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

Purpose: To identify the most effective multidentate 1,2-HOPO and Me-3,2-HO PO ligands For chelation of Pu(IV) in vivo. Materials and methods: Two sets of ligands with four identical backbones we re 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 proc edure. They were evaluated in mouse for acute toxicity and reduction of tis sue (238)pu, in comparison with CaNa3-DTPA (30 mu mol kg(-1)). Results: Nine HOPO ligands, promptly injected or given orally or injected a t low dosage, are superior to CaNa3-DTPA for reducing (238)pU retention in mouse. Five, given by delayed injection or promptly injected or orally admi nistered as ferric complexes, are superior to CaNa3-DTPA or FeNa2-DTPA resp ectively. 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 P u(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 favora ble 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 similar to 300 mu molkg(-1) in mouse) are recommended for further investigation.