Investigation of the complexation of natZr(IV) and 89Zr(IV) by hydroxypyridinones for the development of chelators for PET imaging applications

摘要

Three hydroxypyridinones (HOPOs) positional isomers - 1,2-HOPO (>L¹H) and its water soluble analogue (>L^1′H), 3,2-HOPO (>L²H) and 3,4-HOPO (>L³H)- have been investigated for the complexation of Zr(IV). Potentiometric and UV-Vis spectrometric studies show a higher thermodynamic stability for the formation of Zr(>L^1′)4 in comparison with Zr(>L²)4 and Zr(>L³)4 as well as a higher kinetic inertness in competition studies with EDTA or Fe³⁺ at radiotracer concentration with ⁸⁹Zr. Besides the low pKa of >L¹H or >L^1′H (pKa = 5.01) in comparison with >L²H and >L³H (pKa = 8.83 and 9.55, respectively), the higher stability of Zr(>L^1′)4 can be attributed in part to the presence of the amide group next to the chelating oxygen that induces intramolecular H-bond and amide/π interactions that were observed by X-ray crystallography and confirmed by quantum chemical calculations. The data presented here indicates that the 1,2-HOPO >L^1′ exhibits the best characteristics for Zr(IV) complexation. However, 2,3-HOPO and 3,4-HOPO patterns, if appropriately tuned, for instance with the addition of an amide group as in the 1,2-HOPO ligand, may also become interesting alternatives for the design of Zr(IV) chelators with improved characteristics for application in nuclear imaging with ⁸⁹Zr.