45Ti is an ideal isotope for positron emission tomography (PET) imaging due to its high positron branching ratio (85%), low positron energy, and minimal production of concurrent gamma rays. In addition, 45Ti has a half-life of 3.09 h, which is ideal for targeted imaging with small biomolecules, comparing well to the clinically used radioisotope, 18F. However, the major impediment to the implementation of 45Ti in a clinical setting is a lack of chelators suitable to stabilize the isotope in-vivo due to its extreme hydrolytic nature. For this reason, the aqueous coordination chemistry of Ti4+ remains critically understudied. Previously studied desferrioxamine B (DFO) complexes of titanium were probed and the putative solution structure of Ti-DFO was elucidated using DFT and VT-MS techniques, revealing the formation of a to-date undocumented, seven coordinate species at physiologically and radiochemically relevant pH ranges. We identified the formation of a seven-coordinate hydroxo-species with potentially diminished in vivo stability, affirming the need for the development of robust Ti(IV) chelation approaches that exclude the formation of ternary or competing hydroxo species. Herein, we demonstrate that application of a systematic screening approach using potentiometric and spectrophotometric speciation, variable temperature mass spectrometry (VT-MS), and density functional theory (DFT) techniques can be used to rationally design aqueous Ti4+ coordination complexes that are inert to hydrolysis at radiochemically and physiologically relevant aqueous pH conditions. Specifically, we chose 10 bidentate chelators guided by HSAB theory. Of those tested, four gave promising results for potential development of bifunctional chelators for use in 45Ti PET imaging. Subsequently, chelating hexacoordinate analogues of these chelators were also assessed for their thermodynamic stability and speciation and 45Ti radiolabeling to identify a lead construct that will enable the development of biocompatible, 45Ti-based radiopharmaceuticals.

Use of thermodynamic speciation and rational ligand design towards suitable chelators for 45Ti PET imaging

ACS Fall 2021

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