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

摘要: 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 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 most potent selective TrkB/C characterized to date. It demonstrated readily crosses blood–brain barrier (BBB) rodents selectively binds receptors vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding brain tissue observed vitro, with specific reduction hippocampus Alzheimer’s disease (AD) versus healthy brains. additionally provide preliminary translational data regarding disposition primates including first-in-human assessment. These results illustrate for first time use k...