Abstract
Antibody-based zirconium-89 ((89)Zr)-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 (89)Zr 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 (89)Zr-immunoPET agents. While DFO is efficiently radiolabeled with (89)Zr, vacancies in the unsaturated (89)Zr-DFO coordination sphere can reduce the (89)Zr-DFO complex stability and increase the risk of (89)Zr dissociating and accumulating in nontarget tissues, particularly bone. This potential shortcoming of (89)Zr-DFO can be addressed by using an octadentate chelator to fully saturate the (89)Zr coordination sphere. The octadentate chain-extended DFO analogue DFO* was the first exemplar of this class and showed (89)Zr-DFO* was more stable than (89)Zr-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 PEG(4) unit. Comparison of the two most water-soluble chelators from the set of DFO, DFO* and D8W, showed that compared to [(89)Zr]Zr-DFO-mAb (mAb = Girentuximab), [(89)Zr]Zr-D8W-mAb had improved (89)Zr radiolabeling kinetics and in vitro stability. Key to its utility, bone deposition of (89)Zr was lower for [(89)Zr]Zr-D8W-mAb than [(89)Zr]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 (89)Zr-immunoPET agents.