High-performance liquid chromatographic (HPLC) analysis has shown that 99mTc-diphosphonate skeletal imaging agents are not pure chemical species, but rather are complicated mixtures of technetium-diphosphonate complexes. The focus of this project is the determination of exactly which isolated metal-diphosphonate complexes are the most effective agents for both diagnostic and therapeutic nuclear medicine applications. This will be accomplished through research bridging the disciplines of inorganic chemistry, analytical chemistry, radiology, nuclear medicine, and medicine. Preparative conditions used to generate metal-diphosphonate imaging agents will be varied in order to favor the production of specific metal-diphosphonate complexes, and then HPLC will be used to isolate these component complexes. These HPLC isolated components will be evaluated in animal models for (a) uptake on normal bone relative to uptake in soft tissues, and (b) uptake on abnormal bone (trauma-induced osteogenesis model) relative to uptake on normal bone. Those isolated metal-diphosphonate complexes containing 99m-Tc or 186-RE which appear most effective in animal models will be evaluated as diagnostic agents in human patients with established metastatic disease to bone. """"""""Instant kit"""""""" formulations will be developed in which the yields of the optimum 99mTc-diphosphonate diagnostic agents are maximized. The total therapeutic dose that could be delivered to a metastatic bone cancer site by an isolated metal-diphosphonate complex containing 186-Re, 32-P or 33-P will be estimated by external, conjugate view, counting of patients who have received diagnostic doses of isolated components, and by thermoluminescent dosimetry in animal models. Those components with appropriate scintigraphic and dosimetric properties will be evaluated as palliative therapeutic agents in human patients suffering from metastatic disease to the bone that is not-responsive to conventional therapy.
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