The advent of antibody-based cancer therapeutics has led to the concomitant rise in the development of companion diagnostics for these therapies, particularly nuclear imaging agents. A number of radioisotopes have been employed for antibody-based PET and SPECT imaging, notably 64Cu, 124I, 111In, and 99mTc; in recent years, however, the field has increasingly focused on 89Zr, a radiometal with near ideal physical and chemical properties for immunoPET imaging. In the review at hand, we seek to provide a comprehensive portrait of the current state of 89Zr radiochemical and imaging research, including work into the production and purification of the isotope, the synthesis of new chelators, the development of new bioconjugation strategies, the creation of novel 89Zr-based agents for preclinical imaging studies, and the translation of 89Zr-labeled radiopharmaceuticals to the clinic. Particular attention will also be dedicated to emerging trends in the field, 89Zr-based imaging applications using vectors other than antibodies, the comparative advantages and limitations of 89Zr-based imaging compared to that with other isotopes, and areas that would benefit from more extensive investigation. At bottom, it is hoped that this review will provide both the experienced investigator and new scientist with a full and critical overview of this exciting and fast-developing field.
Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for 89Zr4+; however, accumulation of 89Zr in the bones of mice suggests that 89Zr4+ is released from DFO in vivo. An improved chelator for 89Zr4+ could eliminate the release of osteophilic 89Zr4+ and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of 89Zr-HOPO matched or surpassed that of 89Zr-DFO in every experiment. In healthy mice, 89Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for 89Zr-based PET imaging agents.
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