and 1.0, 1.2, and 1.4 based on --counting of the tissues (n = 3). Immunohistochemical analysis of drug adducts for the two tumor types agreed with the radioactivity analysis. In the Q7 tumor, substantial heterogeneous binding was observed throughout the tumor, whereas in the 9LF tumor minimal binding was found. Conclusion: [¹⁸F]EF1 is an excellent radiotracer for noninvasive imaging of tumor hypoxia.

Key Words: hypoxia • tumor • PET • EF1 • EF3 • imaging • ¹⁸F • rat • hepatoma • glioma

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