Novel Non-invasive Probes for Measuring Tumor-hypoxia by ¹⁹F-Magnetic Resonance Spectroscopy (¹⁹F-MRS). Studies in the SCCVII/C3H Murine Model

Abstract

Background: ¹⁹F-labeled 2-nitroimidazoles bound to hypoxic cells in tumors are known to be useful probes for measuring hypoxia since they can allow for their non-invasive detection by ¹⁹F nuclear magnetic resonance, provided that they do not lose ¹⁹F during their hypoxia-mediated metabolism. Two such compounds, N-(m-trifluoromethylbenzyl)-3-(2-nitro-1-imidazolyl)-propylamine hydrochloride (mTFN-1) and 5,6-dimethyl-4-[3-(2-nitro-1-imidazolyl)-propylamino]-2-trifluoromethylpyrimidine hydrochloride (CF3PM) were selected from a series of analogs, for their in vivo evaluation, based on their high solubility in saline and low toxicity in mice. Materials and Methods: MRS experiments were performed in anesthetized C3H mice bearing SCCVII tumors in their flanks. Fluorinated compounds, mTFN-1 or CF3PM, were injected intraperitoneally (i.p.) at a dose of 110 or 150 mg/kg, respectively, in 0.75 mL saline. A 0.9 cm surface coil tuned to fluorine frequency was positioned directly over the tumor, the head, or the liver and 1800 transients were collected over 20 min in a Bruker Omega 4.7 T instrument. Spectroscopic measurements were taken at 2, 7 and 19 h post injection of the fluorinated drug. Results: CF3PM was detected in the plasma up to 2 h post injection with maximum concentration observed 30 min post administration. In the MRS studies, mTFN-1 signal in the tumor was 68.8, 86.8 and 27.2% of the reference at 1-2, 6-7 and 18-19 h post injection, respectively. The corresponding values in the brain were 0, 125.7 and 26.6%, respectively, whereas the corresponding values in the liver were 359.3, 307.7 and 0%, respectively. CF3PM signal in the tumor was 3.3, 57.7 and 7.1% of the reference at 1-2, 6-7 and 18-19 h post injection, respectively. The corresponding values in the liver were 267.6, 60.5 and 0%, respectively. No CF3PM signal was detected in the brain at any time interval. Conclusion: These results suggest that CF3PM could be used as a potential probe for measuring hypoxia in tumors by ¹⁹F-MRS.