The goal of the proposed research is to develop robust bifunctional chelators for the use of zirconium-89 (89Zr) for Positron Emission Tomography (PET). Antibodies can be radiolabeled with PET radiometals, such as 89Zr, through the attachment of a chelator which can bind the radiometal in question. The resulting imaging agents are extremely useful for the diagnosis and staging of cancer and other diseases. There is evidence of release of 89Zr in the body from complexes made with the current bifunctional chelator. This release of radioactive material can be harmful and leads to the accumulation of 89Zr in the bones of mice during preclinical studies. A more stable chelator will reduce the release of free 89Zr and result in safer radiotracers. Increasing the concern over bone accumulation will enable the more widespread investigation and application of 89Zr-based PET imaging agents which will lead to improvements in the diagnosis and understanding of various cancer types. This project entails the design and synthesis of ligands tailored to zirconium;the radiolabeling and evaluation of the ligand-metal binding;the bifunctionalization of the best suited ligands;and the creation and ultimate biological testing of novel 89Zr-ligand-antibody constructs for PET imaging. The design of the ligands takes into account that Zr requires a hard donor ligand and prefers octadentate coordination. The ligands chosen for development are based on hydroxamate, catechol, and hydroxypyridinone binding groups in keeping with the oxophillic nature of Zr4+. The organic synthesis of the ligands will require intensive development, both for the bare ligands and the bifunctional ligands. The characterization of the non-radioactive Zr-ligand species will be carried out as well as extensive radiolabeling experiments to evaluate the suitability of each ligand for zirconium. An optimal ligand will demonstrate clean and efficient radiolabeling at conditions compatible with antibodies as well as high serum stability. The best candidate ligands will be bifunctionalized and conjugated to antibodies for further evaluation including PET imaging and biodistribution studies in mice, immunoreactivity assays, and stability studies of the 89Zr-antibody construct. This project will be undertaken as part of the doctoral training experience between Memorial Sloan-Kettering Cancer Center and Hunter College. It will include training in synthetic organic, inorganic, and radiochemistry as well as cancer biology, molecular imaging, and translational research. Beyond the research development, additional training will be provided in the form of coursework, seminars, professional conferences, mentoring opportunities, and career development.
The development of a better way to attach 89Zr to an antibody for Positron Emission Tomography (PET) imaging will result in safer imaging agents. A better chelate will eliminate the release of the radiometal in the body which will decrease the accumulation of radioactivity and the radiation absorbed dose to healthy non-target tissue. Safer PET imaging agents will allow for their widespread use and improve the diagnosis and disease staging of cancer.
|Deri, Melissa A; Ponnala, Shashikanth; Zeglis, Brian M et al. (2014) Alternative chelator for ??Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO). J Med Chem 57:4849-60|