1. Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.
- Author
-
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, and Lefker, Bruce A.
- Subjects
GLYCOGEN synthase kinase-3 ,PHOSPHORYLATION ,POSITRON emission tomography ,BRAIN tomography ,TAU proteins ,ALZHEIMER'S disease - 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 FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF