A New Turn in Peptide-Based Imaging Agents: Foldamers Afford Improved Theranostics Targeting Cholecystokinin-2 Receptor-Positive Cancer

Corlett, A; Sani, MA; Van Zuylekom, J; Ang, CS; von Guggenberg, E; Cullinane, C; Blyth, B; Hicks, RJ; Roselt, PD; Thompson, PE; Hutton, CA; Haskali, MB

Author(s): Corlett, A; Sani, MA; Van Zuylekom, J; Ang, CS; von Guggenberg, E; Cullinane, C; Blyth, B; Hicks, RJ; Roselt, PD; Thompson, PE; Hutton, CA; Haskali, MB;
Details: Publication Year 2021-04-22,Volume 64,Issue #8,Page 4841-4856
Journal Title: Journal of Medicinal Chemistry
Publication Type: Research article
Abstract: Proteins adopt unique folded secondary and tertiary structures that are responsible for their remarkable biological properties. This structural complexity is key in designing efficacious peptides that can mimic the three-dimensional structure needed for biological function. In this study, we employ different chemical strategies to induce and stabilize a beta-hairpin fold of peptides targeting cholecystokinin-2 receptors for theranostic application (combination of a targeted therapeutic and a diagnostic companion). The newly developed peptides exhibited enhanced folding capacity as demonstrated by circular dichroism (CD) spectroscopy, ion-mobility spectrometry-mass spectrometry, and two-dimensional (2D) NMR experiments. Enhanced folding characteristics of the peptides led to increased biological potency, affording four optimal Ga-68 labeled radiotracers ([(68)Ga]Ga-4b, [(68)Ga]Ga-11b-13b) targeting CCK-2R. In particular, [(68)Ga]Ga-12b and [(68)Ga]Ga-13b presented improved metabolic stability, enhanced cell internalization, and up to 6 fold increase in tumor uptake. These peptides hold great promise as next-generation theranostic radiopharmaceuticals.
Keywords: Amino Acid Sequence; Animals; Cell Line, Tumor; Gallium Radioisotopes/chemistry; Humans; Mice; Mice, Nude; Neoplasms/*diagnosis/pathology; Peptides/chemical synthesis/*chemistry/metabolism; Positron Emission Tomography Computed Tomography; Precision Medicine; Protein Binding; Protein Structure, Tertiary; Radiopharmaceuticals/*chemistry/metabolism; Receptor, Cholecystokinin B/chemistry/*metabolism; Tissue Distribution; Transplantation, Heterologous
Department(s): Laboratory Research; Cancer Imaging
PubMed ID: 33826325
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.0c02213
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-09-05 01:45:03

Last Modified: 2025-09-05 01:46:46