title: Comparison of two nitroxide labile esters for delivering electron paramagnetic resonance probes into mouse brain.
abstract: In vivo quantitation of O(2) in brain has been hindered by a lack of suitable imaging modalities. Development of low-frequency electron paramagnetic resonance (EPR) spectrometers that can detect free radicals in animals in real time makes it feasible to image paramagnetic oximetry probes such as nitroxides in brain tissue. We have shown that masking the carboxyl group of 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (nitroxide 1) as an esterase-labile acetoxymethyl ester yields 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (nitroxide 2). Nitroxide 2 can cross the blood-brain barrier and is then hydrolyzed in situ by esterases to regenerate nitroxide 1, which becomes entrapped in brain tissue. Seeking to improve the loading of nitroxides into brain, we synthesized the more lipophilic pentanoyloxymethyl ester, 3-pentanoyloxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (nitroxide 3). We report that the higher lipophilicity of nitroxide 3 does not significantly increase its ability to generate EPR signals in the mouse brain. Therefore, irrespective of whether nitroxide 2 or 3 was injected, similar levels of nitroxide were entrapped in brain tissue. These findings suggest that nitroxides 2 and 3 perform comparably well as proimaging agents for measuring O(2) distribution in brain.
authors.affiliation: Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, USA.
authors.forename: Minoru
authors.initials: M
authors.lastname: Miyake
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burks
authors.forename: John
authors.initials: J
authors.lastname: Weaver
authors.forename: Pei
authors.initials: P
authors.lastname: Tsai
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Bigio
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Bauer
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Rosen
authors.forename: Joseph P Y
authors.initials: JP
authors.lastname: Kao
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000502:physiology; D001923:Brain Chemistry; D002138:Calibration; D003497:Cyclic N-Oxides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D003952:Diagnostic Imaging; D004578:Electron Spin Resonance Spectroscopy; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D007202:Indicators and Reagents; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009589:Nitrogen Oxides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013113:Spin Labels
chemical_list: C553086:3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl; D003497:Cyclic N-Oxides; D004952:Esters; D007202:Indicators and Reagents; D008055:Lipids; D009589:Nitrogen Oxides; D013113:Spin Labels; C029910:3-(2-iodoacetamido)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl