Development of Tc-99m Labeled Peptide Tracers-Bombesin like peptides function as autocrine growth factors in a number of cancers and therefore promotes their growth. Somatostatin on the other hand, acts as an inhibitor of the secretions and growth of several cancers. Potent antagonists of bombesin like peptides have the potential for use as therapeutic agent in the same way as has been clinically proven for somatostatin analogues. Our goal is to develop high affinity and high specific activity technetium-99 analogues of bombsein and somatostatin that can be readily available in kit form for use in non-invasive in vivo biochemical characterization of cancers that possess receptors to bombesin like or somatostatin receptors. Such tracers would be useful for use in the selection of patient populations that would benefit from current and emerging therapies. Rhenium-186, analogues of these peptides will also be developed for use in direct therapy of the cancers. The potent bombesin agonist [lys3]-bombesin and the antagonist iso-Butyryl-His- Trp-Ala-Val-D-Ala-His-Leu-NH-CH3 will be the template upon which the bombesin analogues will be based. The somatostatin analogues will be based on Octreotide, D-Phe-Cys-Phe D-Trp-Lys- Thr-Cys-Thr-ol, which is currently used in cancer therapy. The diaminedithiol and the hydrazinonicotinic acid chelating systems will be utilized as bifunctional chelates for carrying the metalonuclides. The binding sites of the peptides will be left intact and will not be targeted for labeling with the chelats. The new analogues will be designed such that the chelate will be carried by a lysine residue at the N terminal region separated by a variable carbon chain length spacer from the template. The design of the new peptides will also include a pharmacokinetic modifier, DTPA, that will increase the negative charges on the labeled peptides to direct clearance of the tracers through the urinary system and minimize hepatobiliary excretion. Biological evaluation of the labeled peptides will include in vitro binding assays in which the affinity and pharmacologic profile will be assessed in rat brain and pancreatic membranes as well as tumor cell lines. In vivo evaluation will involve biodistribution and imaging studies using the technetium-99m analogues in nude mice bearing human small cell lung cancer xenografts as well as therapeutic efficacy studies using the rhenium- 186 analogues.
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