Investigation of the complexation of nat Zr(IV) and 89 Zr(IV) by hydroxypyridinones for the development of chelators for PET imaging applications
Résumé
Three hydroxypyridinone (HOPO) positional isomers – 1,2-HOPO (L 1 H) and its water soluble analogue (L 1' H), 3,2-HOPO (L 2 H) and 3,4-HOPO (L 3 H) 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(L 2) 4 and Zr(L 3) 4 as well as a higher kinetic inertness in competition studies with EDTA or Fe 3+ at a radiotracer concentration with 89 Zr. Besides the low pK a of L 1 H or L 1' H (pK a = 5.01) in comparison with L 2 H and L 3 H (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 89 Zr.
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