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Radiosynthesis and Evaluation of [11C]HD-800, a High Affinity Brain Penetrant PET Tracer for Imaging Microtubules
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    Radiosynthesis and Evaluation of [11C]HD-800, a High Affinity Brain Penetrant PET Tracer for Imaging Microtubules
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    • Kiran Kumar Solingapuram Sai
      Kiran Kumar Solingapuram Sai
      Department of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States
    • Jaya Prabhakaran
      Jaya Prabhakaran
      Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, United States
      Department of Psychiatry, Columbia University Medical Center, New York, United States
    • Gayathri Ramanathan
      Gayathri Ramanathan
      Department of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States
    • Stephanie Rideout
      Stephanie Rideout
      Department of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States
    • Christopher Whitlow
      Christopher Whitlow
      Department of Radiology, Wake Forest School of Medicine, Winston Salem, North Carolina, United States
    • Akiva Mintz
      Akiva Mintz
      Department of Radiology, Columbia University Medical Center, New York, United States
      More by Akiva Mintz
    • J. John Mann
      J. John Mann
      Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, United States
      Department of Psychiatry, Columbia University Medical Center, New York, United States
      Department of Radiology, Columbia University Medical Center, New York, United States
      More by J. John Mann
    • J. S. Dileep Kumar*
      J. S. Dileep Kumar
      Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, United States
      * Fax: 646-774-7521; Tel: 646-774-7522; E-mail: [email protected]
    Other Access OptionsSupporting Information (1)

    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2018, 9, 5, 452–456
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    https://doi.org/10.1021/acsmedchemlett.8b00060
    Published April 30, 2018
    Copyright © 2018 American Chemical Society

    Abstract

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    Microtubules (MTs) are highly abundant throughout the cytoskeleton, and their dysfunction is implicated in the pathogenesis of malignancies, various neurodegenerative disorders, and brain injuries. Validated radiotracers reported so far for MTs are [11C]paclitaxel, [18F]fluoropaclitaxel, and [11C]docetaxel; however, they are well-characterized substrates of efflux transporters and consequently have poor uptake into the brain due to minimal blood brain barrier (BBB) penetration. PET imaging of MT expression requires radiolabeled BBB penetrating MT ligands, and it may offer a direct and more sensitive approach for early diagnosis, monitoring disease progression, and treatment effects in brain diseases and assessing the clinical potential of targeted therapeutics and treatments. We have identified N-(4-methoxyphenyl)-N-5-dimethylfuro[2,3-d]pyrimidin-4-amine (HD-800) as a high affinity and selective colchicine site tubuline inhibitor amenable to radiolabel with C-11, a positron emitting isotope. HD-800 and desmethyl-HD-800 were synthesized in one step with 75% and 80% yields respectively from commercial synthons. The radiosynthesis of [11C]HD-800 was achieved in 45 ± 5% yield at EOS. Ex vivo biodistribution binding data of [11C]HD-800 indicate that the radioligand penetrated the BBB and it was retained in brain with 75% specific binding. Apart from the brain, specific binding was observed in muscle (55%), heart (50%), lungs (43%), blood (37%), and pancreas (30%). MicroPET imaging in mice showed excellent binding in brain that was blocked by preadministration of unlabeled HD-800 and a colchicine site binding MT ligand MPC-6827. The above results indicate that [11C]HD-800 may be a suitable PET ligand for the in vivo quantification of MT inside and outside the brain.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00060.

    • Molecular formula strings of key chemicals, 1H NMR spectra of compound 4, binding affinity of HD-800 to brain targets (Table 1), semipreparative HPLC chromatogram of [11C]HD-800, analytical HPLC chromatogram of [11C]HD-800, and analytical HPLC chromatograms of [11C]HD-800 and unlabeled HD-800 (PDF)

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    Cited By

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    This article is cited by 17 publications.

