title: Synthesis and Initial in Vivo Studies with [(11)C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3.
abstract: Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [(11)C]SB-216763, a high-affinity inhibitor of GSK-3 (K i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [(11)C]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [(11)C]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [(11)C]SB-216763 in 1% noncorrected radiochemical yield (based upon [(11)C]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.
authors.affiliation: Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Shao
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Cole
authors.affiliation: Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Ohnmacht
authors.affiliation: Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ferrari
authors.affiliation: Laboratory for Molecular Imaging, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Young T
authors.initials: YT
authors.lastname: Hong
authors.affiliation: Laboratory for Molecular Imaging, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: David J
authors.initials: DJ
authors.lastname: Williamson
authors.affiliation: Laboratory for Molecular Imaging, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Quesada
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Phillip
authors.initials: P
authors.lastname: Sherman
authors.affiliation: Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Riss
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States ; The Interdepartmental Program in Medicinal Chemistry, The University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
authors.affiliation: Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K. ; Laboratory for Molecular Imaging, Wolfson Brain Imaging Centre, University of Cambridge , Cambridge CB2 1TN, U.K.
authors.forename: Franklin I
authors.initials: FI
authors.lastname: Aigbirhio
keywords: Positron emission tomography; brain PET; carbon-11; glycogen synthase kinase (GSK-3); neuroimaging