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. 2016 Aug 8;55(33):9601-5.
doi: 10.1002/anie.201603797. Epub 2016 Jun 29.

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

Steven H Liang  1 , Jinshan Michael Chen  2 , Marc D Normandin  1 , Jeanne S Chang  2 , George C Chang  2 , Christine K Taylor  2 , Patrick Trapa  3 , Mark S Plummer  2 , Kimberly S Para  2 , Edward L Conn  2 , Lori Lopresti-Morrow  2 , Lorraine F Lanyon  2 , James M Cook  2 , Karl E G Richter  2 , Charlie E Nolan  2 , Joel B Schachter  2 , Fouad Janat  2 , Ye Che  2 , Veerabahu Shanmugasundaram  2 , Bruce A Lefker  3 , Bradley E Enerson  2 , Elijahu Livni  1 , Lu Wang  1 , Nicolas J Guehl  1 , Debasis Patnaik  4 , Florence F Wagner  5 , Roy Perlis  5   4 , Edward B Holson  5 , Stephen J Haggarty  4 , Georges El Fakhri  1 , Ravi G Kurumbail  6 , Neil Vasdev  7
Affiliations

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

Steven H Liang et al. Angew Chem Int Ed Engl. .

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.

Keywords: Alzheimer's disease; glycogen synthase kinase-3; phosphorylation; positron emission tomography; tau proteins.

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Figures

Figure 1
Figure 1
Previous attempts for the development of GSK-3 PET ligands and this work. PF-04802367 is commercially available via Sigma Aldrich (catalog # PZ0313).
Figure 2
Figure 2
In vitro screening and crystallographic structure identifies PF-367 as a potent GSK-3β inhibitor.
Figure 3
Figure 3
PF-367 shows selective modulation of GSK-3 in kinome pathway. PF-367 selectively binds GSK-3α/3β among all 240 kinase tested. Dashed line marks the IC50 value of 500 nM. Kinase activities are given as the mean of triplicate experiments.
Figure 4
Figure 4
In vivo efficacy of PF-367 in Sprague-Dawley rats and transgenic model of human tau mice. (a) inhibition of tau phosphorylation in both CNS and periphery. (b) free fraction of PF-367 in brain correlates directly with % inhibition of pTau in brain. (c) inhibition of tau phosphorylation in transgenic model of human tau mice (Tg4510). (d) PF-367 delivered p.o. inhibits phosphorylation of tau in brain.
Figure 5
Figure 5
[11C]PF-367 visualizes GSK-3β distribution in the living brain. b–c, Representative summed PET images (30–60 min) for baseline and blocking studies. d, Regional time activity curves (cerebellum, cerebral cortex and central w.m.) extracted from the baseline (open markers) and blocking (filled markers) PET studies.
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