The effect of the amide substituent on the biodistribution and tolerance of lanthanide(iii) dota-tetraamide derivatives

Mark Woods, Peter Caravan, Carlos F G C Geraldes, Matthew T. Greenfield, Garry E. Kiefer, Mai Lin, Kenneth McMillan, M. Isabel M Prata, Ana C. Santos, Xiankai Sun, Jufeng Wang, Shanrong Zhang, Piyu Zhao, A. Dean Sherry

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 poly-anionic complexes; a carboxylate series made up of a tri-cationic complex and a mono-anionic complex; and lastly, a tri-cationic complex with an aromatic amide substituent. These complexes were labeled with an appropriate radioisotope, either Gd or Lu, 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.

Original languageEnglish (US)
Pages (from-to)861-870
Number of pages10
JournalInvestigative Radiology
Volume43
Issue number12
DOIs
StatePublished - Dec 2008
Externally publishedYes

Fingerprint

Lanthanoid Series Elements
Amides
Ligands
Organophosphonates
Contrast Media
Spleen
Bone and Bones
Poisons
Liver
Radioisotopes
Urine
Kidney

Keywords

  • Biodistribution
  • Lanthanide complexes
  • MRI contrast agents
  • PARACEST agents

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

The effect of the amide substituent on the biodistribution and tolerance of lanthanide(iii) dota-tetraamide derivatives. / Woods, Mark; Caravan, Peter; Geraldes, Carlos F G C; Greenfield, Matthew T.; Kiefer, Garry E.; Lin, Mai; McMillan, Kenneth; Prata, M. Isabel M; Santos, Ana C.; Sun, Xiankai; Wang, Jufeng; Zhang, Shanrong; Zhao, Piyu; Sherry, A. Dean.

In: Investigative Radiology, Vol. 43, No. 12, 12.2008, p. 861-870.

Research output: Contribution to journalArticle

Woods, M, Caravan, P, Geraldes, CFGC, Greenfield, MT, Kiefer, GE, Lin, M, McMillan, K, Prata, MIM, Santos, AC, Sun, X, Wang, J, Zhang, S, Zhao, P & Sherry, AD 2008, 'The effect of the amide substituent on the biodistribution and tolerance of lanthanide(iii) dota-tetraamide derivatives', Investigative Radiology, vol. 43, no. 12, pp. 861-870. https://doi.org/10.1097/RLI.0b013e318186531d
Woods, Mark ; Caravan, Peter ; Geraldes, Carlos F G C ; Greenfield, Matthew T. ; Kiefer, Garry E. ; Lin, Mai ; McMillan, Kenneth ; Prata, M. Isabel M ; Santos, Ana C. ; Sun, Xiankai ; Wang, Jufeng ; Zhang, Shanrong ; Zhao, Piyu ; Sherry, A. Dean. / The effect of the amide substituent on the biodistribution and tolerance of lanthanide(iii) dota-tetraamide derivatives. In: Investigative Radiology. 2008 ; Vol. 43, No. 12. pp. 861-870.
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