Metal Complexes as MRI Contrast Enhancement Agents

Abstract

Magnetic resonance imaging is one of the most efficient diagnostic modalities in clinical radiology and biomedical research. To enhance image contrast, paramagnetic complexes, mainly Gd3+ chelates, are used. Today, around one third of all medical MR images are generated with the use of a contrast medium and this number is expected to increase with the development of new applications and new agents. Recently, molecular imaging has emerged as a new area aiming at non-invasive visualisation of expression and function of bioactive molecules at the cellular level. Since any molecular imaging application requires a specific imaging probe, new chemical approaches become increasingly important. In this chapter, we discuss first proton relaxivity, the parameter that directly translates to the effectiveness of an MRI contrast agent. Many microscopic factors, including the hydration number, the water exchange rate, the rotational dynamics, as well as the electron spin relaxation, influence proton relaxivity for Gd3+ complexes. We show how the structure, the charge or the size of the chelate affects these factors. We also review the different strategies derived to obtain high-relaxivity probes. Non-toxicity of these agents is primordial for their application; therefore we also address the main physico-chemical aspects related to the in vivo stability of Gd3+-based agents, such as thermodynamic stability and kinetic inertness. The second part of the chapter is devoted to new-generation MRI contrast media, such as smart or responsive contrast agents that are capable of reporting on the physico-chemical environment in tissues. Among the huge number of systems reported in the field of smart MRI probes, we focus only on sensing of pH, redox state and metal ions. Many pathologies, such as stroke, infections, kidney disease and cancer are associated with significant pH variations. Accurate, high resolution, in vivo MRI pH mapping would be of great interest not only for diagnostic purposes but also for monitoring disease progression, choice and response to therapy. The partial oxygen pressure, pO2, is also significant in metabolic processes of cells, and its variation from normal values often indicates pathologies (ischemic diseases, strokes, tumors). As for metal ions, several of them play a crucial role in biological processes, whereas others are toxic. Alteration of the metal concentration in the body can often be correlated to disease states. Our objective here is to illustrate, via a few selected examples of Gd3+-based or Paramagnetic Chemical Exchange Saturation Transfer (PARACEST) agents, the major design principles in coordination chemistry to derive smart MRI probes using lanthanide complexes.