title: Acetoxymethoxycarbonyl nitroxides as electron paramagnetic resonance proimaging agents to measure O2 levels in mouse brain: a pharmacokinetic and pharmacodynamic study.
abstract: Measurement of O(2) concentration and distribution in brain is essential to understanding the pathophysiology of stroke. Low-frequency electron paramagnetic resonance (EPR) spectroscopy with a paramagnetic probe is an attractive imaging modality that can potentially map O(2) concentration in the brain. In a previous study, we demonstrated that, after intraperitoneal administration of 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (1) to mice, this nitroxide crossed the blood-brain barrier into brain tissue where, after hydrolysis, 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (2) was liberated and entrapped. This pilot study suggested that nitroxide 1 is a proimaging agent that can deliver nitroxide 2 to brain tissue, where O(2) levels can be estimated. In the present study, we conducted a series of pharmacokinetic and pharmacodynamic experiments designed to assess the uptake of structurally disparate nitroxides into brain tissue and retention, after hydrolysis, of the anions of the corresponding nitroxide acids. From these findings, nitroxide 1 and trans-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (5) meet the requirement as EPR proimaging agents for mapping O(2) distribution in the brain following stroke.
authors.affiliation: University of New Mexico, Albuquerque, USA.
authors.forename: Minoru
authors.initials: M
authors.lastname: Miyake
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
authors.forename: Shimin
authors.initials: S
authors.lastname: Liu
authors.forename: Honglian
authors.initials: H
authors.lastname: Shi
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.forename: Zhongrui
authors.initials: Z
authors.lastname: Yuan
authors.forename: Aaron
authors.initials: A
authors.lastname: Pritchard
authors.forename: Joseph P Y
authors.initials: JP
authors.lastname: Kao
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010100:Oxygen / Q000097:blood*; D051381:Rats; D020521:Stroke / Q000378:metabolism
chemical_list: D009589:Nitrogen Oxides; D010100:Oxygen