Sponsor
The authors thank the National Institutes of Health (CA-115531, DK-058398, EB-004582, and RR-02584) and the Robert A Welch Foundation (AT-584) (ADS); the Foundation for Science and Technology (FCT), Portugal (PTDC/ QUI/70063/2006), FEDER, the EU Network of Excellence European Molecular Imaging Laboratory (EMIL, LSCH-2004-503569), and the EU COST Action D38 “Metal-Based Systems for Molecular Imaging Applications” (CFGCG, MIMP, ACS); and new faculty start-up funds from the Harold C. Simmons Comprehensive Cancer Center and Department of Radiology, UT Southwestern Medical Center (XS) for financial support.
Published In
Investigative Radiology
Document Type
Post-Print
Publication Date
12-2008
Subjects
Rare earth metals -- Magnetic properties, Biomedical materials, Magnetic resonance imaging, Contrast media (Diagnostic imaging)
Abstract
Objectives—Recent advances in the design of MRI contrast agents have rendered the lanthanide complexes of DOTA-tetraamide ligands of considerable interest, both as responsive MR agents and paramagnetic chemical exchange saturation transfer agents. The potential utility of these complexes for in vivo applications is contingent upon them being well tolerated by the body. The purpose of this study was to examine how the nature of the amide substituent, and in particular its charge, affected the fate of these chelates postinjection.
Materials and Methods—Complexes of 6 DOTA-tetraamide ligands were prepared in which the nature of the amide substituent was systematically altered. The 6 ligands formed 3 series: a phosphonate series that included tri-cationic, mono-anionic, and polyanionic complexes; a carboxylate series made up of a tri-cationic complex and a mono-anionic complex; and lastly, a tricationic complex with an aromatic amide substituent. These complexes were labeled with an appropriate radioisotope, either 153Gd or 177Lu, and the biodistribution profiles in rats recorded 2 hours postinjection.
Results—Biodistribution profiles were initially acquired at low doses to minimize adverse effects. All the complexes studied were found to be excreted primarily through the renal system, with the majority of the dose being found in the urine. None of the complexes exhibited substantial uptake by bone, liver, and spleen, except for a complex with 4 phosphonate groups that exhibited significant bone targeting capabilities. Increasing the dose of each complex to that of a typical MR contrast agent was found to render all 3 tri-cationic complexes studied here acutely toxic. In contrast, no ill effects were observed after administration of similar doses of the corresponding anionic complexes.
Conclusions—The absence of uptake by the liver and spleen indicate that irrespective of the ligand structure and charge, these complexes are not prone to dissociation in vivo. This is in agreement with previously published work that indicates high kinetic inertness for this class of compounds. At low doses, all complexes were well tolerated; however, for applications that require higher doses, the structure and charge of the ligand becomes a fundamentally important parameter. The results reported herein demonstrate the importance of incorporating negatively charged groups on amide substituents if a DOTA-tetraamide complex is to be employed at high doses in vivo.
DOI
10.1097/RLI.0b013e318186531d
Persistent Identifier
https://archives.pdx.edu/ds/psu/32564
Citation Details
Woods, M., Caravan, P., Geraldes, C. F., Greenfield, M. T., Kiefer, G. E., Lin, M., ... & Wang, J. (2008). The effect of the amide substituent on the biodistribution and tolerance of lanthanide (III) DOTA-tetraamide derivatives. Investigative radiology, 43(12), 861.
Description
This is the authors' version of an article that subsequently appeared in Investigative Radiology, vol. 43, no.12: 861–870. The version of record may be found at https://dx.doi.org/10.1097/RLI.0b013e318186531d.
Note: At the time of writing Mark Woods was affiliated with the University of Texas at Dallas.