This is a proposal to continue work (and generate new insights) for utilizing external detectable radiopharmaceuticals to gain an understanding of the phenomena of normal growth, tumor growth and metabolism, and the response of tumors to therapy. 1) New treatments for thyroid disorders are to be investigated. Three subsections are described. The first deals with the diagnosis and therapy of medullary carcinoma of the thyroid (MCT). Since Tc-99m-DMSA shows an affinity for MCT, analogues of DMSA will be studied for their binding of Tc-99m as well as arsenic radionuclides. These will be tested for uptake by MCT, and possible therapeutic use. A second section involves the search for agents which delay the release of iodide or iodinated compounds from the thyroid, thus increasing the radiation dose from radioiodide. Antitubulin agents (colchicine relatives are shown to be promising in this regard) and several other compounds are discussed. Another subsection investigates agents for potentially enhancing effects of I-131 radiation of the thyroid. Compounds to be studied include known radiosensitizers, pyrazole and analogues, and calcium channel blockers. 2) Arsenic can substitute for phosphorus, nitrogen, or carbon in selected organic molecules. Since As has radionuclides with imaging or therapeutic characteristics, approaches to the synthesis or arsenic radiopharmaceuticals will be explored and their biological handling systematically studied. Another member of the N, P, As family, antimony can be incorporated into a small number of pharmaceuticals. However, antimony has a particularly attractive radionuclide (Sb-117) and the synthesis and biological handling of selected radiopharmaceuticals will be explored. 3) Although a number of Tc-99m-phosphates are available for bone imaging, deposition of the agents is sensitive but non-specific. we propose to study a series of novel compounds which may begin to give insights to boen metabolism/kinetics and differential uptake in or around selected bone lesions, infarcts or tumors. The effects of added carrier and pharmacological manipulations will be explored to investigate bone metabolism.
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