title: Brain contrasting ability of blood-brain-barrier-permeable nitroxyl contrast agents for magnetic resonance redox imaging.
abstract: The detailed in vivo T1 -weighted contrasting abilities of nitroxyl contrast agents, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, in mouse brain were investigated.
  
  
  
  Distribution and pharmacokinetics of five types of five-membered-ring nitroxyl radical compound were compared using T1 -weighted MRI.
  
  
  
  The blood-brain barrier (BBB) -impermeable 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP) could not be distributed in the brain. The slightly lipophilic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP) showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl (MCP) had good initial uniform distribution in the brain and showed typical 2-phase signal decay profiles. A brain-seeking nitroxyl probe, acetoxymethyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl-3-carboxylate (CxP-AM), showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 4-(N-methyl piperidine)-2,2,5,5-tetramethylpyrroline-N-oxyl (23c) was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay.
  
  
  
  Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool. Magn Reson Med 76:935-945, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Radio-Redox-Response Research Team, Advanced Particle Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Radio-Redox-Response Research Team, Advanced Particle Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan.|Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Translational Research Group, Health Science Research Center, FANCL Research Institute, Totsuka-ku, Yokohama, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ishikawa
authors.affiliation: Radio-Redox-Response Research Team, Advanced Particle Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Radio-Redox-Response Research Team, Advanced Particle Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nakanishi
authors.affiliation: Multimodal Molecular Imaging Team, Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sekita
authors.affiliation: Multimodal Molecular Imaging Team, Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan.|Research Center Hospital, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kamada
authors.affiliation: Multimodal Molecular Imaging Team, Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: Ichio
authors.initials: I
authors.lastname: Aoki
authors.affiliation: Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.|JST, PRESTO, Kawaguchi, Saitama, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology; D003198:Computer Simulation; D003287:Contrast Media / Q000493:pharmacokinetics*; D005260:Female; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008657:Metabolic Clearance Rate; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D009589:Nitrogen Oxides / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D009589:Nitrogen Oxides; C039900:nitroxyl
keywords: T1-weighted contrast; mouse brain; nitroxyl radical; pharmacokinetics; redox-sensitive contrast agent; theranostics