Bioimaging and Biodistribution of the Metal‐Ion‐Controlled Self‐Assembly of PYY3–36 Studied by SPECT/CT

The controlled self‐assembly of peptide‐ and protein‐based pharmaceuticals is of central importance for their mode of action and tuning of their properties. Peptide YY3–36 (PYY3–36) is a 36‐residue peptide hormone that reduces food intake when peripherally administered. Herein, we describe the synthesis of a PYY3–36 analogue functionalized with a metal‐ion‐binding 2,2’‐bipyridine ligand that enables self‐assembly through metal complexation. Upon addition of CuII, the bipyridine‐modified PYY3–36 peptide binds stoichiometric quantities of metal ions in solution and contributes to the organization of higher‐order assemblies. In this study, we aimed to explore the size effect of the self‐assembly in vivo by using non‐invasive quantitative single‐photon emission computed tomography/computed tomography (SPECT/CT) imaging. For this purpose, bipyridine‐modified PYY3–36 was radiolabeled with a chelator holding 111InIII, followed by the addition of CuII to the bipyridine ligand. SPECT/CT imaging and biodistribution studies showed fast renal clearance and accumulation in the kidney cortex. The radiolabeled bipyridyl‐PYY3–36 conjugates with and without CuII presented a slightly slower excretion 1 h post injection compared to the unmodified‐PYY3–36, thus demonstrating that higher self‐assemblies of the peptide might have an effect on the pharmacokinetics. Peptide self‐assembly: Radiolabeling of a re‐engineered peptide YY3–36 (PYY3–36) with a 2,2’‐bipyridine ligand enabled higher‐order self‐assemblies through coordination with CuII. We studied the effect of the self‐assembly in vivo by using non‐invasive quantitative bioimaging. Abiotic ligands might influence the controlled release of biopharmaceuticals from subcutaneous depots.