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

Abstract

Three hydroxypyridinone (HOPO) 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 a radiotracer concentration with ⁸⁹Zr. Besides the low pK_a of L¹H or L^1′H (pK_a = 5.01) in comparison with L²H and L³H (pK_a = 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 indicate that the 1,2-HOPO L^1′ exhibits the best characteristics for Zr(IV) complexation. However, 3,2-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 applications in nuclear imaging with ⁸⁹Zr.