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Title: 1,2-Hydroxypyridonates as Contrast Agents for Magnetic ResonanceImaging: TREN-1,2-HOPO

Abstract

1,2-Hydroxypyridinones (1,2-HOPO) form very stable lanthanide complexes that may be useful as contrast agents for Magnetic Resonance Imaging (MRI). X-ray diffraction of single crystals established that the solid state structures of the Eu(III) and the previously reported [Inorg. Chem. 2004, 43, 5452] Gd(III) complex are identical. The recently discovered sensitizing properties of 1,2-HOPO chelates for Eu(III) luminescence allow direct measurement of the number if water molecules in the metal complex. Fluorescence measurements of the Eu(III) complex corroborate that in solution two water molecules coordinate the lanthanide (q = 2) as proposed from the analysis of NMRD profiles. In addition, fluorescence measurements have verified the anion binding interactions of lanthanide TREN-1,2-HOPO complexes in solution, studied by relaxivity, revealing only very weak oxalate binding (K{sub A} = 82.7 {+-} 6.5 M{sup -1}). Solution thermodynamic studies of the metal complex and free ligand have been carried out using potentiometry, spectrophotometry and fluorescence spectroscopy. The metal ion selectivity of TREN-1,2-HOPO supports the feasibility of using 1,2-HOPO ligands for selective lanthanide binding [pGd = 19.3 (2); pZn = 15.2 (2), pCa = 8.8 (3)].

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director, Office of Science; National Institutes ofHealth
OSTI Identifier:
928585
Report Number(s):
LBNL-62682
Journal ID: ISSN 0020-1669; INOCAJ; R&D Project: 403015; BnR: KC0302030; TRN: US200811%%413
DOE Contract Number:
DE-AC02-05CH11231; NIHHL69832
Resource Type:
Journal Article
Resource Relation:
Journal Name: Inorganic Chemistry; Journal Volume: 46; Journal Issue: 22; Related Information: Journal Publication Date: 10/03/2007
Country of Publication:
United States
Language:
English
Subject:
37; ANIONS; CHELATES; FLUORESCENCE; FLUORESCENCE SPECTROSCOPY; LUMINESCENCE; MAGNETIC RESONANCE; MONOCRYSTALS; OXALATES; POTENTIOMETRY; RARE EARTHS; SPECTROPHOTOMETRY; THERMODYNAMICS; WATER; X-RAY DIFFRACTION

Citation Formats

Jocher, Christoph J., Moore, Evan G., Xu, Jide, Avedano, Stefano, Botta, Mauro, Aime, Silvio, and Raymond, Kenneth N. 1,2-Hydroxypyridonates as Contrast Agents for Magnetic ResonanceImaging: TREN-1,2-HOPO. United States: N. p., 2007. Web. doi:10.1021/ic700985j.
Jocher, Christoph J., Moore, Evan G., Xu, Jide, Avedano, Stefano, Botta, Mauro, Aime, Silvio, & Raymond, Kenneth N. 1,2-Hydroxypyridonates as Contrast Agents for Magnetic ResonanceImaging: TREN-1,2-HOPO. United States. doi:10.1021/ic700985j.
Jocher, Christoph J., Moore, Evan G., Xu, Jide, Avedano, Stefano, Botta, Mauro, Aime, Silvio, and Raymond, Kenneth N. Tue . "1,2-Hydroxypyridonates as Contrast Agents for Magnetic ResonanceImaging: TREN-1,2-HOPO". United States. doi:10.1021/ic700985j. https://www.osti.gov/servlets/purl/928585.
@article{osti_928585,
title = {1,2-Hydroxypyridonates as Contrast Agents for Magnetic ResonanceImaging: TREN-1,2-HOPO},
author = {Jocher, Christoph J. and Moore, Evan G. and Xu, Jide and Avedano, Stefano and Botta, Mauro and Aime, Silvio and Raymond, Kenneth N.},
abstractNote = {1,2-Hydroxypyridinones (1,2-HOPO) form very stable lanthanide complexes that may be useful as contrast agents for Magnetic Resonance Imaging (MRI). X-ray diffraction of single crystals established that the solid state structures of the Eu(III) and the previously reported [Inorg. Chem. 2004, 43, 5452] Gd(III) complex are identical. The recently discovered sensitizing properties of 1,2-HOPO chelates for Eu(III) luminescence allow direct measurement of the number if water molecules in the metal complex. Fluorescence measurements of the Eu(III) complex corroborate that in solution two water molecules coordinate the lanthanide (q = 2) as proposed from the analysis of NMRD profiles. In addition, fluorescence measurements have verified the anion binding interactions of lanthanide TREN-1,2-HOPO complexes in solution, studied by relaxivity, revealing only very weak oxalate binding (K{sub A} = 82.7 {+-} 6.5 M{sup -1}). Solution thermodynamic studies of the metal complex and free ligand have been carried out using potentiometry, spectrophotometry and fluorescence spectroscopy. The metal ion selectivity of TREN-1,2-HOPO supports the feasibility of using 1,2-HOPO ligands for selective lanthanide binding [pGd = 19.3 (2); pZn = 15.2 (2), pCa = 8.8 (3)].},
doi = {10.1021/ic700985j},
journal = {Inorganic Chemistry},
number = 22,
volume = 46,
place = {United States},
year = {Tue May 08 00:00:00 EDT 2007},
month = {Tue May 08 00:00:00 EDT 2007}
}
  • 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 ofmore » 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.« less
  • Tris-bidentate HOPO-based ligands developed in our laboratory were designed to complement the coordination preferences of Gd{sup 3+}, especially its oxophilicity. The HOPO ligands provide a hexadentate coordination environment for Gd{sup 3+} in which all he donor atoms are oxygen. Because Gd{sup 3+} favors eight or nine coordination, this design provides two to three open sites for inner-sphere water molecules. These water molecules rapidly exchange with bulk solution, hence affecting the relaxation rates of bulk water olecules. The parameters affecting the efficiency of these contrast agents have been tuned to improve contrast while still maintaining a high thermodynamic stability for Gd{supmore » 3+} binding. The Gd- HOPO-based contrast agents surpass current commercially available agents ecause of a higher number of inner-sphere water molecules, rapid exchange of inner-sphere water molecules via an associative mechanism, and a long electronic relaxation time. The contrast enhancement provided by these agents is at least twice that of commercial contrast gents, which are based on polyaminocarboxylate ligands.« less
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