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J Med Chem. 2017 Aug 24;60(16):6897-6910. doi: 10.1021/acs.jmedchem.7b00396. Epub 2017 Jul 21.

A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human.

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Department of Oncology, Division of Oncological Imaging, University of Alberta , Edmonton, Alberta T6G 2R3, Canada.
Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich , Marchioninistrasse 15, Munich 81377, Germany.
Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute , 6875 Boulevard LaSalle, Montreal, Quebec H4H 1R3, Canada.
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg , Heidelberg 69120, Germany.
McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University , 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
Biospective Inc. , 6100 Avenue Royalmount, Montreal, Quebec H4P 2R2, Canada.
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
Jewish General Hospital, Lady Davis Institute , Montreal, Quebec HT3 1E2, Canada.
Program in Neurosciences and Mental Health, Hospital for Sick Children , Toronto, Ontario M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto , Toronto, Ontario M5S1A8, Canada.
Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University , Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany.
The Interdepartmental Program in Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.


The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [11C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer's disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [11C]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human.

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