Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.
Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3β inhibitors. Radiosynthesis of a potential GSK-3β tracer [18F]10ais achieved. Preliminaryin vivoPET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [18F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted.
Department of Chemistry, and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Kongzhen
K
Hu
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Massachusetts General Hospital and Harvard Medical School , Boston Massachusetts 02114, United States.
Debasis
D
Patnaik
Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Thomas Lee
TL
Collier
Department of Chemistry, and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Katarzyna N
KN
Lee
Department of Chemistry, and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Han
H
Gao
Department of Chemistry, and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Matthew R
MR
Swoyer
Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Benjamin H
BH
Rotstein
Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Hema S
HS
Krishnan
Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Steven H
SH
Liang
Department of Chemistry, and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Jin
J
Wang
State Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, Jilin, China.
Zhiqiang
Z
Yan
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
Jacob M
JM
Hooker
Gordon Center for Medical Imaging & Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Neil
N
Vasdev
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Massachusetts General Hospital and Harvard Medical School , Boston Massachusetts 02114, United States.
Stephen J
SJ
Haggarty
Department of Chemistry, and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Ming-Yu
MY
Ngai
Glycogen synthase kinase-3; PET imaging; maleimide; radiofluorination