Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging. Issue 33 (29th June 2016)

• Record Type: Journal Article
• Authors: Liang, Steven H.; Chen, Jinshan Michael; Normandin, Marc D.; Chang, Jeanne S.; Chang, George C.; Taylor, Christine K.; Trapa, Patrick; Plummer, Mark S.; Para, Kimberly S.; Conn, Edward L.; Lopresti‐Morrow, Lori; Lanyon, Lorraine F.; Cook, James M.; Richter, Karl E. G.; Nolan, Charlie E.; Schachter, Joel B.; Janat, Fouad; Che, Ye; Shanmugasundaram, Veerabahu; Lefker, Bruce A.; Enerson, Bradley E.; Livni, Elijahu; Wang, Lu; Guehl, Nicolas J.; Patnaik, Debasis; Wagner, Florence F.; Perlis, Roy; Holson, Edward B.; Haggarty, Stephen J.; El Fakhri, Georges; Kurumbail, Ravi G.; Vasdev, Neil;
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 33(2016)
• Page Start: 9601
• Page End: 9605
• Publication Date: 2016-06-29
• Subjects: Alzheimer's disease -- glycogen synthase kinase-3 -- phosphorylation -- positron emission tomography -- tau proteins; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201603797
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : A highly potent inhibitor has been identified as a highly selective antagonist of glycogen synthase kinase‐3 (GSK‐3). Its efficacy in modulation of tau phosphorylation was demonstrated. A 11 C‐isotopologue was synthesized, and preliminary PET imaging studies confirmed that the two major obstacles for imaging GSK‐3 have been overcome: reasonable brain permeability and displaceable binding.