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  • [J Labelled Comp Radiopharm.] High-yield synthesis of a tau PET radioligand and its nonradioactive ligand using an alternative protection and deprotection strategy

    성균관의대 / 김현정, 최연성*

  • 출처
    J Labelled Comp Radiopharm.
  • 등재일
    2021 Apr
  • 저널이슈번호
    64(4):150-158. doi: 10.1002/jlcr.3894. Epub 2020 Nov 26.
  • 내용

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    Abstract
    Recently developed tau imaging radiopharmaceuticals show specific uptake in tau protein-rich regions in human brains without off-target binding. These radiopharmaceuticals and their nonradioactive reference ligands are generally obtained in low (radio)chemical yields. In the present study, we investigated high-yield synthesis of 18 F-RO948 ([18 F]1) and its nonradioactive ligand (1). The ligand 1 was synthesized by a Suzuki-Miyaura coupling reaction between 9-(4-methoxybenzyl)-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl trifluoromethanesulfonate (3) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4), followed by oxidative removal of the para-methoxybenzyl (PMB) group with ceric ammonium nitrate (CAN). This two-step reaction gave 1 in 55.8% yield. The precursor for [18 F]1 was synthesized from 3 and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6). The resulting PMB-protected precursor 8 was obtained in 74.5% yield. [18 F]1 was synthesized by radiofluorination of 8 (radiochemical conversion (RCC): 95.7 ± 1.7%), followed by deprotection of the PMB group with CAN. This one-pot, two-step radiochemical synthesis followed by HPLC purification gave [18 F]1 in high decay-corrected radiochemical yield (54-60%). The RCC of [18 F]fluoride to [18 F]1 in our two-step synthesis method was similar to that in a one-step radiofluorination reaction of a tert-butoxycarbonyl (BOC)-protected precursor 10 that proceeds with concomitant thermal deprotection of the BOC group. Taken together, the results of this study suggest that this high-yield synthesis method is useful for the synthesis of 18 F-labeled (NH)heteroarene compounds.

     

     

    Affiliations

    Hyunjung Kim  1 , Yearn Seong Choe  1   2
    1 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
    2 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.

     

  • 키워드
    18F-RO948; ceric ammonium nitrate; high-yield synthesis; nonradioactive reference ligand; para-methoxybenzyl protecting group; radiopharmaceutical; tau proteins.
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