Multidentate hydroxypyridinonate ligands for Pu(IV) chelation in vivo: comparative efficacy and toxicity in mouse of ligands containing 1,2-HOPO or Me-3,2-HOPO

Author： Durbin P. W. Kullgren B. Raymond K. N.

Publisher： Informa Healthcare

ISSN： 1362-3095

Source： International Journal of Radiation Biology, Vol.76, Iss.2, 2000-02, pp. : 199-214

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Abstract

Purpose: To identify the most effective multidentate 1,2-HOPO and Me-3,2-HOPO ligands for chelation of Pu(IV) in vivo. Materials and methods: Two sets of ligands with four identical backbones were prepared containing two, three or four bidentate 1,2-HOPO or Me-3,2-HOPO groups, and 3,4,3-LI(1,2-HOPO) was resynthesized in a higher yielding procedure. They were evaluated in mouse for acute toxicity and reduction of tissue ²³⁸Pu, in comparison with CaNa₃-DTPA (30mumolkg^-1).Results: Nine HOPO ligands, promptly injected or given orally or injected at low dosage, are superior to CaNa₃-DTPA for reducing ²³⁸Pu retention in mouse. Five, given by delayed injection or promptly injected or orally administered as ferric complexes, are superior to CaNa₃-DTPA or FeNa₂-DTPA respectively. The Me-3,2-HOPO ligands are more effective than their structural 1,2-HOPO analogues, demonstrating the greater affinity of Me-3,2-HOPO for Pu(IV) in vivo. Conclusions: The most efficacious ligand, 3,4,3-LI(1,2-HOPO), contains the less stably binding 1,2-HOPO group; therefore, its linear spermine backbone must confer advantages for Pu(IV) binding (greater solubility, more favorable arrangement of ligating groups, more flexible backbone). Effective low toxicity tetradentate 5-LIO(Me-3,2-HOPO) and hexadentate TREN(Me-3,2-HOPO) and highly effective but moderately toxic 3,4,3-LI(1,2-HOPO) (LD₅₀ ~300mumolkg^-1 in mouse) are recommended for further investigation.