Methods to enhance the metabolic stability of peptide-based PET radiopharmaceuticals

Brendan J. Evans, Andrew T. King, Andrew Katsifis, Lidia Matesic, Joanne F. Jamie*

*Corresponding author for this work

    Research output: Contribution to journalReview articlepeer-review

    76 Citations (Scopus)
    84 Downloads (Pure)


    The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of D- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals.

    Original languageEnglish
    Article number2314
    Number of pages24
    Issue number10
    Publication statusPublished - 2 May 2020

    Bibliographical note

    Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


    • Radiopharmaceuticals
    • Peptides
    • Positron emission tomography
    • Proteolysis
    • Metabolic stability


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