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

被引：69

作者：

Liang, Steven H. ^{[1
,2
]}

Chen, Jinshan Michael ^{[3
]}

Normandin, Marc D. ^{[1
,2
]}

Chang, Jeanne S. ^{[3
]}

Chang, George C. ^{[3
]}

Taylor, Christine K. ^{[3
]}

Trapa, Patrick ^{[4
]}

Plummer, Mark S. ^{[3
]}

Para, Kimberly S. ^{[3
]}

Conn, Edward L. ^{[3
]}

Lopresti-Morrow, Lori ^{[3
]}

Lanyon, Lorraine F. ^{[3
]}

Cook, James M. ^{[3
]}

Richter, Karl E. G. ^{[3
]}

Nolan, Charlie E. ^{[3
]}

Schachter, Joel B. ^{[3
]}

Janat, Fouad ^{[3
]}

Che, Ye ^{[3
]}

Shanmugasundaram, Veerabahu ^{[3
]}

Lefker, Bruce A. ^{[4
]}

Enerson, Bradley E. ^{[3
]}

Livni, Elijahu ^{[1
,2
]}

Wang, Lu ^{[1
,2
]}

Guehl, Nicolas J. ^{[1
,2
]}

Patnaik, Debasis ^{[6
,7
]}

Wagner, Florence F. ^{[5
]}

Perlis, Roy ^{[5
,6
,7
]}

Holson, Edward B. ^{[5
]}

Haggarty, Stephen J. ^{[6
,7
]}

El Fakhri, Georges ^{[1
,2
]}

Kurumbail, Ravi G. ^{[3
]}

Vasdev, Neil ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Gordon Ctr Med Imaging & Nucl Med & Mol Imaging, Boston, MA 02114 USA

[2] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA

[3] Pfizer Worldwide Res & Dev, Groton Labs, Eastern Point Rd, Groton, CT 06340 USA

[4] Pfizer Worldwide Res & Dev, 610 Main St, Cambridge, MA 02139 USA

[5] Broad Inst, Stanley Ctr Psychiat Res, 415 Main St, Cambridge, MA 02142 USA

[6] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, 185 Cambridge St, Boston, MA 02114 USA

[7] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, 185 Cambridge St, Boston, MA 02114 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2016年 / 55卷 / 33期

关键词：

Alzheimer's disease; glycogen synthase kinase-3; phosphorylation; positron emission tomography; tau proteins; ALZHEIMERS-DISEASE; TRANSGENIC MICE; GSK-3-BETA; RADIOSYNTHESIS; RADIOTRACER; VIVO;

D O I：

10.1002/anie.201603797

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 PF367) 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 C-11-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.

引用

页码：9601 / 9605

页数：5

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