Synthesis and Evaluation as a Blood-Brain Barrier-Permeable Probe of 7-N-(PROXYL-3-yl-methyl)theophylline

Chem Pharm Bull (Tokyo). 2018;66(9):887-891. doi: 10.1248/cpb.c18-00333.

Abstract

The drug-nitroxide radical hybrid-compound 7-N-((2,2,5,5-tetramethylpyrrolidine-1-yloxy(PROXYL))-3-yl-methyl)theophylline (3) was synthesized by coupling 7-N-tosyltheophylline with 3-hydroxymethyl-PROXYL, HMP). The stability of 3 relative to that of HMP was examined in the presence of the anti-oxidant, ascorbic acid (AsA). The initial reduction rate constants of 3 and HMP were 11.9±5.3 and 6.1±5.2 M-1 min-1, respectively. In the presence of glutathione (GSH), these constants increased slightly to 22.3±6.8 and 9.1±2.4 M-1 min-1, respectively. Two-dimensional cranial electron paramagnetic resonance imaging of mice intravenously injected with 3 via the tail vein revealed that probe 3 enters the mouse brain by passing through the blood-brain barrier (BBB).

Keywords: blood–brain barrier; pyrrolidine nitroxide; redox status; theophylline.

MeSH terms

  • Animals
  • Antioxidants / chemistry
  • Blood-Brain Barrier / metabolism*
  • Contrast Media / chemical synthesis
  • Contrast Media / metabolism*
  • Cyclic N-Oxides / chemistry
  • Electron Spin Resonance Spectroscopy
  • Glutathione / chemistry
  • Kinetics
  • Mice
  • Molecular Structure
  • Oxidation-Reduction
  • Pyrrolidines / chemistry
  • Spin Labels
  • Theophylline / analogs & derivatives*
  • Theophylline / chemical synthesis
  • Theophylline / metabolism*

Substances

  • Antioxidants
  • Contrast Media
  • Cyclic N-Oxides
  • Pyrrolidines
  • Spin Labels
  • 3-hydroxymethyl-2,2,5,5-tetramethylpyrroline-N-oxyl
  • Theophylline
  • Glutathione