Work in progress: Nuclear magnetic resonance study of a paramagnetic nitroxide contrast agent for enhancement of renal structures in experimental animals

Brasch, Robert C.; London, D A; Wesbey, George E.; Tozer, Thomas N.; Nitecki, Danute E.; Williams, Richard D.; Doemeny, John; Tuck, L. Dallas; Lallemand, D

doi:10.1016/0730-725x(84)90140-1

Cited by 13 publications

(18 citation statements)

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“…Like these gadolinium-based agents, nitroxide radicals have a single unpaired electron and therefore have the potential to provide T 1 contrast. The use of nitroxide radicals as T 1 contrast agents in MRI was known [51][52][53] prior to their use as in vivo EPRI as probes [54], but were felt to be suboptimal as MRI contrast agents due to their rapid in vivo reduction to the undetectable diamagnetic products [55]. In addition to their biologic instability, nitroxide probes have only one unpaired electron, as compared to seven for Gd 3+ resulting in a lower relaxivity.…”

Section: Functional Imagingmentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

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Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

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Section: Functional Imagingmentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

View full text Add to dashboard Cite

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“…Though the use of nitroxide as a T 1 -enhancing MRI contrast agent was realized early [20][21][22][23], the bio-reduction and rapid clearance have made them less useful than the metal-based Gd 3+ complex contrast agents [24;25], which had a long biological half life and high molar relaxivity, compared with the single, odd-electron containing nitroxides. However, the bioreduction of nitroxides can be monitored to effectively probe the redox status of tissues [4; 26].…”

Section: Introductionmentioning

confidence: 99%

Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI

Hyodo

Murugesan

Matsumoto

et al. 2008

Journal of Magnetic Resonance

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A comparative study of tissue redox-status imaging using commonly used redox sensitive nitroxides has been carried out using electron paramagnetic resonance imaging (EPRI), Overhauser magnetic resonance imaging (OMRI) and conventional T 1 -weighted magnetic resonance imaging, MRI. Imaging studies using phantoms of different nitroxides at different concentration levels showed that EPRI and OMRI sensitivities were found to be linearly dependent on line width of nitroxides up to 2 mM, and the enhancement in MRI intensity was linear up to 5 mM. The sensitivity and resolution of EPRI and OMRI images depended significantly on the line width of the nitroxides whereas the MRI images were almost independent of EPR line width.Reduction of the paramagnetic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (3CP) by ascorbic acid (AsA) to the diamagnetic by hydroxylamine was monitored from a sequence of temporal images, acquired using the three imaging modalities. The decay rates determined by all the three modalities were found to be similar. However the results suggest that T 1 weighted MRI can monitor the redox status, in addition to providing detailed anatomical structure in a short time. Therefore, a combination of MRI with nitroxides as metabolically responsive contrast agents can be a useful technique for the in vivo imaging probing tissue redox status.

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“…Nitroxides are stable organic free radicals having a single unpaired electron and are therefore capable of providing image contrast via shortening T 1 similar to Gd 3+ complexes (19,20). Although nitroxides compare unfavorably to conventional T 1 contrast agents such as Gd 3+ complexes in terms of relaxivity, being cell permeable, their volume distribution is significantly greater (21,22).…”

Section: Introductionmentioning

confidence: 99%

“…This partially compensates for their lower relaxivity compared with the cell-impermeable gadolinium complexes and provides useful T 1 contrast enhancement per unit volume similar to unchelated Mn 2+ (23). Nitroxides were initially evaluated as potential contrast agents in MRI and were found suboptimal in the 1980s because of their lower molar relaxivity compared with Gd 3+ (19). In addition, the rapid bioreduction of the paramagnetic nitroxide to the corresponding diamagnetic hydroxylamine compromised their utility as contrast agents (24).…”

Section: Introductionmentioning

confidence: 99%

Probing the Intracellular Redox Status of Tumors with Magnetic Resonance Imaging and Redox-Sensitive Contrast Agents

et al. 2006

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Nitroxide radicals are paramagnetic contrast agents, used in magnetic resonance imaging (MRI), that also exert antioxidant effects. Participating in cellular redox reactions, they lose their ability to provide contrast as a function of time after administration. In this study, the rate of contrast loss was correlated to the reducing power of the tissue or the ''redox status.'' The preferential reduction of nitroxides in tumors compared with normal tissue was observed by MRI. The influence of the structure of the nitroxide on the reduction rate was investigated by MRI using two cell-permeable nitroxides, 4-hydroxy-2,2,6,6,-tetramethyl-1-piperidynyloxyl (Tempol) and 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (3CP), and one cell-impermeable nitroxide, 3-carboxy-2, 2,5,5,5-tetramethylpyrrolidine-1-oxyl (3CxP). Pharmacokinetic images of these nitroxides in normal tissue, tumor, kidney, and artery regions in mice were simultaneously obtained using MRI. The decay of Tempol and 3CP in tumor tissue was significantly faster than in normal tissue. No significant change in the total nitroxide (oxidized + reduced forms) was noted from tissue extracts, suggesting that the loss in contrast as a function of time is a result of intracellular bioreduction. However, in the case of 3CxP (membrane impermeable), there was no difference in the reduction rates between normal and tumor tissue. The time course of T 1 enhancement by 3CxP and the total amount of 3CxP (oxidized + reduced) in the femoral region showed similar pharmacokinetics. These results show that the differential bioreduction of cell-permeable nitroxides in tumor and normal tissue is supported by intracellular processes and the reduction rates are a means by which the intracellular redox status can be assessed noninvasively.

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Work in progress: Nuclear magnetic resonance study of a paramagnetic nitroxide contrast agent for enhancement of renal structures in experimental animals

Cited by 13 publications

References 0 publications

The chemistry and biology of nitroxide compounds

The chemistry and biology of nitroxide compounds

Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI

Probing the Intracellular Redox Status of Tumors with Magnetic Resonance Imaging and Redox-Sensitive Contrast Agents

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