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 YY 3-36 (PYY 3-36) is a 36-residue peptide hormone that reduces food intake when peripherally administered. Herein, we describe the synthesis of a PYY 3-36 analogue functionalized with a metal-ion-binding 2,2'bipyridine ligand that enables self-assembly through metal complexation. Upon addition of Cu II , the bipyridine-modified PYY 3-36 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, bipyridinemodified PYY 3-36 was radiolabeled with a chelator holding 111 In III , followed by the addition of Cu II to the bipyridine ligand. SPECT/ CT imaging and biodistribution studies showed fast renal clearance and accumulation in the kidney cortex. The radiolabeled bipyridyl-PYY 3-36 conjugates with and without Cu II presented a slightly slower excretion 1 h post injection compared to the unmodified-PYY 3-36 , thus demonstrating that higher self-assemblies of the peptide might have an effect on the pharmacokinetics.

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