title: 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.
abstract: OBJECTIVE
  To identify the most effective multidentate 1,2-HOPO and Me-3,2-HOPO ligands for chelation of Pu(IV) in vivo.
  
  
  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 (30 micromol kg(-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 approximately 300 micromol kg(-1) in mouse) are recommended for further investigation.
authors.affiliation: Chemical Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Durbin
authors.forename: B
authors.initials: B
authors.lastname: Kullgren
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: K N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008024:Ligands; D051379:Mice; D011005:Plutonium / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C094869:4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone; D002614:Chelating Agents; D008024:Ligands; D011728:Pyridones; D011005:Plutonium