title: Chelation of 238Pu(IV) in vivo by 3,4,3-LICAM(C): effects of ligand methylation and pH.
abstract: The linear tetracarboxycatecholate ligand, 3,4,3-LICAM(C) (N1,N5,N10,N14-tetrakis(2,3-dihydroxy-4-carboxybenzoyl-tetraaza tet radecane, tetra sodium salt) injected within 1 h after injection of Pu(IV) citrate, removes about the same fraction of Pu from animals as CaNa3-DTPA (diethylenetriaminepentaacetate, calcium, sodium salt) but removes less inhaled Pu than CaNa3-DTPA and leaves a Pu residue in the renal cortex. However, the formation constant of the expected Pu-3,4,3-LICAM(C) complexes are orders of magnitude greater than that of Pu-DTPA, and 3,4,3-LICAM(C) is 100 times more efficient than CaNa3-DTPA for removing Pu from transferrin in vitro. Because the formation constants of their actinide complexes are central to in vivo actinide chelation, ligand design strategies are dominated by the search for ligands with large Pu complex stabilities, and it was necessary to explain the failure of 3,4,3-LICAM(C) to achieve its thermodynamic potential in vivo. All the batches of 3,4,3-LICAM(C) prepared at Berkeley or in France [Euro-LICAM(C)] were found by high-pressure liquid chromatography to be mixtures of the pure ligand [55% in Berkeley preparations, 8.5% in Euro-LICAM(C)] and its four methylesters. A revised synthesis for 3,4,3-LICAM(C) is appended to this report. All of the incompletely hydrolyzed 3,4,3-LICAM(C) preparations and the pure ligand were tested for removal of Pu from mice [238Pu(IV) citrate intravenous, 30 mumol kg-1 of ligand at 1 h, kill at 24 h, radioanalyze tissues and separated excretal]. The presence of methylesters did not significantly impair the ability of the ligands to remove Pu from mice, and it did not alter the fraction of injected Pu deposited in kidneys. Temporary elevation (reduction) of plasma and urine pH of mice by 0.5 mL of 0.1 M NaHCO3 (NH4Cl) injected before or simultaneously with pure 3,4,3-LICAM(C) somewhat improved (significantly reduced) Pu excretion but had little influence on Pu deposition in kidneys. Review of the investigations of Pu removal from animals by 3,4,3-LICAM(C) revealed that the fractional renal Pu deposit was characteristic of the species and that it could be reduced by vigorous alkalinization which indicated the need to examine the details of the pH dependence of Pu complexation by 3,4,3-LICAM(C).(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Division of Research Medicine and Radiation Biophysics and Materials and Chemical Sciences, Lawrence Berkeley Laboratory, Berkeley, CA 94720.
authors.forename: P W
authors.initials: PW
authors.lastname: Durbin
authors.forename: D L
authors.initials: DL
authors.lastname: White
authors.forename: N L
authors.initials: NL
authors.lastname: Jeung
authors.forename: F L
authors.initials: FL
authors.lastname: Weitl
authors.forename: L C
authors.initials: LC
authors.lastname: Uhlir
authors.forename: E S
authors.initials: ES
authors.lastname: Jones
authors.forename: F W
authors.initials: FW
authors.lastname: Bruenger
authors.forename: K N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000627:therapeutic use*; D003666:Decontamination / Q000379:methods*; D005260:Female; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D015201:Meta-Analysis as Topic; D051379:Mice; D011005:Plutonium / Q000378:metabolism*; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use
chemical_list: D002614:Chelating Agents; D011005:Plutonium; C034834:LICAM-C; D013095:Spermidine