Development of a platform for the rapid synthesis and evaluation of new chelators for radiometals.

69 Introduction: Early diagnosis of cancer not only reduces the cost of treating patients with cancer but also increases the patient’s survival rate. Molecular imaging with PET is a non-invasive and powerful technique that provides detailed quantitative information on cellular and metabolic events. Zirconium-89 features a half-life (78.4 hours) that is well matched to antibody biovectors, favorable decay characteristics for PET imaging, and routine production at a growing number of cyclotron sites world-wide. However, the successful exploitation of these features for PET imaging critically relies upon the careful choice of the bifunctional chelator (BFC), which holds Zr-89 tightly while it is attached to the targeting vector (e.g. antibody). To avoid chelate-instability and leaching of free zirconium-89 into the patient’s body, a BFC with eight oxo-coordination sites to Zr(IV) is ideal. Since the gold-standard chelator for zirconium-89 — desferrioxamine (DFO) — provides a sub-optimal six oxo-coordination sphere, new BFCs with eight oxo-donor sites have been sought after by many research groups in recent years. Although a few successful new BFCs for zirconium-89 have been published in recent years, we have designed a new family of BFCs based on DFO (including our chelators DFO2, DFO2glu, DFO2ʹ) with a synthetic platform that features simple and rapid synthesis of new derivatives to enable binding with Zr(IV) as well as other metal ions. More importantly, we are investigating the use of EXAFS spectroscopy and DFT computational methods with the goal of validating and then integrating these methods with our rapid synthesis platform and traditional radiochemical stability assays. We have determined the most accurate combination of DFT functionals and basis sets for predicting the coordination environment of our large and complicated chelate systems (potential coordination numbers 8-12) by using the accurate bond length values obtained from EXAFS spectroscopy as standard values. We have performed invitro radiochemical stability assays (e.g. serum, transferrin, albumin, hydroxyapatite, EDTA competitions), which have demonstrated that zirconium-89 complexes of DFO2 and several of its derivatives are more stable than DFO. Evaluation of in vivo stability of the bifunctional derivatives of DFO2-type chelators conjugated to the model antibody traustuzumab are ongoing in order to determine the most relevant assays to predict stability. We hope to find a predictive link between our spectroscopic and computational studies and in vivo performance. The ultimate goal is a well-defined and rapid pipeline for new chelator development.

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