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The effect of regioisomerism on the coordination chemistry and CEST properties of lanthanide(III) NB-DOTA-tetraamide chelates

JBIC Journal of Biological Inorganic Chemistry volume 19, pages 173–189 (2014)Cite this article

Abstract

Chemical exchange saturation transfer (CEST) offers many advantages as a method of generating contrast in magnetic resonance images. However, many of the exogenous agents currently under investigation suffer from detection limits that are still somewhat short of what can be achieved with more traditional Gd3+ agents. To remedy this limitation we have undertaken an investigation of Ln3+ DOTA-tetraamide chelates (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) that have unusually rigid ligand structures: the nitrobenzyl derivatives of DOTA-tetraamides with (2-phenylethyl)amide substituents. In this report we examine the effect of incorporating hydrophobic amide substituents on water exchange and CEST. The ligand systems chosen afforded a total of three CEST-active isomeric square antiprismatic chelates; each of these chelates was found to have different water exchange and CEST characteristics. The position of a nitrobenzyl substituent on the macrocyclic ring strongly influenced the way in which the chelate and Ln3+ coordination cage distorted. These differential distortions were found to affect the rate of water proton exchange in the chelates. But, by far the greatest effect arose from altering the position of the hydrophobic amide substituent, which, when forced upwards around the water binding site, caused a substantial reduction in the rate of water proton exchange. Such slow water proton exchange afforded a chelate that was 4.5 times more effective as a CEST agent than its isomeric counterparts in dry acetonitrile and at low temperatures and very low presaturation powers.

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Acknowledgments

The authors thank the National Institutes of Health (EB-11687), the Oregon Nanoscience and Microtechnologies Institute (N00014-11-1-0193), Portland State University, and the Oregon Opportunity for Biomedical Research for financial support of this work.

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Authors and Affiliations

  1. Department of Chemistry, Portland State University, 1719 SW 10th Avenue, Portland, OR, 97201, USA

    Jacqueline R. Slack & Mark Woods

  2. Advanced Imaging Research Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Mark Woods

Authors
  1. Jacqueline R. Slack
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  2. Mark Woods
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Correspondence to Mark Woods.

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Responsible editor: Valerie C. Pierre.

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Slack, J.R., Woods, M. The effect of regioisomerism on the coordination chemistry and CEST properties of lanthanide(III) NB-DOTA-tetraamide chelates. J Biol Inorg Chem 19, 173–189 (2014). https://doi.org/10.1007/s00775-013-1060-y

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  • DOI: https://doi.org/10.1007/s00775-013-1060-y

Keywords

  • Conformational control
  • Lanthanide chelates
  • Macrocyclic ligands
  • Paramagnetic chemical exchange saturation transfer agents
  • Stereoisomerism