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In vivo ¹⁹F Magnetic Resonance Spectroscopy and Chemical Shift Imaging of Tri-Fluoro-Nitroimidazole as a Potential Hypoxia Reporter in Solid Tumors

Authors' Affiliations: Departments of ¹ Medical Physics, ² Radiology, and ³ Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York and ⁴ CRM Consulting Services, Penticton, BC, Canada

Requests for reprints: Daniel Procissi, California Institute of Technology, Brain Imaging Center, 1200 E. California Blvd., Pasadena, CA 91125. Phone: 626-395-5782; Fax: 626-395-2000; E-mail: procissi{at}caltech.edu.

Purpose: 2-Nitro--[(2,2,2-trifluoroethoxy)methyl]-imidazole-1-ethanol (TF-MISO) was investigated as a potential noninvasive marker of tissue oxygen levels in tumors using ¹⁹F magnetic resonance spectroscopy (MRS) and ¹⁹F chemical shift imaging.

Experimental Designs: 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 ¹⁹F 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 ¹⁹F 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 ¹⁹F signal under conditions of maximum hypoxia. Late time point (>6 h) tumor tissue concentrations, as obtained from ¹⁹F 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.

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