Noninvasive detection of tumor hypoxia using the 2-nitroimidazole [F-18]EF1

The noninvasive assessment of tumor hypoxia in vivo is under active investi gation because hypoxia has been shown to be an important prognostic factor for therapy resistance. Various nuclear medicine imaging modalities are bei ng used, including PET imaging of F-18-containing compounds. In this study, we report the development of F-18-labeled EF1 for noninvasive imaging of h ypoxia. EF1 is a 3-monofluoro analog of the well-characterized hypoxia mark er EF5, 2(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamid e, which has been used to detect hypoxia in tumor and nontumor systems usin g immunohistochemical methods. Methods: We have studied 2 rat tumor types: the hypoxic Morris 7777 (Q7) hepatoma and the oxic 9LF glioma tumor, each g rown in subcutaneous sites. PET studies were performed using a pharmacologi cal dose of nonradioactive carrier in addition to [F-18]EF1 to optimize and assess drug biodistribution. After PET imaging of the tumor-bearing rats, tissues were obtained for gamma-counting of the F-18 in Various tissues and immunohistochemical detection of intracellular drug adducts in tumors. In one pair of tumors, Eppendorf needle electrode studies were performed. Resu lts: [F-18]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 o n PET studies and 2.1, 2.5, and 3.0 based on gamma-counting of the tissues (n = 3). in contrast, the T/M ratio of [F-18]EF1 in the 9LF glioma tumor wa s 0.8 and 0.5 based on PET studies and 1.0, 1.2, and 1.4 based on gamma-cou nting of the tissues (n = 3). Immunohistochemical analysis of drug adducts for the two tumor types agreed with the radioactivity analysis. In the Q7 t umor, substantial heterogeneous binding was observed throughout the tumor, whereas in the 9LF tumor minimal binding was found. Conclusion: [F-18]EF1 i s an excellent radiotracer for noninvasive imaging of tumor hypoxia.