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Syntheses and Evaluation of Carbon-11- and Fluorine-18-Radiolabeled pan-Tropomyosin Receptor Kinase (Trk) Inhibitors: Exploration of the 4-Aza-2-oxindole Scaffold as Trk PET Imaging Agents
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    Syntheses and Evaluation of Carbon-11- and Fluorine-18-Radiolabeled pan-Tropomyosin Receptor Kinase (Trk) Inhibitors: Exploration of the 4-Aza-2-oxindole Scaffold as Trk PET Imaging Agents
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    Experimental Medicine, Department of Medicine, McGill University, 1110 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
    Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada
    § Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, Quebec H4H 1R3, Canada
    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada
    Department of Neurology and Neurosurgery, McGill University, Jewish General Hospital, 3755 Cote St. Catherine Rd., Montreal, Quebec H2T 1E2, Canada
    *Prof. R. Schirrmacher. Fax: (+1) 514-340-7502; E-mail: [email protected]
    *Vadim Bernard-Gauthier. E-mail: [email protected]
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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2015, 6, 2, 260–276
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    https://doi.org/10.1021/cn500193f
    Published October 28, 2014
    Copyright © 2014 American Chemical Society

    Abstract

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    Tropomyosin receptor kinases (TrkA/B/C) are critically involved in the development of the nervous system, in neurological disorders as well as in multiple neoplasms of both neural and non-neural origins. The development of Trk radiopharmaceuticals would offer unique opportunities toward a more complete understanding of this emerging therapeutic target. To that end, we first developed [11C]GW441756 ([11C]9), a high affinity photoisomerizable pan-Trk inhibitor, as a lead radiotracer for our positron emission tomography (PET) program. Efficient carbon-11 radiolabeling afforded [11C]9 in high radiochemical yields (isolated RCY, 25.9% ± 5.7%). In vitro autoradiographic studies in rat brain and TrkB-expressing human neuroblastoma cryosections confirmed that [11C]9 specifically binds to Trk receptors in vitro. MicroPET studies revealed that binding of [11C]9 in the rodent brain was mostly nonspecific despite initial high brain uptake (SUVmax = 2.0). Modeling studies of the 4-aza-2-oxindole scaffold led to the successful identification of a small series of high affinity fluorinated and methoxy derivatized pan-Trk inhibitors based on our lead compound 9. Out of this series, the fluorinated compound 10 was selected for initial evaluation and radiolabeled with fluorine-18 (isolated RCY, 2.5% ± 0.6%). Compound [18F]10 demonstrated excellent Trk selectivity in a panel of cancer relevant kinase targets and a promising in vitro profile in tumors and brain sections but high oxidative metabolic susceptibility leading to nonspecific brain distribution in vivo. The information gained in this study will guide further exploration of the 4-aza-2-oxindole scaffold as a lead for Trk PET ligand development.

    Copyright © 2014 American Chemical Society

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    Supporting Information

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    Conformational equilibrium of 9, structure of (E)- and (Z)-9 and MeOH·(Z)-9, predicted binding mode of (E)-9 within TrkA, comparison of (Z)-9 binding with TrkB and TrkA, mechanistic explanation for the formation of (Z)-[11C]9 from (E)-16, UV-visible spectra changes upon treatment 9 (E/Z mixture) with NaOH(aq), predicted sites of metabolism using IMPACT for (Z)-9, HPLC chromatograms over 90 min for the RLM assay with (E/Z)-9 and (E/Z)-10, 1H-NMR spectra at different time points during photoisomerization of (Z)-10, LC-MS/MS analysis of the 10E/Z mixture, dose–response curves for the [γ-33P]ATP-based enzymatic in vitro assays of TrkA, TrkB, and TrkC with 16, 10, and 18ae, autoradiography of human neuroblastoma tumors with [18F]10 alone and in co-incubation with inhibitors 3, mechanistic rationale for synthesis of (Z)-9, chemical synthesis of 2-fluoroethyl 4-methylbenzenesulfonate, and crystallographic data for compounds 12 and (Z)-9. This material is available free of charge via the Internet at http://pubs.acs.org.

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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2015, 6, 2, 260–276
    Click to copy citationCitation copied!
    https://doi.org/10.1021/cn500193f
    Published October 28, 2014
    Copyright © 2014 American Chemical Society

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