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

J Med Chem. 2021 Apr 22;64(8):4841-4856. doi: 10.1021/acs.jmedchem.0c02213. Epub 2021 Apr 7.

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 β-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 ([68Ga]Ga-4b, [68Ga]Ga-11b-13b) targeting CCK-2R. In particular, [68Ga]Ga-12b and [68Ga]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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Gallium Radioisotopes / chemistry
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms / diagnosis*
  • Neoplasms / pathology
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / metabolism
  • Positron Emission Tomography Computed Tomography
  • Precision Medicine
  • Protein Binding
  • Protein Structure, Tertiary
  • Radiopharmaceuticals / chemistry*
  • Radiopharmaceuticals / metabolism
  • Receptor, Cholecystokinin B / chemistry
  • Receptor, Cholecystokinin B / metabolism*
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Gallium Radioisotopes
  • Peptides
  • Radiopharmaceuticals
  • Receptor, Cholecystokinin B
  • Gallium-68