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

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.