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.
Highlights
The toxicity of gadolinium-based contrast agents (GBCAs) has been covered extensively elsewhere in the literature[22–24], and strategies to increase complex stability through ligand design have often been motivated by the desire to reduce potential adverse effects on patients
As released Gd3+ precipitates as GdPO4, it can be assessed by measuring the increase in proton relaxation time. They used this method to evaluate all approved GBCAs and found that transmetallation is much quicker for acyclic chelates compared to macrocyclic species
The results showed that under these conditions, Gd3+ release by the approved GBCAs followed the order: non-ionic linear >ionic linear >macrocyclic
Summary
Some GBCAs with acyclic ligands has resulted in the restriction of their administration by the European Medicines Agency (EMA). As released Gd3+ precipitates as GdPO4, it can be assessed by measuring the increase in proton relaxation time They used this method to evaluate all approved GBCAs and found that transmetallation is much quicker for acyclic chelates compared to macrocyclic species. Cyclic ligands for gadolinium(III) One ligand is frequently referred to as the “gold standard” in trivalent gadolinium chelation: 1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid (H4dota) This ligand consists of the macrocycle cyclen, which is N-functionalised with four acetic acid pendant arms and is octadentate with four nitrogen and four oxygen donor atoms (Fig. 1c) and [Gd(OH2)(dota)]− remains the most thermodynamically stable GBCA in clinical use[50].
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