169237-40-5Relevant academic research and scientific papers
Gadolinium complex of tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)eth yl]-amine: A new class of gadolinium magnetic resonance relaxation agents
Xu,Franklin,Whisenhunt Jr.,Raymond
, p. 7245 - 7246 (1995)
Complexes of gadolinium(III) have proven to be especially effecrive MRI contrast agents; Gd3+ (S = 7/2) is unique in having the highest isotropic magnetic moment. The injection of gram quantities of potentially toxic metal cations requires that the complexes be stable to in vivo transmetalation, particularly with the competing calcium(II) ion in high concentration. while relaxivity is dependent on both the number and the rate of exchange of water molecules from the complex inner sphere. This competition between strong complexation and free water coordination sites is a challenge to MRI enhancement agent design. We report here the synthesis and characterization of Gd(III) TREN-Me-3,2-HOPO (7) {TREN-Me-3,2-HOPO = tris[(3-hydroxy-1-methyl-2-oxo-1,2- didehydropyridine-4-carboxamido)ethyl]amine}, which represents a promising new class of lanthanide compounds that meet these criteria. The hydroxypyridinonate (HOPO) monoanions are bidentate ligands that form effective multidentate sequestering agents, particularly when the HOPO ring carbon adjacent to the carbonyl or hydroxy group is functionalized and attached through an amide linkage to a suitable backbone. The geometry thus imposed promotes strong chelation of metal ions in general, and of Gd(III) in particular.
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
Xu,Kullgren,Durbin,Raymond
, p. 2606 - 2614 (2007/10/03)
A new family of chelating agents based on 4-(substituted-carbamoyl)-3- hydroxy-2-pyridinones is reported. These have optional terminal substituents on the nitrogens, and the hydroxypyridonate (HOPO) rings are attached to molecular backbones through amide linkages. A very important feature of the methyl-substituted ligand derivatives (Me-3,2-HOPOs) is that, similarly to the catechoylamide complexes of the siderophore enterobactin and its analogs, these HOPO derivatives form strong hydrogen bonds between the amide proton and the adjacent oxygen of the phenolate 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 conditions. All 13 compounds studied significantly enhanced Pu excretion from mice compared with Pu-injected controls. Eight of the ligands studied promoted significantly more Pu excretion than an equal molar amount of CaNa3-DTPA (the compound in present clinical use). Five injected and two orally administered Me-3,2-HOPO ligands promoted as much or slightly 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. Surprisingly, although plutonium has an eight-coordination requirement, tetra- and hexadentate Me- 3,2-HOPO ligands were essentially as effective as the one octadentate ligand studied. These observations suggest that even the tetradentate Me-3,2-HOPO ligands compete with mammalian transferrin for Pu(IV). For the three most promising compounds, there is no acute toxicity seen up to the highest dose administered, which was 1000 μmol/kg. One compound, the hexadentate TREN- (Me-3,2-HOPO), is particularly effective, either injected or orally, and an exceptionally good in vivo chelator of several actinides in addition to Pu(IV). Three of these compounds studied have low toxicity and are relatively simple and inexpensive to prepare. They are promising therapeutic agents.
