Positron emission tomography (PET) is a sensitive diagnostic modality and has been demonstrated to give highly sensitive detection and staging of various diseases. Among the positron emitting radionuclides utilized for PET imaging, Zr-89 has the advantage of a relatively long physical half-life (t1/2 = 78.4 h) and is suitable for use in immuno-PET imaging where a sensitive antibody with a long biological half-life is employed. In antibody-targeted PET imaging, an effective bifunctional chelator is expected to complex Zr-89 rapidly and tightly to minimize radiolytic damage resulting from extended exposure of the antibody during radiolabeling and in vivo toxicity from dissociation of Zr-89 from the complex.<br/>Although the Zr-89-immuno-PET holds great promise for imaging of many diseases as evidenced by numerous preclinical trials, the absence of an optimal bifunctional ligand for complexation of Zr-89 with high in vivo stability limited broad and successful clinical applications of Zr-89 based PET imaging.<br/>In an effort to develop superior bifunctional ligands of Zr-89, we have assessed various donor systems for complextaion with Zr-89. In this presentation, we report synthesis and evaluation of new bifuncitonal ligands with structural variations. The new chelators were evaluated for radiolabeling kinetics with Zr-89 at room temperature. In vitro stability of the corresponding complexes in human serum and when challenged by exess EDTA were assessed in comparison to desferoxamine (DFO). DFO is one of the most frequently explored chelators for PET imaging applications. The new lead chelators were extremely rapid in binding Zr-89 (&gt; 99% radiolabeling efficiency, room temperature) and present a favourable serum stability profile. The new bifunctional ligands were successfully conjugated to a HER2-specific antibody (Herceptin) for comparative in vivo evaluation using mice. The result of the radiolabeing kinetics and serum stability data indicate that the new bifunctional chelators of Zr-89 are promising candidates for immuno-PET imaging applications.

New bifunctional ligands of Zr-89 for potential applications in antibody-targeted positron emission tomography (PET) imaging and precision medicine

256th National Meeting (2018)

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