Novel fluorinated hypoxia-targeted compounds as Non-invasive probes for measuring tumor-hypoxia by 19F-magnetic resonance spectroscopy (19F-MRS).

BACKGROUND

19F-labeled 2-nitroimidazoles bound to hypoxic cells in tumors are known to be useful probes for measuring hypoxia, since they can allow their non-invasive detection to be carried out by 19F nuclear magnetic resonance.

MATERIALS AND METHODS

Seven different multifluorinated nitroimidazole-based compounds have been synthesized to furnish this aim: N,N-bis(m-trifluoromethylbenzyl)-3-(2-nitro-1-imidazolyl)propylamine hydrochloride (Bis-mTFN-1); N,N-bis(p-trifluoro-methylbenzyl)-3-(2-nitro-1-imidazolyl)propylamine hydrochloride (Bis-pTFN-1); N-3,5-di-trifluoro-methylbenzyl, 3-(2-nitro-1-imidazolyl)propylamine hydrochloride (DiCF3); N-(m-trifluoromethyl-benzyl)-3-(2-nitro-1-imidazolyl)-propylamine hydrochloride (mTFN-1); N-(p-trifluoromethylbenzyl)-3-(2-nitro-1-imidazolyl)propylamine hydrochloride (pTFN-1); N-(p-trifluoromethylbenzylcarbonyl)-3-(2-nitro-1-imidazolyl)propylamine (pTFA-1) and 5,6-dimethyl-4-[3-(2-nitro-1-imidazolyl)propylamino]-2-trifluoromethylpyrimidine hydrochloride (CF3PM). The compounds were studied in V79 cells in vitro, whereas selected compounds were tested for systemic toxicity in BALB/c mice.

RESULTS

With the exception of pTFA-1, all compounds were soluble in water or saline. All compounds were stable at room temperature as solids, or at 0-5 degrees C as aqueous solutions. Very good uptake were obtained in aerobic V79 cells with selected compounds. Thus, intracellular vs. extracellular concentration ratios (Ci/Ce) were increasing with input concentration up to 200. All compounds behaved as hypoxia-selective cytotoxins in V79 cells, in vitro, with selectivity ranging between 2.0 (DiCF3) to 15.5 (CF3PM). No lethality or body weight loss was observed with all tested compounds. Some signs of neurotoxicity were seen with bis-pTFN-1, mTFN-1 and pTFN-1 at the higher tested i.p. doses. No adverse effects were observed with CF3PM at any tested dose.

CONCLUSION

These results suggest that some of the above compounds could be utilized as 19F-MRS probes for measuring tumor-hypoxia, by accumulation and binding into the hypoxic regions of tumors.