Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 8, Issue 3, Pages 287-292Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00405
Keywords
Glycogen synthase kinase-3; PET imaging; radiofluorination; maleimide
Categories
Funding
- National Institute of General Medical Sciences [R35GM119652]
- National Institute on Aging of the National Institute of Health
- Stony Brook University [R01AG054473]
- National Natural Science Foundation of China [21403208]
- NIH Chemical -Biology [T32GM092714]
- Tau Consortium
- National Institute on Drug Abuse [DA038000]
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Dysregulation of glycogen synthase kinase-3 beta (GSK-3 beta) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3 beta 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-3 beta 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-3 beta inhibitors. Radiosynthesis of a potential GSK-3 beta tracer [F-18]10a is achieved. Preliminary in vivo PET 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 [F-18]-labeled GSK-3 beta radiotracers for PET imaging of the central nervous system is warranted.
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