    1. Paul Josef Myburgh, Kiran Kumar Solingapuram Sai. Development and Optimization of 11C-Labeled Radiotracers: A Review of the Modern Quality Control Design Process. ACS Pharmacology & Translational Science 2023, 6 (11) , 1616-1631. https://doi.org/10.1021/acsptsci.3c00200
    2. Bhuvanachandra Bhoopal, Krishna Kumar Gollapelli, Naresh Damuka, Mack Miller, Ivan Krizan, Avinash Bansode, Thomas Register, Brett M. Frye, Jeongchul Kim, Akiva Mintz, Miranda Orr, Suzanne Craft, Christopher Whitlow, Samuel N. Lockhart, Carol A. Shively, Kiran Kumar Solingapuram Sai. Preliminary PET Imaging of Microtubule-Based PET Radioligand [11C]MPC-6827 in a Nonhuman Primate Model of Alzheimer’s Disease. ACS Chemical Neuroscience 2023, 14 (20) , 3745-3751. https://doi.org/10.1021/acschemneuro.3c00527
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    6. Naresh Damuka, Thomas J. Martin, Avinash H. Bansode, Ivan Krizan, Conner W. Martin, Mack Miller, Christopher T. Whitlow, Michael A. Nader, Kiran Kumar Solingapuram Sai. Initial Evaluations of the Microtubule-Based PET Radiotracer, [11C]MPC-6827 in a Rodent Model of Cocaine Abuse. Frontiers in Medicine 2022, 9 https://doi.org/10.3389/fmed.2022.817274
    7. Kiran Kumar Solingapuram Sai, Xiaofei Chen, Zhe Li, Caigang Zhu, Kirtikar Shukla, Tom E. Forshaw, Hanzhi Wu, Stephen A. Vance, Buddhika Liyana Pathirannahel, Megan Madonna, Mark W. Dewhirst, Allen W. Tsang, Leslie B. Poole, Nimmi Ramanujam, S. Bruce King, Cristina M. Furdui. [18F]Fluoro-DCP, a first generation PET radiotracer for monitoring protein sulfenylation in vivo. Redox Biology 2022, 49 , 102218. https://doi.org/10.1016/j.redox.2021.102218
    8. Dileep Kumar, Ramesh Neelamegam, Thomas Chaly. Radiosynthesis and in Vivo Imaging of Vegfr2 Pet Ligand [11c]Btfp. SSRN Electronic Journal 2022, https://doi.org/10.2139/ssrn.4058983
    9. Ramesh Neelamegam, Thomas Chaly, J.S. Dileep Kumar. Radiosynthesis and in vivo imaging of [11C]BTFP, a potent inhibitor of VEGFR2. Results in Chemistry 2022, 4 , 100381. https://doi.org/10.1016/j.rechem.2022.100381
    10. Ruiqing Ni. Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis: Translational Implications. Pharmaceuticals 2021, 14 (11) , 1179. https://doi.org/10.3390/ph14111179
    11. Anton Lindberg, Andrew V. Mossine, Arturo Aliaga, Robert Hopewell, Gassan Massarweh, Pedro Rosa-Neto, Xia Shao, Vadim Bernard-Gauthier, Peter J. H. Scott, Neil Vasdev. Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET. Frontiers in Neuroscience 2021, 15 https://doi.org/10.3389/fnins.2021.725873
    12. Michael R. Kilbourn. Targeted Diagnostic Radiopharmaceuticals: Design Options for Small‐Molecule Radiotracers. 2020, 1-21. https://doi.org/10.1002/9781119500575.ch1
    13. Kiran Kumar Solingapuram Sai, Jaya Prabhakaran, Naresh Damuka, Suzanne Craft, Shamyaa A. Rajagopal, Akiva Mintz, John Mann, Dileep Kumar. Synthesis and Initial In Vivo Evaluations of [ 11 C]WX‐132‐18B, a Microtubule PET Imaging Agent. ChemistrySelect 2020, 5 (31) , 9623-9625. https://doi.org/10.1002/slct.202001827
    14. Naresh Damuka, Paul W. Czoty, Ashley T. Davis, Michael A. Nader, Susan H. Nader, Suzanne Craft, Shannon L. Macauley, Lindsey K. Galbo, Phillip M. Epperly, Christopher T. Whitlow, April T. Davenport, Thomas J. Martin, James B. Daunais, Akiva Mintz, Kiran Kumar Solingapuram Sai. PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains. Molecules 2020, 25 (10) , 2289. https://doi.org/10.3390/molecules25102289
    15. J.S. Dileep Kumar, Jaya Prabhakaran, Naresh Damuka, Justin Wayne Hines, Skylar Norman, Meghana Dodda, J. John Mann, Akiva Mintz, Kiran Kumar Solingapuram Sai. In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands. Bioorganic & Medicinal Chemistry Letters 2020, 30 (2) , 126785. https://doi.org/10.1016/j.bmcl.2019.126785
    16. Kiran Kumar Solingapuram Sai, Nagaraju Bashetti, Xiaofei Chen, Skylar Norman, Justin W. Hines, Omsai Meka, J. V. Shanmukha Kumar, Sriram Devanathan, Gagan Deep, Cristina M. Furdui, Akiva Mintz. Initial biological evaluations of 18F-KS1, a novel ascorbate derivative to image oxidative stress in cancer. EJNMMI Research 2019, 9 (1) https://doi.org/10.1186/s13550-019-0513-x
    17. Jaya Prabhakaran, Kiran Kumar Solingapuram Sai, Anirudh Sattiraju, Akiva Mintz, J. John Mann, J.S. Dileep Kumar. Radiosynthesis and evaluation of [11C]CMP, a high affinity GSK3 ligand. Bioorganic & Medicinal Chemistry Letters 2019, 29 (6) , 778-781. https://doi.org/10.1016/j.bmcl.2019.01.033

    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2018, 9, 5, 452–456
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.8b00060
    Published April 30, 2018
    Copyright © 2018 American Chemical Society

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