Evaluation of a Fluorinated 2-Nitroimidazole Binding to Hypoxic Cells in Tumor-Bearing Rats by¹⁹ F Magnetic Resonance Spectroscopy and Immunohistochemistry

We have examined a hexafluorinated 2-nitroimidazole, CCI-103F, as a probe for hypoxic tumor cells by in vivo¹⁹ F magnetic resonance spectroscopy (MRS). Following initial intraperitoneal injections of the drug in tumor-bearing (Dunning R3327-AT1-Matlylu) rats,¹⁹ F spectra were obtained on an Otsuka 2.0T Vivospec spectrometer using a 1.5-cm surface coil. Signal at 1- and 2-h time points indicated initial biodistribution of drug in the tumor. At 4 and 8 h, a progressive increase in signal intensity was observed, indicating retention of drug within the tumor. Tumor signal remained detectable in 4 of 10 rats at 24 h, indicating possible nitroreductive bioactivation by hypoxic cells. Immunohistochemistry of these tumors revealed a staining pattern consistent with labeling of hypoxic cells. No detectable¹⁹ F signal was found at 24 h for the other rats, indicating complete washout of unbound drug. Immunohistochemical assessment of these tumors revealed some staining for bound drug at the periphery of necrotic zones. <tex-math>${}^{31}{\rm P}\text{-}{\rm MRS}$</tex-math> of the tumors showed good correlation with the presence or absence of hypoxia as evaluated by <tex-math>${}^{19}{\rm F}\text{-}{\rm MRS}$</tex-math>, <tex-math>$T_{1}\text{-}$</tex-math> and <tex-math>$T_{2}\text{-weighted}$</tex-math> images, and immunohistochemistry. These results provide the groundwork for further studies using this misonidazole analog for noninvasive identification of hypoxic tumor cells in vivo by MRS.