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      Ligand design strategies to increase stability of gadolinium-based magnetic resonance imaging contrast agents

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          Abstract

          Gadolinium(III) complexes have been widely utilised as magnetic resonance imaging (MRI) contrast agents for decades. In recent years however, concerns have developed about their toxicity, believed to derive from demetallation of the complexes in vivo, and the relatively large quantities of compound required for a successful scan. Recent efforts have sought to enhance the relaxivity of trivalent gadolinium complexes without sacrificing their stability. This review aims to examine the strategic design of ligands synthesised for this purpose, provide an overview of recent successes in gadolinium-based contrast agent development and assess the requirements for clinical translation.

          Abstract

          Gadolinium(III) complexes are strong enhancers of magnetic resonance imaging (MRI) signals, thus are widely used as contrast agents despite their potential toxicity. Here, the authors review ligand design approaches aimed at improving the stability of Gd(III)-based MRI contrast agents.

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          Most cited references118

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          Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy.

          To use inductively coupled plasma mass spectroscopy (ICP-MS) to evaluate gadolinium accumulation in brain tissues, including the dentate nucleus (DN) and globus pallidus (GP), in subjects who received a gadolinium-based contrast agent (GBCA).
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            Being excited by lanthanide coordination complexes: aqua species, chirality, excited-state chemistry, and exchange dynamics.

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              Primer on gadolinium chemistry.

              Gadolinium is widely known by all practitioners of magnetic resonance imaging (MRI) but few appreciate the basic solution chemistry of this trivalent lanthanide ion. Given the recent linkage between gadolinium contrast agents and nephrogenic systemic fibrosis, some basic chemistry of this ion must be more widely understood. This short primer on gadolinium chemistry is intended to provide the reader the background principles necessary to understand the basics of chelation chemistry, water hydration numbers, and the differences between thermodynamic stability and kinetic stability or inertness. We illustrate the fundamental importance of kinetic dissociation rates in determining gadolinium toxicity in vivo by presenting new data for a novel europium DOTA-tetraamide complex that is relatively unstable thermodynamically yet extraordinarily inert kinetically and also quite nontoxic. This, plus other literature evidence, forms the basis of the fundamental axiom that it is the kinetic stability of a gadolinium complex, not its thermodynamic stability, that determines its in vivo toxicity. J. Magn. Reson. Imaging 2009;30:1240-1248. (c) 2009 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                klwong@hkbu.edu.hk
                n.long@imperial.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                29 March 2019
                29 March 2019
                2019
                : 10
                : 1420
                Affiliations
                [1 ]Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane London, W12 0BZ UK
                [2 ]ISNI 0000 0004 1764 5980, GRID grid.221309.b, Department of Chemistry, , Hong Kong Baptist University, ; Kowloon Tong Hong Kong SAR, China
                Author information
                http://orcid.org/0000-0002-6499-9760
                http://orcid.org/0000-0002-8298-938X
                Article
                9342
                10.1038/s41467-019-09342-3
                6441101
                30926784
                8487fc8d-05db-4972-9c12-c6ddc33150d0
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 July 2018
                : 20 December 2018
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