A new octadentate chelator for the rapid complexation of ⁸⁹Zr.

Objectives Zirconium-89 is a prominent radionuclide for immuno-PET as its physical half-life matches the biological half-life of antibodies well and its emission properties are suited for PET imaging. The currently available gold standard chelator for ⁸⁹Zr, desferrioxamine (DFO), shows stability deficits that result in bone uptake. Herein we report an alternative octadentate chelator that can bind ⁸⁹Zr under mild radiolabeling conditions.

Methods We synthesized a new acyclic octadentate chelator that is based on four 3-hydroxy-4-pyridinone (3,4-HOPO) units and studied its complexation potential with ^natZr(IV). Complex formation was characterized using mass spectrometry, NMR-, FT-IR-, and UV-Vis spectroscopy. The kinetics and complexation yield were then studied with ⁸⁹Zr at room temperature and different pH conditions using radio-TLC and radio-HPLC.

Results The chelator was found to quantitatively complex ⁸⁹Zr within 15 min at room temperature and neutral pH (6.5-7.5). At lower pH values slower radiolabeling kinetics were observed. Mass spectrometry indicated the formation of the 1:1 metal:ligand complex. The complex formation was also observed by a redshift of the UV-Vis absorption maximum from 282 to 302 nm, shifts in the FT-IR absorption bands, as well as a loss of symmetry as observed via the ¹H-NMR spectrum.

Conclusions The novel chelator was found to be a promising candidate for the complexation of ⁸⁹Zr. It provides efficient radiolabeling at room temperature and neutral pH within 15 min. The monometallic complex was characterized using different analytical techniques. The rapid complex formation at room temperature is interesting for the compatibility with large molecular weight biomolecules such as antibodies. We are in the process of assessing the complex stability by transchelation challenge experiments and biodistribution in vivo. Further studies are focused on a bifunctional version of the chelator for immuno-PET.