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.
Steven H Liang  1 ,  Jinshan Michael Chen  2 ,  Marc D Normandin  1 ,  Jeanne S Chang  2 ,  George C Chang  2 ,  Christine K Taylor  2 ,  Patrick Trapa  3 ,  Mark S Plummer  2 ,  Kimberly S Para  2 ,  Edward L Conn  2 ,  Lori Lopresti-Morrow  2 ,  Lorraine F Lanyon  2 ,  James M Cook  2 ,  Karl E G Richter  2 ,  Charlie E Nolan  2 ,  Joel B Schachter  2 ,  Fouad Janat  2 ,  Ye Che  2 ,  Veerabahu Shanmugasundaram  2 ,  Bruce A Lefker  3 ,  Bradley E Enerson  2 ,  Elijahu Livni  1 ,  Lu Wang  1 ,  Nicolas J Guehl  1 ,  Debasis Patnaik  4 ,  Florence F Wagner  5 ,  Roy Perlis  5  4 ,  Edward B Holson  5 ,  Stephen J Haggarty  4 ,  Georges El Fakhri  1 ,  Ravi G Kurumbail  6 ,  Neil Vasdev  7
Affiliations
  • 1. Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
  • 2. Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
  • 3. Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA, 02139, USA.
  • 4. Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA.
  • 5. Stanley Center for Psychiatric Research, Broad Institute, 415 Main Street, Cambridge, MA, o2142, USA.
  • 6. Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA. [email protected].
  • 7. Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA. [email protected].
PMID: 27355874 DOI: 10.1002/anie.201603797
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.
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