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

Abstract

Purpose: 2-Nitro-α-[(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.

Molecular Imaging of Hypoxia

“…This is the molecular basis for an imaging agent that is trapped at a level proportional to the intracellular demand for O 2 and is not limited by blood flow, meeting the design requirements for a hypoxia imaging agent. 2-Nitroimidazoles are most commonly labeled with PET radionuclides such as 18 (59,60). Because of their long history, this review provides substantial detail on labeled nitroimidazoles for PET, especially fluoromisonidazole, the most widely studied hypoxia imaging agent (46).…”

Non-invasive molecular and functional imaging of cytosine deaminase and uracil phosphoribosyltransferase fused with red fluorescence protein

“…catheter was inserted into the tail vein of the mice to allow 5-FU or 5-FC to be administered after positioning the animals inside the magnet and after shimming. Mice were kept anesthetized during the MR measurements with isoflurane mixed in 100% oxygen administered through a nose cone as described previously [21]. A home built two-turn radiofrequency solenoid coil with a diameter of 12 mm was used to collect MRS data.…”

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

“…Furthermore, perfluorocarbons (19F MRS) are used in combination with nitroimidazole to design a probe, namely 2-nitro-α-[(2, 2, 2-trifluoroethoxy) methyl]-imidazole-1-ethanol, that undergoes reduction when it binds to the endogenous molecules of hypoxic cells. This enables it to determine the severity of hypoxia in vivo [26]. Usually, the nitroimidazole-based probe involves the biomarker SR4554, which was experimented on 26 different patients with predominant gastrointestinal cancer [27].…”