In vivo 19F magnetic resonance spectroscopy and chemical shift imaging of tri-fluoro-nitroimidazole as a potential hypoxia reporter in solid tumors.
OBJECTIVE
2-Nitro-alpha-[(2,2,2-trifluoroethoxy)methyl]-imidazole-1-ethanol (TF-MISO) was investigated as a potential noninvasive marker of tissue oxygen levels in tumors using (19)F magnetic resonance spectroscopy (MRS) and (19)F chemical shift imaging.


METHODS
In vitro data were obtained using high-performance liquid chromatography on tumor cells incubated under varying oxygen conditions to determine the oxygen-binding characteristics. In vivo data were obtained using a well-characterized hypoxic murine breast tumor (MCa), in addition to studies on a rat prostate tumor model (R3327-AT) implanted in nude mice. Detection of intratumor (19)F signal from TF-MISO was done using MRS for up to 10 h following a 75 mg/kg i.v. injection. Localized distribution of the compound in the implanted MCa tumor has been imaged using slice-selective two-dimensional chemical shift imaging 6 h after injection.


RESULTS
The in vitro results showed that TF-MISO preferentially accumulates in cells incubated under anoxic conditions. The in vivo (19)F MR spectral features (line width and chemical shift) were recorded as a function of time after injection, and the results indicate that the fluorine atoms are indeed sensitive to changes in the local environment while still providing a detectable MR signal. Ex vivo spectra were collected and established the visibility of the (19)F signal under conditions of maximum hypoxia. Late time point (>6 h) tumor tissue concentrations, as obtained from (19)F MRS, suggest that TF-MISO is reduced and retained in hypoxic tumor. The feasibility of obtaining TF-MISO tumor distribution maps in a reasonable time frame was established.


CONCLUSIONS
Based on the results presented herein, it is suggested that TF-MISO has the potential to be a valid magnetic resonance hypoxia imaging reporter for both preclinical hypoxia studies and hypoxia-directed clinical therapy.
Procissi
Daniel
D
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. procissi@caltech.edu
Claus
Filip
F
Burgman
Paul
P
Koziorowski
Jacek
J
Chapman
J Donald
JD
Thakur
Sunitha B
SB
Matei
Cornelia
C
Ling
C Clifton
CC
Koutcher
Jason A
JA
D000818:Animals; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*
D005462:Fluorine Radioisotopes; C059168:1-(2-nitro-1-imidazoyl)-3-(2,2,2-trifluoroethoxy)-2-propanol; D008920:Misonidazole