Synthesis and initial evaluation for in vivo chelation of Pu(IV) of a mixed octadentate spermine-based ligand containing 4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone and 6-carbamoyl-1-hydroxy-2(1H)-pyridinone.
An improved synthesis for a series of 1-hydroxy-2(1H)-pyridinone-based octadentate ligands is reported. The mixed chelate, octadentate ligand, 3,4,3-LI(1,2-Me-3,2-HOPO), was designed, synthesized, and tested for in vivo chelation of Pu in a mouse model. This ligand incorporates both 1,2-HOPO and Me-3,2-HOPO metal chelating units; the latter has higher affinity toward actinide ions than does 1,2-HOPO at physiological pH. Injected or administered orally to fasted or normally fed mice at the standard clinical dose 30 micromol/kg, both 3,4,3-LI(1,2-HOPO) and 3,4,3-LI(1,2-Me-3,2-HOPO) remove significantly more Pu than injected CaNa(3)DTPA. Injected doses of 0.1 micromol/kg of these HOPO ligands are as effective as 30 micromol/kg of injected CaNa(3)DTPA. Ten daily injections of 30 micromol/kg of a HOPO ligand did not induce detectable acute toxicity in mice. The mixed HOPO ligand is somewhat more effective than 3,4,3-LI(1,2-HOPO) when given orally, and the enhanced reduction of liver Pu by the mixed ligand is statistically significant. Thus, both octadentate HOPO ligands meet the criterion of low toxicity at doses that are more effective than the standard dose of CaNa(3)DTPA. Their improved effectiveness at low dose along with great oral activity (despite low gastrointestinal absorption) implies that new treatment regimens can be developed using the HOPO ligands alone or as adjuncts to CaNa(3)DTPA therapy, which will greatly exceed the amount of Pu excretion that is achievable with CaNa(3)DTPA alone.
Department of Chemistry and Glenn T. Seaborg Center, Chemical Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.
Jide
J
Xu
Patricia W
PW
Durbin
Birgitta
B
Kullgren
Shirley N
SN
Ebbe
Linda C
LC
Uhlir
Kenneth N
KN
Raymond
D000284:Administration, Oral; D000818:Animals; D002614:Chelating Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D008024:Ligands; D051379:Mice; D004369:Pentetic Acid / Q000008:administration & dosage / Q000494:pharmacology; D011005:Plutonium; D011728:Pyridones / Q000737:chemistry*; D013096:Spermine / Q000031:analogs & derivatives / Q000737:chemistry*; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
C465462:1,14-bis(1-hydroxy-2-pyridon-6-oyl)-5,10-bis(3-hydroxy-1-methyl-2-pyridon-4-oyl)-1,5,10,14-tetraazatetradecane; C094869:4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone; D002614:Chelating Agents; D008024:Ligands; D011728:Pyridones; D013096:Spermine; D011005:Plutonium; D004369:Pentetic Acid