Improving the Effectiveness of ParaCEST Agents by Controlling the Conformation

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DESCRIPTION (provided by applicant): The long range goal of the proposed research is to revolutionize the role of MRI in clinical diagnosis. 'Smart' contrast agents that report the presence of specific marker for diseased state (targeted agents) or that respond by an increase in signal to the presence of an endogenous species of interest (responsive agents) of currently of significant interest. Currently available contrast agents are extremely successful and valuable tools for enhancing the diagnostic ability of MRI; however, their mode of action is entirely non-specific. In other words, they do not target specific tissue types, or respond to changes in the local environment. One can envision agents that would do just that, and that such agents could offer a dramatic increase in the amount and value of information gathered by MR imaging. For instance, if agents could be induced to localize in a diseased tissue type such as a cancer then it is clear how much easier tumor diagnosis could become. If they could respond to variations in endogenous species such as H+ or lactate then clearly the diagnosis of ischemia, such as occurs in a stroke, would be made that much more facile. Both Gd3+-chelates (traditional MR agents) and super-paramagnetic nanoparticles (such as SPIOs) have been widely envisioned as 'smart' agents with some striking results. Nonetheless, despite these advances there remain problems with applying these 'smart' agents in imaging experiments. Targeted agents are usually used in a pre-/post- imaging setting in which a pre- contrast image is subtracted from a post-contrast image, any movement by the patient between or during the image acquisition can seriously undermine the validity of the imaging results. Responsive agents can only provide information on the levels of endogenous species present if the concentration of the agent is known. ParaCEST agents are a new class of imaging agent that offer potential solutions to these problems. The contrast generated by paraCEST agents can be turned on or off by the operator. A low energy pre-saturation pulse is applied to turn on contrast; if the pulse is not applied then a 'without contrast' image is acquired. Thus, by using paraCEST agents the pre- and post- contrast images could be acquired simultaneously by interleaving the acquisitions. In this way motion artifacts could be reduced or even eliminated. Similarly, the use of responsive agents could be made more viable by introducing a ratiometric method of detection. Ratiometric methods compare two different effects from the same agent and are a concentration independent method of acquiring information. ParaCEST agents have been shown to be amenable to ratiometric detection suggesting that responsive agents could eventually be applied to in vivo imaging work. However, paraCEST agents suffer one major drawback: their detection limits are about one order of magnitude higher than those of traditional Gd3+ chelates. The scale of this drawback is more apparent when on considers that a typical dose of Gd3+ for a human is 5 - 10g. Unless the detection limits of paraCEST agents can be reduced then the potential benefits they offer will never be able to be realized in practical imaging settings. This grant proposes methods by which the water exchange kinetics of paraCEST agent can be controlled and improved for greater CEST and lower detection limits. Water exchange rates are a key factor in governing the amount of CEST a paraCEST agent can generate. To control water exchange kinetics we intend to apply methods that we have successfully used previously to control the water exchange rates in Gd3+. From theory and preliminary data we are confident that these methods will reduce the detection limits of paraCEST agents to at least those of traditional Gd3+ chelates and perhaps beyond. If these goals can be achieved it would open the door for new targeted and responsive agents to be developed that can be practically applied to imaging experiments. PUBLIC HEALTH RELEVANCE: The development of a new generation of 'smart' MRI contrast agents will be vital to improving the diagnostic ability of clinical medicine. Despite significant advances in other fields, paraCEST agents continue to offer some potential advantages over the alternatives. However, these potential advantages cannot be realized unless the major drawback of these agents, their high detection limits or, in other words, high dose requirements are addressed. This grant aims to investigate ways in which these detection limits can be lowered and thereby opening a whole new vista on MR imaging.