title: Biomimetic actinide chelators: an update on the preclinical development of the orally active hydroxypyridonate decorporation agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO).
abstract: The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.
authors.affiliation: Chemical Sciences Division, Glenn T. Seaborg Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. rjabergel@lbl.gov
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Abergel
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Durbin
authors.forename: Birgitta
authors.initials: B
authors.lastname: Kullgren
authors.forename: Shirley N
authors.initials: SN
authors.lastname: Ebbe
authors.forename: Jide
authors.initials: J
authors.lastname: Xu
authors.forename: Polly Y
authors.initials: PY
authors.lastname: Chang
authors.forename: Deborah I
authors.initials: DI
authors.lastname: Bunin
authors.forename: Eleanor A
authors.initials: EA
authors.lastname: Blakely
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Bjornstad
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: David K
authors.initials: DK
authors.lastname: Shuh
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D008671:Actinoid Series Elements / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003666:Decontamination / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D008094:Lithium / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004369:Pentetic Acid / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C094869:4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone; D008671:Actinoid Series Elements; D002614:Chelating Agents; D008024:Ligands; D009942:Organometallic Compounds; D011728:Pyridones; D004369:Pentetic Acid; D008094:Lithium