Dipicolinic acid (DPA)-based chelators for zirconium-89 PET imaging applications

We report the synthesis and evaluation of pyridine-based chelators for ⁸⁹Zr with applications in positron emission tomography (PET) imaging. A series of pyridine-containing small molecule ligands were screened for spectroscopic Zr(IV) complexation kinetics and radiolabeling with ⁸⁹Zr. Among these ligands, dipicolinic acid (DPA) was identified as the most effective donor system for ⁸⁹Zr(IV). Two DPA units were linked using a tetraethylene glycol (TEG) spacer to generate an acyclic chelator TEG-DPA₂ that can form a neutral complex with ⁸⁹Zr(IV). The chelator TEG-DPA₂ rapidly bound ⁸⁹Zr at room temperature, and the resulting ⁸⁹Zr-labeled TEG-DPA₂ complex exhibited high serum stability. In vivo biodistribution studies showed renal excretion of the hydrophilic ⁸⁹Zr-TEG-DPA₂ complex, resulting in rapid blood clearance and low uptake in normal tissues including liver, muscle, and bone in healthy mice. In summary, we demonstrate for the first time the potential of DPA-based donor systems for ⁸⁹Zr radiolabeling and identify TEG-DPA₂ as a lead chelator for further structural optimization and applications in ⁸⁹Zr PET imaging.