Heading toward Macromolecular and Nanosized Bioresponsive MRI Probes for Successful Functional Imaging

Conspectus The quest for bioresponsive or smart contrast agents (SCAs) in molecular imaging, in particular magnetic resonance imaging (MRI), is progressively increasing since they allow for the monitoring of essential biological processes on molecular and cellular levels in a dynamic fashion. These are offshoot molecules of common contrast agents that are sensitive to biochemical changes in their environment, capable of reporting on such changes by inducing MRI signal alteration. Various mechanistic approaches and different types of SCAs have been developed in order to visualize desired processes, using diverse imaging protocols and methods. To date, the most frequently exploited probes are paramagnetic molecules that change longitudinal or transverse relaxation at proton frequency, or so-called T 1- and T 2-weighted probes, respectively. Moreover, SCAs operating by the chemical exchange saturation transfer mechanism, suitable for 19F MRI or possessing hyperpolarized nuclei have also appeared in the past decade, slowly finding their role in functional imaging studies. Following these mechanistic principles, a large number of SCAs suitable for diverse targets have been reported to date. This Account condenses this exciting progress, particularly focusing on probes designed for abundant targets that are suitable for practical, in vivo utilization. To date, the greatest advancements have been certainly made in the preparation of pH sensitive probes, which usually contain protonable groups that interact with paramagnetic centers, or take advantage of supramolecular (dis)­assembling to induce the MRI signal change, thereupon enabling pH mapping in vivo. In a complementary approach, a combination of metal chelating ligands for Ca2+ or Zn2+ with MR reporting units results in a wide variety of SCAs that operate with different contrast mechanisms and can be used for initial functional experiments. Finally, the first examples of molecular sensing by creating host–guest complexes to track neurotransmitter flux have also been recently reported, allowing the study of brain function in an unprecedented manner. Nevertheless, wider SCA utilization in vivo has not yet been achieved. There are a few reasons for this disparity between their nominal potential and practical usage, with one of the major reasons being the low sensitivity of the MRI technique. Subsequently, the production of detectable signal change can be achieved using higher concentrations of the bioresponsive