Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging
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- 作者：Prof. Dr. Steven H. Liang ; Dr. Jinshan Michael Chen ; Prof. Dr. Marc D. Normandin ; Dr. Jeanne S. Chang ; Dr. George C. Chang ; Dr. Christine K. Taylor ; Dr. Patrick Trapa ; Dr. Mark S. Plummer ; Dr. Kimberly S. Para ; Dr. Edward L. Conn ; Dr. Lori Lopresti-Morrow ; Dr. Lorraine F. Lanyon ; Dr. James M. Cook ; Dr. Karl E. G. Richter ; Dr. Charlie E. Nolan ; Dr. Joel B. Schachter ; Dr. Fouad Janat ; Dr. Ye Che ; Dr. Veerabahu Shanmugasundaram ; Dr. Bruce A. Lefker ; Dr. Bradley E. Enerson ; Prof. Dr. Elijahu Livni ; Lu Wang ; Dr. Nicolas J. Guehl ; Dr. Debasis Patnaik ; Florence F. Wagner ; Prof. Dr. Roy Perlis ; Dr. Edward B. Holson ; Prof. Dr. Stephen J. Haggarty ; Prof. Dr. Georges El Fakhri ; Dr. Ravi G. Kurumbail and Prof. Dr. Neil Vasdev
- 刊名：Angewandte Chemie International Edition
- 出版年：2016
- 出版时间：August 8, 2016
- 年：2016
- 卷：55
- 期：33
- 页码：9601-9605
- 全文大小：2873K
- ISSN：1521-3773
文摘
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 11C-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.