Novel Chemistries For Activatable Molecular Imaging Probes Applicable To Magnetic Resonance Imaging And Positron Emission Tomography

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Enzymes and highly reactive, naturally occurring small molecules are the workhorses of the cell, and exert their effects on physiology through well-defined chemical mechanisms. The activity of these biochemical species is well regulated during health, but often changes substantially during disease processes. By measuring the activity of these biochemical workhorses, the subcellular processes that may ultimately result in the onset of disease, or its reversal through treatment efforts, can be detected very early on before any outward signs or symptoms occur. Molecular imaging is an emerging field that is specifically concerned with imaging these sorts of subcellular activities, and is heavily reliant on novel chemistries through which imaging tracers can be developed. These small molecule tracers are injected prior to imaging, and are acted upon by the workhorse target of interest to change their behavior in the area of disease, for example in a tumor. This results in a chemical change to the tracer that can be detected non-invasively through magnetic resonance imaging (MRI) or positron emission tomography (PET) scans. MRI and PET are important tools for fundamental research regarding disease and treatment, as well as clinical medicine, offering non-invasive, three-dimensional images with resolution and sensitivity unmatched by other imaging modalities. While MRI and PET molecular imaging holds promise to enhance the way health and disease can be studied and tracked, it has not yet reached its potential due to a lack of tracer chemistry available to interrogate workhorse activities using these modalities. My work has proved the principle of a new molecular imaging strategy: designing small molecule tracers that self-assemble into large structures in cells and tissues when a particular workhorse is present and active. The proposed research program will move this molecular imaging strategy of self-assembly into practice. New chemical approaches will be developed to design a large self-assembly toolbox containing tracer chemistry platforms applicable to a broad range of workhorse targets for both MR and PET imaging. The research program will also reevaluate the safety of materials currently used as MRI tracers, since there have been concerns regarding their necessary incorporation of heavy metal atoms. Materials will be made that lack these toxic heavy metals but that can still produce imaging contrast for MRI. With these new chemical tools for tracer design, the capacity to interrogate the activity of important biochemical workhorses would have substantial short term impact on studying fundamental processes in disease and innovative treatments, and a potential for long term impact on clinical molecular imaging in Canada and the management of disease.