Principles of how responsive agents work will be discussed

Examples of responsive agents will be discussed

Needs for advancement of the area will be presented

This talk will benefit researchers interested in learning how responsive contrast agents for MRI work.Because of the information presented, learners will be able to understand the design principles that make responsive contrast agents work and be made aware of some examples of stimuli responsive agents can be used to detect.The purpose of this talk is to introduce the topic of responsive contrast agents to listeners.The talk will include a discussion of basic design principles that are used to generate responsive contrast agents and describe examples of responsive contrast agents from the literature.

Responsive contrast agents for MRI are contrast agents that change the level of contrast in response to a stimulus. These agents are designed to chemically respond to a desired stimulus resulting in a chemically modified agent that changes how it enhances contrast relative to before the stimulus. The range of stimuli that have been explored is wide and includes enzyme activity; changing temperature; transport of biologically important metal ions including iron, calcium, and zinc; changes in pH; and changes in redox environment including oxygen levels. The chemical alterations to contrast agents that these stimuli impart include making or breaking of covalent bonds, speeding or slowing of ligand or proton exchange rates; changing the number or arrangement of ligands including water, causing or disrupting aggregation, modification of electronic shielding or hydrogen bonding of nearby atoms, and inducing binding to macromolecules. Each of these chemical alterations has a direct impact on the extent to which the contrast agent can influence contrast, and some of these alterations are reversible and some are irreversible. Consequently, changes in contrast can be correlated to chemical modifications of the contrast agents that are a direct consequence of the molecular stimulus.

To understand how responsive contrast agents work and how to design new responsive contrast agents, it is important to know some basic coordination chemistry terminology because the majority of responsive agents involve metal complexes. Ligands are molecules that bind to metals. The binding can be thought of as a Lewis acid–Lewis base interaction where the ligand is the Lewis base (electron pair donor) and the metal is the Lewis acid (electron pair acceptor). The denticity of the ligand describes how many times it is coordinated to the metal ion. Denticity is important because there is often a relationship between denticity and thermodynamic and kinetic stabilities, which have implications to toxicity. Furthermore, some responsive contrast agents function because a stimulus leads to a change in the denticity of the ligand and subsequent change in contrast enhancement. For example, if a Gd^III-containing complex contains a substrate for an enzyme, and the substrate occupies a coordination site of the Gd^III ion, then after enzymatic cleavage of the substrate, a coordination site will be opened that can be occupied by water. The complex with one extra water molecule would be expected to enhance contrast to a greater extent than the complex with the substrate. Thus, enzymatic cleavage of the substrate would lead to an increase in contrast enhancement. Another important coordination chemistry term is ligand exchange. Rapidly exchanging ligands are referred to as labile, and slowly exchanging ligands are referred to as inert. A change in ligand exchange rate induced by a stimulus, especially if the ligand is water, can lead to a change in contrast enhancement.

In addition to metal–ligand interactions, the way in which a metal complex interacts with the environment can be used to influence responses. These interactions can be described with correlation times specific to a paramagnetic complex, and the correlation times can often be used to produce responsive contrast agents. For example, bound water residency lifetime (the inverse of water-exchange rate) and rotational correlation time impact the relaxivity (a measure of the efficiency of a contrast agent) of paramagnetic contrast agents for MRI. These correlation times can be altered by stimulus-induced changes to ligands. For example, if a stimulus causes small paramagnetic complexes to aggregate, that aggregation will increase rotational correlation time, leading to increased relaxivity.

Another aspect of paramagnets that can influence contrast is the oxidation state of the metal or the ligand. Redox events in the ligand or metal can lead to changes in the ability to influence contrast because more unpaired electrons tend to lead to increased contrast enhancement. For example, the Eu^II ion influences contrast to roughly the same extent as Gd^III; however, under physiological conditions, the Eu^II ion can be oxidized to the Eu^III ion that does not influence contrast to a measurable extent. Therefore, prior to oxidation, complexes of Eu^II produce contrast enhancement that disappears after oxidation of the metal ion. This change makes Eu^II-containing complexes responsive to oxidation, and this response was recently used to differentiate necrotic tumor tissue from non-necrotic tumor tissue in mice.

In addition to small single ion paramagnetic contrast agents, larger particles can be turned into responsive contrast agents. For example, if iron oxide particles are caused to aggregate based on changes to their surface coating, then the aggregated particles will have a greater influence on contrast, making that system a responsive contrast agent. Furthermore, the chemical features that make chemical exchange saturation transfer agents produce contrast can be made responsive to stimuli resulting in responsive contrast agents. Similar systems can be designed for other nuclei, expanding the scope of responsive contrast agents to include more than just ¹H-MRI.

While responsive contrast agents are promising, current limitations that present opportunities for future research include low sensitivity (millimolar amounts of agent are often needed), small changes in contrast enhancement level, and delivery to specific areas of interest. Many research groups are working toward addressing these challenging issues.

While not currently used in the clinic, responsive contrast agents for MRI are relevant because they offer the potential monitor physiologically important molecular events such as enzyme activity or metal ion movement non-invasively. Tracking molecular events associated with disease is likely to be important to the development of new therapies and diagnosis of disease.