Synthesis and Evaluation of D8W, an Octadentate Desferrioxamine Analogue with Enhanced Water Solubility Designed for ⁸⁹ Zr-ImmunoPET Imaging

Antibody-based zirconium-89 (⁸⁹Zr)-containing immunological positron emission tomography (immuno-PET) agents have applications in high-precision cancer imaging. These agents require a bifunctional chelator to bind the positron-emitting ⁸⁹Zr isotope and facilitate the covalent attachment to a cancer-targeting monoclonal antibody (mAb). The hexadentate hydroxamic acid chelator desferrioxamine B (DFO) is commonly used in the development of ⁸⁹Zr-immunoPET agents. While DFO is efficiently radiolabeled with ⁸⁹Zr, vacancies in the unsaturated ⁸⁹Zr-DFO coordination sphere can reduce the ⁸⁹Zr-DFO complex stability and increase the risk of ⁸⁹Zr dissociating and accumulating in nontarget tissues, particularly bone. This potential shortcoming of ⁸⁹Zr-DFO can be addressed by using an octadentate chelator to fully saturate the ⁸⁹Zr coordination sphere. The octadentate chain-extended DFO analogue DFO* was the first exemplar of this class and showed ⁸⁹Zr-DFO* was more stable than ⁸⁹Zr-DFO. The current work designed, synthesized, and evaluated the properties of a new octadentate DFO analogue, named D8W, where "W" designates "water-soluble". This property has been built into D8W by including water-solubilizing ether oxygen atoms in the hydroxamic acid extension unit appended to DFO and a PEG₄ unit. Comparison of the two most water-soluble chelators from the set of DFO, DFO* and D8W, showed that compared to [⁸⁹Zr]Zr-DFO-mAb (mAb = Girentuximab), [⁸⁹Zr]Zr-D8W-mAb had improved ⁸⁹Zr radiolabeling kinetics and <i>in vitro</i> stability. Key to its utility, bone deposition of ⁸⁹Zr was lower for [⁸⁹Zr]Zr-D8W-mAb than [⁸⁹Zr]Zr-DFO-mAb, as assessed by PET imaging in a CAIX-expressing HT-29 tumor-bearing Balb/C nude mouse model. The performance of D8W coupled with its water solubility supports its merit in its use in ⁸⁹Zr-immunoPET agents.