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: 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.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Liang
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Jinshan Michael
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Normandin
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Jeanne S
authors.initials: JS
authors.lastname: Chang
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Chang
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Taylor
authors.affiliation: Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trapa
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Plummer
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Para
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Conn
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Lopresti-Morrow
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Lorraine F
authors.initials: LF
authors.lastname: Lanyon
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Karl E G
authors.initials: KE
authors.lastname: Richter
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Charlie E
authors.initials: CE
authors.lastname: Nolan
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Schachter
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Fouad
authors.initials: F
authors.lastname: Janat
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Che
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Veerabahu
authors.initials: V
authors.lastname: Shanmugasundaram
authors.affiliation: Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Enerson
authors.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Elijahu
authors.initials: E
authors.lastname: Livni
authors.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Guehl
authors.affiliation: Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA.
authors.forename: Debasis
authors.initials: D
authors.lastname: Patnaik
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute, 415 Main Street, Cambridge, MA, o2142, USA.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: 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.
authors.forename: Roy
authors.initials: R
authors.lastname: Perlis
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute, 415 Main Street, Cambridge, MA, o2142, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.affiliation: Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Georges
authors.initials: G
authors.lastname: El Fakhri
authors.affiliation: Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT, 06340, USA. ravi.g.kurumbail@pfizer.com.
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.affiliation: Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA. vasdev.neil@mgh.harvard.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D059906:Neuroimaging; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D010080:Oxazoles; C000628213:PF-04802367; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; glycogen synthase kinase-3; phosphorylation; positron emission tomography; tau proteins