Targetable Exploratory Multinuclear MRI Contrast Agents

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DESCRIPTION (provided by applicant): Magnetic Resonance Imaging (MRI) is an extraordinarily useful method for diagnostic imaging and it is noted for the high spatial resolution it can provide to images needed by clinical physicians without the use of radionuclides. The use of gadolinium (III) ion as an injectable non-toxic DOTA chelate intensifies the MRI signals by increasing the nuclear spin relaxation rate of the protons in water molecules associated with the Gd (III) ion contrast agent, itself having seven unpaired electrons. Another emerging biomedical application of magnetic resonance phenomena is the use of paramagnetic Gd (III) contrast agents as labels for important molecules or cancer cells whose location can be spatially tracked by MR contrast agent response (molecular imaging). Molecular imaging is important to understanding how contrast agent labeled molecules or cells travel though a living animal and the eventual treatment of disease. The molecular imaging process can be made significantly more effective. If multinuclear Gd (III) species can be made by the attachment of several Gd (III) centers to a central molecular collection point and the resulting array bonded to a large cancer-seeking antibody molecule which would target the cancer to be imaged, the efficacy of the MRI process would increase. The aims of this R21 Exploratory/Developmental Grant from the National Cancer Institute are centered on the exploratory synthesis and evaluation of members of a new family of potentially valuable MR contrast agents having the characteristics mentioned above. Structurally, these proposed agents consist of a central collection species comprised of a very stable icosahedral B12(-2) cage. Each vertex, except one, of this B12(-2) cage may be covalently bound to an organic linker arm carrying a DOTA-chelated Gd (III) center. Thus, eleven Gd(lll) contrast agent centers may be attached to a single B12(-2) core which is then connected to a biomolecule capable of selective bonding to a cancer cell to provide molecular imaging. The presence of eleven Gd(lll) MR contrast centers intensifies the observed signal generated per antibody molecule thus enhancing the sensitivity of the method. Studies will be concerned with the chemical synthesis of these new contrast agent structures (closomers), the exploration of new methodologies to increase performance by minimizing intramolecular motion of the Gd(lll) chelate groups, and the development of structures allowing the attachment of biomolecules molecular targeting of cancer.