SPECIFIC SEQUESTERING AGENTS FOR THE ACTINIDES .28. SYNTHESIS AND INITIAL EVALUATION OF MULTIDENTATE 4-CARBAMOYL-3-HYDROXY-1-METHYL-2(1H)-PYRIDINONE LIGANDS FOR IN-VIVO PLUTONIUM(IV) CHELATION

A new family of chelating agents based on 4-(substituted-carbamoyl)-3- hydroxy-2-pyridinones is reported. These have optional terminal substi tuents on the nitrogens, and the hydroxypyridonate (HOPO) rings are at tached to molecular backbones through amide linkages. A very important feature of the methyl-substituted ligand derivatives (Me-3,2-HOPOs) i s that, similarly to the catechoylamide complexes of the siderophore e nterobactin and its analogs, these HOPO derivatives form strong hydrog en bonds between the amide proton and the adjacent oxygen of the pheno late in the metal complex; this enhances the stability of the complex. This rigidity helps to explain the great affinity of the Me-3,2-HOPO ligands for plutonium(IV), as observed here under physiological condit ions. All 13 compounds studied significantly enhanced Pu excretion fro m mice compared with Pu-injected controls. Eight of the Ligands studie d promoted significantly more Pu excretion than an equal molar amount of CaNa3-DTPA (the compound in present clinical use). Five injected an d two orally administered Me-3,2-HOPO ligands promoted as much or slig htly more Pu excretion than an equal molar amount of the octadentate 3 ,4,3-LI(1,2-HOPO), the previously most effective in vivo ligand. Surpr isingly, although plutonium has an eight-coordination requirement, tet ra and hexadentate Me-3,2-HOPO ligands were essentially as effective a s the one octadentate ligand studied. These observations suggest that even the tetradentate Me-3,2-HOPO ligands compete with mammalian trans ferrin for Pu(IV). For the three most promising compounds, there is no acute toxicity seen up to the highest dose administered, which was 10 00 mu mol/kg. One compound, the hexadentate TREN-(Me-3,2-HOPO), is par ticularly effective, either injected or orally, and an exceptionally g ood in vivo chelator of several actinides in addition to Pu(IV). Three of these compounds studied have low toxicity and are relatively simpl e and inexpensive to prepare. They are promising therapeutic agents.