A new nitroxyl-probe with high retention in the brain and its application for brain imaging

Free Radic Biol Med. 2000 Mar 15;28(6):959-69. doi: 10.1016/s0891-5849(00)00184-2.


In order to estimate free radical reactions and image them in the brain of living animals, a nitroxyl spin-probe, carboxy-PROXYL acetoxymethyl ester (CxP-AM) was newly synthesized. CxP-AM was designed to be hydrolyzed by esterase, but not by lipase, so that it would pass through the blood-brain barrier and be retained in the cytosolic phase of parenchymal cells in the brain after intravenous injection. The pharmacokinetics of CxP-AM was compared with those of carboxy-PROXYL (CxP) and its methyl ester (CxP-M). Carboxyl esterase almost completely hydrolyzed CxP-AM within 3 min. After intravenous injection, the brain retained 1.8 times more CxP-AM than CxP-M, and retained it for more than 30 min. Electron spin resonance computed tomographic (ESR-CT) imaging of CxP-AM in the heads of mice produced marked contrast in the encephalon region, while CxP was distributed only in the extracranial region and CxP-M was distributed in both regions, confirming the pharmacokinetics of CxP-AM. The decay rate of CxP-AM determined with time-resolved ESR-CT imaging was different in the two brain regions, suggesting regional differences in the total reducing capability. CxP-AM should become a powerful probe for the investigation and diagnosis of free radical reactions and their imaging in the brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier
  • Brain / anatomy & histology
  • Brain / metabolism*
  • Brain Diseases / diagnosis*
  • Carboxylesterase
  • Carboxylic Ester Hydrolases / metabolism
  • Cyclic N-Oxides / chemical synthesis*
  • Cyclic N-Oxides / metabolism
  • Diagnostic Imaging / methods
  • Electron Spin Resonance Spectroscopy
  • Female
  • Free Radicals / metabolism
  • Mice
  • Mice, Inbred Strains
  • Pyrrolidines / chemical synthesis*
  • Spin Labels / chemical synthesis*


  • Cyclic N-Oxides
  • Free Radicals
  • Pyrrolidines
  • Spin Labels
  • acetoxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylate
  • Carboxylic Ester Hydrolases
  • Carboxylesterase