title: A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector.
abstract: Individuals are exposed to ionizing radiation during medical procedures and nuclear disasters, and this exposure can be carcinogenic, toxic, and sometimes fatal. Drugs that protect individuals from the adverse effects of radiation may therefore be valuable countermeasures against the health risks of exposure. In the current study, the LD(50/30) (the dose resulting in 50% of exposed mice surviving 30 days after exposure) was determined in control C3H mice and mice treated with the nitroxide radioprotectors Tempol, 3-CP, 16c, 22c, and 23c. The pharmacokinetics of 22c and 23c were measured with magnetic resonance imaging (MRI) in the brain, blood, submandibular salivary gland, liver, muscle, tongue, and myocardium. It was found that 23c was the most effective radioprotector of the five studied: 23c increased the LD(50/30) in mice from 7.9±0.15Gy (treated with saline) to 11.47±0.13Gy (an increase of 45%). Additionally, MRI-based pharmacokinetic studies revealed that 23c is an effective redox imaging agent in the mouse brain, and that 23c may allow functional imaging of the myocardium. The data in this report suggest that 23c is currently the most potent known nitroxide radioprotector, and that it may also be useful as a contrast agent for functional imaging.
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. ryan.m.davis@duke.edu
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Davis
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Sowers
authors.forename: William
authors.initials: W
authors.lastname: DeGraff
authors.forename: Marcelino
authors.initials: M
authors.lastname: Bernardo
authors.forename: Angela
authors.initials: A
authors.lastname: Thetford
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000528:radiation effects; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003497:Cyclic N-Oxides; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D011832:Radiation Injuries / Q000209:etiology / Q000517:prevention & control; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011859:Radiography; D013113:Spin Labels
chemical_list: D003287:Contrast Media; D003497:Cyclic N-Oxides; D011837:Radiation-Protective Agents; D013113:Spin Labels; D009569:Nitric Oxide; C001803:tempol