Binding of the hypoxia tracer [3H]misonidazole in cerebral ischemia.

Hoffman, John M.; Rasey, Janet S.; Spence, Alexander M.; Shaw, Dennis; Krohn, Kenneth A.

doi:10.1161/01.str.18.1.168

Cited by 44 publications

(21 citation statements)

References 21 publications

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“…The selectivity of nitroimidazoles for hypoxic regions has been demonstrated in rat myocytes (69), the gerbil stroke model (215,216), pig and rat liver (217)(218)(219), and dog myocardium (201,202). In ischemic stroke, 18 F-FMISO was able to identify the areas of brain tissue to which a stroke extended (220,221).…”

Section: Clinical Role Of Hypoxia Imagingmentioning

confidence: 99%

Molecular Imaging of Hypoxia

2008

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Section: Clinical Role Of Hypoxia Imagingmentioning

confidence: 99%

Molecular Imaging of Hypoxia

2008

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“…In gerbils, 17 3 H-misonidazole was shown to have good brain penetration and binding to hypoxic-ischemic tissue in correlation to stroke severity. Subsequently, 25,26 a correlation to histological infarction was demonstrated, though direct comparisons could not be made. Trapping was consistently found in regions with reduced rCBF, yet a correlation to CBF was not ascertained.…”

Section: Experimental Stroke Studiesmentioning

confidence: 99%

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

Takasawa

Moustafa

Baron

2008

Stroke

108

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Background and Purpose-Nitroimidazole imaging is a promising contender for noninvasive in vivo mapping of brain hypoxia after stroke. However, there is a dearth of knowledge about the behavior of these compounds in the various pathophysiologic situations encountered in ischemic stroke. In this article we report the findings from a systematic review of the literature on the use of the nitroimidazoles to map hypoxia after stroke. Summary of Review-We describe the characteristics of nitroimidazoles as imaging tracers, their pharmacology, and results of both animal and clinical studies during and after focal cerebral ischemia. Findings in brain tumors are also presented to the extent that they enlighten results in stroke. Early results from application of kinetic modeling for quantitative measurement of tracer binding are briefly discussed. Conclusions-Based on this literature review, nitroimidazole hypoxia imaging agents are of considerable interest in stroke because they appear, both in animal models and in humans, to specifically detect the severely hypoxic viable tissue, but not the reperfused nor the necrotic tissue. To fully realize this potential in stroke, however, formal validation by concurrent measurement of tissue oxygen tension, together with development of novel ligands with faster distribution kinetics, faster clearance from normal tissue, and well-defined trapping mechanisms, are important goals for future investigations.

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“…A biological characteristic of 4-Br 18 FPN is that both the liver and kidneys showed higher uptake than most other normal tissues, as observed with 18 FMISO and 18 FPN, 17,18) indicative of extensive metabolism in the liver and urinary excretion. Brain uptake as a function of time after injection is depicted graphically in Fig.…”

Section: Synthesis and Evaluation Of 4-mentioning

confidence: 89%

Synthesis and Evaluation of 4-Bromo-1-(3-[18F]fluoropropyl)-2-nitroimidazole with a Low Energy LUMO Orbital Designed as Brain Hypoxia-Targeting Imaging Agent.

Yamamoto

Aoki

Furusawa

et al. 2002

Biological & Pharmaceutical Bulletin

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2-Nitroimidazole derivatives typified by misonidazole (MISO), originally developed as hypoxic radiosensitizers for radiation therapy, have been shown to be susceptible to reduction trapping in regions of low oxygen tension. Although the mechanism of nitroimidazole binding to hypoxic tissue is still not fully understood, the nitro group is believed to undergo a one-electron reduction in viable cells to produce a radical anion, while in hypoxic cells this intermediate is further reduced to a species which reacts with cellular components and is hereby trapped within the cell. In normoxic conditions reoxidation rapidly takes place, and the compound eventually diffuses out of the cell.1-3) This is the why most efforts to develop selective markers for imaging hypoxic tissue have used 2-nitroimidazole derivatives. 4)18 F-Labeled fluoromisonidazole ( 18 FMISO) has shown potential in humans as an agent to map hypoxic tissue with positron emission tomography (PET). [5][6][7][8] However, this agent has drawbacks due to its relatively low concentration within hypoxic tissue and the necessity to wait a long time (2-4 h) to achieve acceptable target-background ratios for imaging. The target tissues have mostly been the myocardium or tumors, with less attention centered on the brain. The utility of 18 FMISO as a hypoxic imaging agent for brain studies appears to be limited because of its low blood-brain barrier (BBB) permeability. 9,10) We have been interested in the development of new PET markers exhibiting more rapid localization in the hypoxic region in the brain with a greater BBB permeability than 18 FMISO, based on the same principle of metabolic binding of nitroreduction products. In a previous paper, we reported the synthesis and evaluation of the two lipophilic 2-nitroimidazoles, 1-(3-[ 11) The high lipophilicity of 18 FPN and 18 FON resulted in the increased initial uptake into normal rat brain, relative to 18 FMISO, but both compounds had significantly lower tumor uptake and lower tumor-toblood ratios than 18 FMISO, suggestive of a poor trapping mechanism within the tumor tissue. One of the primary reasons for these disappointing results appeared to be the lack of a sufficiently high reduction potential (electron affinity) undergoing more rapid bioreduction of the nitro group. Therefore, we have now designed 4-bromo-1-(3-fluoropropyl)-2-nitroimidazle (4-BrFPN), based on the molecular orbital calculations, to improve the electron affinic property of the 2-nitroimidazole ring, with sufficient lipophilicity to penetrate the BBB to image cerebral hypoxia. In this paper we describe the design, synthesis and radiolabeling with fluorine-18 of 4-BrFPN. Additionally, the in vivo biodistribution of this designed compound is also characterized in normal rats and in tumor-bearing mice to evaluate its potential use as a marker of hypoxic tissue in comparison with 18 FMISO and 18 FPN. RESULTS AND DISCUSSIONDesign Reduction potential, as well as lipophilicity, is considered important in the rational design of hypoxia-selec- * To w...

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Binding of the hypoxia tracer [3H]misonidazole in cerebral ischemia.

Cited by 44 publications

References 21 publications

Molecular Imaging of Hypoxia

Molecular Imaging of Hypoxia

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

Synthesis and Evaluation of 4-Bromo-1-(3-[18F]fluoropropyl)-2-nitroimidazole with a Low Energy LUMO Orbital Designed as Brain Hypoxia-Targeting Imaging Agent.

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