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

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

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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