Novel non-invasive probes for measuring tumor-hypoxia by 19F-magnetic resonance spectroscopy (19F-MRS). Studies in the SCCVII/C3H murine model.
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.


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.


CONCLUSIONS
These results suggest that CF3PM could be used as a potential probe for measuring hypoxia in tumors by 19F-MRS.
Papadopoulou
Maria V
MV
Evanston Northwestern Healthcare, Department of Radiation Medicine, 2650 Ridge Avenue, Evanston, IL 60201, USA. m-papadopoulou@northwestern.edu
Pouremad
Reza
R
Bloomer
William D
WD
Wyrwicz
Alice
A
D000818:Animals; D014408:Biomarkers, Tumor / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles