Responsive MRI Agents for Sensing Metabolism in Vivo

Magnetic resonance imaging (MRI) has inherent advantages in safety, three-dimensional output, and clinical relevance when compared with optical and radiotracer imaging methods. However, MRI contrast agents are inherently less sensitive than agents used in other imaging modalities primarily because MRI agents are detected indirectly by changes in either the water proton relaxation rates (T-1, T-2, and T-2) or water proton intensities (chemical exchange saturation transfer and paramagnetic chemical exchange saturation transfer, CEST and PARACEST). Consequently, the detection limit of an MRI agent is determined by the characteristics of the background water signal; by contrast, optical and radiotracer-based methods permit direct detection of the agent itself. By virtue of responding to background water (which reflects bulk cell properties), however, MRI contrast agents have considerable advantages in "metabolic" imaging, that is, spatially resolving tissue variations in pH, redox state, oxygenation, or metabolite levels. In this Account, we begin by examining sensitivity limits, in targeted contrast agents and then address contrast agents that respond to a physiological change; these responsive agents are effective metabolic imaging sensors. The sensitivity requirements for a metabolic imaging agent are quite different from those for a targeted Gd3+-based T-1 agent (for example, sensing cell receptors). Targeted Gd3+ agents must have either an extraordinarily high water proton relaxivity (r(1)) or multiple Gd3+ complexes clustered together at the target site on a polymer platform or nanoparticle assembly. Metabolic MRI agents differ in that the high relaxivity requirement, although helpful, is eased because these agents respond to bulk properties of tissues rather than low concentrations of a specific biological target. For optimal sensing, metabolic imaging agents should display a large change in relaxivity (Delta r(1)) in response to the physiological or metabolic parameter of interest. Metabolic imaging agents have only recently begun to appear in the literature and only a few have been demonstrated in vivo. MRI maps of absolute tissue pH have been obtained with Gd3+-based T-1 sensors. The requirement of an independent measure of agent concentration in tissues complicates these experiments, but if qualitative changes in tissue pH are acceptable, then these agents can be quite useful. In this review, we describe examples of imaging extracellular pH in brain tumors, ischemic hearts, and pancreatic islets with Gd3+-based pH sensors and discuss the potential of CEST and PARACET agents as metabolic imaging sensors.