A Novel Bifunctional Chelating Agent for Tyrosine-Specific Radiolabeling of Peptides and Proteins

Abstract

Site-specific radiolabeling is utilized for the development of antibody-or peptide-based radiotheranostic agents. Although tyrosine can be exploited as one of the target residues for site-specific radiolabeling of peptides and proteins, a tyrosinespecific radiolabeling method has not been established. In this study, we newly designed and synthesized a novel bifunctional chelating agent, TBD-DO3A, consisting of a triazabutadiene (TBD) scaffold and metal chelator, 1,4,7,10-tetraazacyclododecane 1,4,7-triacetic acid (DO3A). Conjugation of TBD-DO3A with Ac-Tyr-NHMe followed by 111 In-labeling afforded [ 111 In]In-Tyr-DO3A, which showed high-level stability in mouse plasma. Then, we selected the tyrosine-containing cyclic peptide c(RGDyK) as a model ligand and synthesized [ 111 In]In-RYD. [ 111/nat In]In-RYD showed in vitro binding properties for integrin α v β 3 equivalent to those of [ 111/nat In]In-RKD, a lysine residue-labeled control compound. In in vivo biodistribution and SPECT/CT imaging studies using U87MG/PC-3 tumor-bearing mice, [ 111 In]In-RYD and [ 111 In]In-RKD were selectively accumulated and facilitated U87MG tumor visualization at 24 h postinjection. These results indicate that TBD-DO3A has fundamental properties as a bifunctional chelator for tyrosine-specific radiolabeling of peptides and proteins.