The long-range goal of this project is to develop bioactivated magnetic resonance (MR) contrast agents for imaging in vivo process from gene expression to secondary messenger activation. This project is focused on obtaining insights into the interrelated problems of developmental biology and clinical diseases by i. generating MR probes that function as real-time in vivo enzyme reporters, ii. tracking gene expression in whole animals and correlate this information with on going developmental events, and iii. developing biocompatible scaffolds for the efficient delivery of agents in experimental animals, and ultimately humans. It is clear that MR imaging has become one of the most important tools for the diagnosis of a range of clinical problems and in order to maximize the impact of this technique, functional contrast agents must be investigated and developed. Further, the study of developmental biology in whole-animals using a modality that provides temporal resolution, coupled with bioactivated MR contrast agents will result in a deeper understanding of the role of spatial organization with mechanism. Therefore, to create an in vivo MRI assay of enzymatic activities and secondary messengers, MR contrast agents will be designed and synthesized with removable protection groups that largely prevent access of water to a paramagnetic center. By limiting the access of bulk water (q-modulation) the unprocessed agent is designed to be an ineffective contrast agent. Five macrocyclic platforms will be used to generate reversible and irreversible MR reporters of enzymes and secondary messengers that include: sugars, peptides, calcium, phosphorylation. Complexes will be designed, tested and optimized for Beta-galactosidase, Beta-glucoronidase, caspases, MMP's, cathepsin, kinases, and intracellular calcium. We have defined five primary objectives: I. Synthesize and characterize MRI contrast agents with enzyme substrates as water blocking groups of (q-modulation). II. Investigate the relationship between the structure of the agent with observed contrast enhancement, enzyme kinetics, clearance and toxicity. III. Develop intracellular delivery vehicles for MR contrast agents. IV. Synthesize multimodal probes for in vivo validation and co-registration. V. Evaluate the effectiveness of the bioactivated contrast agents in vitro and in vivo.
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