title: In vivo imaging of reactive oxygen species in mouse brain by using [3H]hydromethidine as a potential radical trapping radiotracer.
abstract: To assess reactive oxygen species (ROS) production by detecting the fluorescent oxidation product, hydroethidine has been used extensively. The present study was undertaken to evaluate the potential of the hydroethidine derivative as a radiotracer to measure in vivo brain ROS production. [(3)H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([(3)H]Hydromethidine) was synthesized, and evaluated using in vitro radical-induced oxidization and in vivo brain ROS production model. In vitro studies have indicated that [(3)H]Hydromethidine is converted to oxidized products by a superoxide radical (O(2)(•)-) and a hydroxyl radical (OH(•)-) but not hydrogen peroxide (H(2)O(2)). In vivo whole-body distribution study showed that [(3)H]Hydromethidine rapidly penetrated the brain and then was washed out in normal mice. Microinjection of sodium nitroprusside (SNP) into the brain was performed to produce ROS such as OH(•)- via Fenton reaction. A significant accumulation of radioactivity immediately after [(3)H]Hydromethidine injection was seen in the side of the brain treated with SNP (5 and 20 nmol) compared with that in the contralateral side. These results indicated that [(3)H]Hydromethidine freely penetrated into the brain where it was rapidly converted to oxidized forms, which were trapped there in response to the production of ROS. Thus, [(3)H]Hydromethidine should be useful as a radical trapping radiotracer in the brain.
authors.affiliation: Research Laboratory for Development, Department of Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Research Laboratory for Development, Department of Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takai
authors.affiliation: Research Laboratory for Development, Department of Applied Chemistry and Analysis, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Fukumoto
authors.affiliation: Research Laboratory for Development, Department of Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Imamoto
authors.affiliation: Research Laboratory for Development, Department of Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Tonomura
authors.affiliation: Research Laboratory for Development, Department of Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Ito
authors.affiliation: Research Laboratory for Development, Department of Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanegawa
authors.affiliation: Research Laboratory for Development, Department of Applied Chemistry and Analysis, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Research Laboratory for Development, Department of Applied Chemistry and Analysis, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Todoroki
authors.affiliation: School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017665:Hydroxyl Radical / Q000138:chemical synthesis* / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D008845:Microinjections; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011877:Radionuclide Imaging; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014316:Tritium
chemical_list: C000594898:N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010617:Phenanthridines; D017382:Reactive Oxygen Species; D014316:Tritium; D009599:Nitroprusside; D017665:Hydroxyl Radical; C058428:hydroethidine