Molecular and supramolecular routes to enhance Gadolinium-based contrast agents relaxivity: How far are we from the theoretical optimal value?

Abstract

Gadolinium Based Contrast Agents (GBCAs) are routinely used in the clinical practice to enhance the diagnostic potential of MRI. Their contrast enhancing capabilities rely on their ability to increase the relaxation rate of tissue water protons. This property is expressed by the relaxivity, whose value is determined by structural, electronic and dynamic characteristics of the GBCA. Based on extensive experimental work over the past four decades and the well-established theory of paramagnetic relaxation, it is usually possible to correlate observed relaxivity values to specific molecular properties. Key determinants include the number of water molecules and/or exchangeable protons in the first and second coordination spheres, their distance from the paramagnetic Gd³⁺ ion, the ion's electronic relaxation time, molecular reorientation time, and the exchange rate of the coordinated water molecules. Understanding the key factors that affect relaxivity has enabled the design of systems with optimized structural and dynamic properties. However, some examples demonstrate exceptional relaxivity which cannot be fully explained by the established theory. In particular, GBCAs within confined environments show significant promise for developing high-relaxivity agents. Overall, one may state that nowadays it is possible to attain highly efficient GBCAs thanks to the in-depth understanding of the structural and dynamic determinants of their relaxivity, together with the optimization of their in vivo stability and biodistribution/excretion properties. This knowledge is crucial for the rational design of the next generation of MRI CAs. The domain of Molecular Imaging will also largely benefit from these efforts.