title: Feasibility of in vivo three-dimensional T2*mapping using dicarboxy-PROXYL and CW-EPR-based single-point imaging.
abstract: OBJECTIVE
  The aim of this study was to demonstrate the feasibility of in vivo three-dimensional (3D) relaxation time T2*mapping of a dicarboxy-PROXYL radical using continuous-wave electron paramagnetic resonance (CW-EPR) imaging.
  
  
  METHODS
  Isotopically substituted dicarboxy-PROXYL radicals, 3,4-dicarboxy-2,2,5,5-tetra(2H3)methylpyrrolidin-(3,4-2H2)-(1-15N)-1-oxyl (2H,15N-DCP) and 3,4-dicarboxy-2,2,5,5-tetra(2H3)methylpyrrolidin-(3,4-2H2)-1-oxyl (2H-DCP), were used in the study. A clonogenic cell survival assay was performed with the2H-DCP radical using squamous cell carcinoma (SCC VII) cells. The time course of EPR signal intensities of intravenously injected2H,15N-DCP and2H-DCP radicals were determined in tumor-bearing hind legs of mice (C3H/HeJ, male, n = 5). CW-EPR-based single-point imaging (SPI) was performed for 3D T2*mapping.
  
  
  RESULTS
  2H-DCP radical did not exhibit cytotoxicity at concentrations below 10 mM. The in vivo half-life of2H,15N-DCP in tumor tissues was 24.7 ± 2.9 min (mean ± standard deviation [SD], n = 5). The in vivo time course of the EPR signal intensity of the2H,15N-DCP radical showed a plateau of 10.2 ± 1.2 min (mean ± SD) where the EPR signal intensity remained at more than 90% of the maximum intensity. During the plateau, in vivo 3D T2*maps with2H,15N-DCP were obtained from tumor-bearing hind legs, with a total acquisition time of 7.5 min.
  
  
  CONCLUSIONS
  EPR signals of2H,15N-DCP persisted long enough after bolus intravenous injection to conduct in vivo 3D T2*mapping with CW-EPR-based SPI.
authors.affiliation: Division of Bioengineering and Bioinformatics, Graduate School of Information Science and Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, 060-0814, Japan.
authors.forename: Harue
authors.initials: H
authors.lastname: Kubota
authors.affiliation: Division of Bioengineering and Bioinformatics, Graduate School of Information Science and Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, 060-0814, Japan.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Komarov
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, 060-0815, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.affiliation: Division of Bioengineering and Bioinformatics, Graduate School of Information Science and Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, 060-0814, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, North 18, West 9, Kita-ku, Sapporo, 060-0818, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Inanami
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9, Ac. Lavrentieva Ave., Novosibirsk, 630090, Russia.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Kirilyuk
authors.affiliation: Department of Biochemistry, West Virginia University, Robert C. Byrd Health Sciences Center, 1 Medical Center Drive, Morgantown, WV, 26506, USA.
authors.forename: Valery V
authors.initials: VV
authors.lastname: Khramtsov
authors.affiliation: Division of Bioengineering and Bioinformatics, Graduate School of Information Science and Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, 060-0814, Japan. hhirata@ist.hokudai.ac.jp.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0002-6906-1608
authors.initials: H
authors.lastname: Hirata
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D005240:Feasibility Studies; D005609:Free Radicals / Q000737:chemistry; D007089:Image Enhancement; D007090:Image Interpretation, Computer-Assisted; D021621:Imaging, Three-Dimensional / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D057054:Molecular Imaging; D064847:Multimodal Imaging / Q000379:methods*; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D009589:Nitrogen Oxides / Q000737:chemistry; D010092:Oximetry / Q000379:methods*; D010100:Oxygen / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000072258:Tumor Hypoxia
chemical_list: D014408:Biomarkers, Tumor; D005609:Free Radicals; D009589:Nitrogen Oxides; C039900:nitroxyl; D010100:Oxygen
keywords: Clonogenic assay; In vivo EPR; In vivo nitroxyl radical kinetics; Nitroxyl radical; Single-point imaging; T 2 * mapping