Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [11C]CO2 fixation method

Bioorg Med Chem Lett. 2020 May 1;30(9):127068. doi: 10.1016/j.bmcl.2020.127068. Epub 2020 Mar 6.

Abstract

Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect Aβ deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.

Keywords: Alzheimer’s disease; CYP46A1; Cholesterol 24-hydroxylase; Positron emission tomography; [(11)C]CO(2) fixation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbon Dioxide / chemistry*
  • Carbon Isotopes*
  • Cholesterol 24-Hydroxylase / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Mice
  • Molecular Structure
  • Neuroimaging
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Tissue Distribution

Substances

  • Carbon Isotopes
  • Enzyme Inhibitors
  • Radiopharmaceuticals
  • Carbon Dioxide
  • Cholesterol 24-Hydroxylase