Building Blocks for the Construction of Bioorthogonally Reactive Peptides via Solid-Phase Peptide Synthesis

Authors

  • Dr. Brian M. Zeglis,

    1. Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (USA)
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  • Fabien Emmetiere,

    1. Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (USA)
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  • Dr. Nagavarakishore Pillarsetty,

    1. Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (USA)
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  • Prof. Ralph Weissleder,

    1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114 (USA)
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  • Prof. Jason S. Lewis,

    Corresponding author
    1. Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (USA)
    2. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (USA)
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  • Prof. Thomas Reiner

    Corresponding author
    1. Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (USA)
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Abstract

The need for post-synthetic modifications and reactive prosthetic groups has long been a limiting factor in the synthesis and study of peptidic and peptidomimetic imaging agents. In this regard, the application of biologically and chemically orthogonal reactions to the design and development of novel radiotracers has the potential to have far-reaching implications in both the laboratory and the clinic. Herein, we report the synthesis and development of a series of modular and versatile building blocks for inverse electron-demand Diels–Alder copper-free click chemistry: tetrazine-functionalized artificial amino acids. Following the development of a novel peptide coupling protocol for peptide synthesis in the presence of tetrazines, we successfully demonstrated its effectiveness and applicability. This versatile methodology has the potential to have a transformational impact, opening the door for the rapid, facile, and modular synthesis of bioorthogonally reactive peptide probes.

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