Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

Angew Chem Int Ed Engl. 2016 Aug 8;55(33):9601-5. doi: 10.1002/anie.201603797. Epub 2016 Jun 29.

Abstract

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.

Keywords: Alzheimer's disease; glycogen synthase kinase-3; phosphorylation; positron emission tomography; tau proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Brain / diagnostic imaging*
  • Brain / drug effects*
  • Brain / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neuroimaging*
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Phosphorylation / drug effects
  • Positron-Emission Tomography*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • tau Proteins / antagonists & inhibitors*
  • tau Proteins / metabolism

Substances

  • MAPT protein, human
  • Oxazoles
  • PF-04802367
  • Protein Kinase Inhibitors
  • Triazoles
  • tau Proteins
  • Glycogen Synthase Kinase 3