| Literature DB >> 27355874 |
Steven H Liang1, Jinshan Michael Chen2, Marc D Normandin1, Jeanne S Chang2, George C Chang2, Christine K Taylor2, Patrick Trapa3, Mark S Plummer2, Kimberly S Para2, Edward L Conn2, Lori Lopresti-Morrow2, Lorraine F Lanyon2, James M Cook2, Karl E G Richter2, Charlie E Nolan2, Joel B Schachter2, Fouad Janat2, Ye Che2, Veerabahu Shanmugasundaram2, Bruce A Lefker3, Bradley E Enerson2, Elijahu Livni1, Lu Wang1, Nicolas J Guehl1, Debasis Patnaik4, Florence F Wagner5, Roy Perlis5,4, Edward B Holson5, Stephen J Haggarty4, Georges El Fakhri1, Ravi G Kurumbail6, Neil Vasdev7.
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.Entities:
Keywords: Alzheimer's disease; glycogen synthase kinase-3; phosphorylation; positron emission tomography; tau proteins
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Year: 2016 PMID： 27355874 PMCID： PMC4983481 DOI： 10.1002/anie.201603797
Source DB: PubMed Journal: Angew Chem Int Ed Engl ISSN： 1433-7851 Impact factor: 15.336