There is tremendous potential for using receptor-targeted technetium-99m radiopharmaceuticals for diagnostic imaging for the detection of cancer, and imaging of neuroreceptors in degenerative diseases such as Parkinson's. This approach also extends to the potential treatment of cancer using the related therapeutic radionuclides Re-186,188. Tc-99m has excellent properties for imaging, and is inexpensive and available at most hospitals. New, more efficient bifunctional chelates are needed to overcome the problems of available ligands for the successful development of receptor targeted radiopharmaceuticals. The linkage must provide a strong connection between the organic substrate and the metal core that is sterically non-intrusive, nonpolar, and does not interfere with the receptor binding affinity or biodistribution. The recent interest in the tricarbonyI-Tc(I) complex has stimulated the search for a ligand system that can be labeled directly in water. This proposal focuses on the synthesis of receptor targeted radiopharmaceuticals based on a novel pyridylhydrazine ligand system that was designed for the tricarbonyI-Tc(I)/Re(I) core.
The aims are 1) To synthesize and evaluate (pyridin-2-yl)-hydrazine chelate derivatives (PyHZ-N-chelate) as a new class of bifunctional chelators for receptor targeted tricarbonyI-Tc(I)/Re(I) radiopharmaceuticals. 2) To synthesize PyHZ-N-chelate-Re(CO)3 conjugates of biotin, estradiol, octreotide, and tropane as receptor targeted radiopharmaceuticals. 3) To optimize the radiopharmaceutical properties of the tricarbonyI-Re(I) complexes, and investigate Tc-99m labeling of the receptor targeted (pyridin-2-yl)-hydrazine-N-chelates. The project involves the development of novel heterocyclic substrates for catalytic cross coupling reactions. The completion of these aims will provide a series of important new receptor targeted radiopharmaceutical candidates. These compounds will be optimized to achieve high binding affinities and to exhibit favorable physical characteristics. We will develop experimental conditions for Tc-radiolabeling that are suitable for use in a nuclear medicine clinical environment. The novel compounds and methodology developed in these studies will provide the inertia for establishing a consortium of synthetic chemistry, radiochemistry, and clinical research scientists.
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