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

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.

Authors:
 [1];  [2];  [1];  [2];  [2];  [2];  [3];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3] more »;  [2];  [1];  [1];  [1];  [4];  [5];  [6];  [5];  [4];  [1];  [2];  [1] « less
+ Show Author Affiliations
  1. Gordon Center for Medical Imaging &, Nuclear Medicine and Molecular Imaging Massachusetts General Hospital &, Department of Radiology Harvard Medical School Boston MA 02114 USA
  2. Pfizer Worldwide Research and Development, Groton Laboratories Eastern Point Road Groton CT 06340 USA
  3. Pfizer Worldwide Research and Development 610 Main Street Cambridge MA 02139 USA
  4. Departments of Neurology &, Psychiatry Massachusetts General Hospital Harvard Medical School 185 Cambridge Street Boston MA 02114 USA
  5. Stanley Center for Psychiatric Research Broad Institute 415 Main Street Cambridge MA o2142 USA
  6. Stanley Center for Psychiatric Research Broad Institute 415 Main Street Cambridge MA o2142 USA, Departments of Neurology &, Psychiatry Massachusetts General Hospital Harvard Medical School 185 Cambridge Street Boston MA 02114 USA
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1401450
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Angewandte Chemie
Additional Journal Information:
Journal Name: Angewandte Chemie Journal Volume: 128 Journal Issue: 33; Journal ID: ISSN 0044-8249
Publisher:
Wiley Blackwell (John Wiley & Sons)
Country of Publication:
Germany
Language:
English

Citation Formats

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., and Vasdev, Neil. Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging. Germany: N. p., 2016. Web. doi:10.1002/ange.201603797.
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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. Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging. Germany. https://doi.org/10.1002/ange.201603797
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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., and Vasdev, Neil. Wed . "Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging". Germany. https://doi.org/10.1002/ange.201603797.
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@article{osti_1401450,
title = {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. and Chen, Jinshan Michael and Normandin, Marc D. and Chang, Jeanne S. and Chang, George C. and Taylor, Christine K. and Trapa, Patrick and Plummer, Mark S. and Para, Kimberly S. and Conn, Edward L. and Lopresti‐Morrow, Lori and Lanyon, Lorraine F. and Cook, James M. and Richter, Karl E. G. and Nolan, Charlie E. and Schachter, Joel B. and Janat, Fouad and Che, Ye and Shanmugasundaram, Veerabahu and Lefker, Bruce A. and Enerson, Bradley E. and Livni, Elijahu and Wang, Lu and Guehl, Nicolas J. and Patnaik, Debasis and Wagner, Florence F. and Perlis, Roy and Holson, Edward B. and Haggarty, Stephen J. and El Fakhri, Georges and Kurumbail, Ravi G. and Vasdev, Neil},
abstractNote = {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.},
doi = {10.1002/ange.201603797},
journal = {Angewandte Chemie},
number = 33,
volume = 128,
place = {Germany},
year = {Wed Jun 29 00:00:00 EDT 2016},
month = {Wed Jun 29 00:00:00 EDT 2016}
}
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https://doi.org/10.1002/ange.201603797
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