Proposal describes the design of new conjugates of synthetic bombesin (BBN) analogues that form high specific activity site-directed radio-pharmaceuticals for specific in vivo targeting of neoplastic cells that express gastric releasing peptide (GRP) receptors (including small cell lung cancer - SCLC). Radiopharmaceuticals that result from this research would be labeled with Tc-99m, Re-188 or I-123/125. All of these radionuclides are available in no-carrier added (NCA) levels and have half-lives that are compatible for preparing radiopharmaceuticals based on relatively small biomolecular targeting agents (e.g., peptides). The specific objectives of this research are to: 1) develop new synthetic BBN analogues, labeled with Tc-99m, Re-188 or I-123/125, that exhibit high specific binding affinities to cells expressing GRP receptors, 2) use normal and tumor bearing animal models to identify which of the promising radiolabeled peptides (identified using in vitro binding studies) also exhibit optimal tumor uptake and pharmacokinetic properties. The new BBN-analogue- conjugates, synthesized in-house, using an automated peptide synthesizer, will be purified and characterized and both tracer and macroscopic levels. Methods to prepare radiolabeled BBN-analogues specific to maximize activities and stability of the final drug product will be developed. Approaches and methods to conjugate or incorporate Tc-99m and Re-188 chelate receptor binding, as well as maintaining good in vitro and in vivo stability, will be developed. The most promising radiolabeled BBN analogues will be evaluated in athymic mice with tumors expressing GRP receptors, to assess their ability to specifically target SCLC's or other GRP expressing neoplasms. The pharmacokinetic studies (including clearance of radioactivity from blood and other non-target organs (e.g., kidneys)] will be performed in both normal and athymic mice to identify radiolabeled BBN-analogues that produce maximal target to non-target uptake rates. Ligand frameworks that form Tc-99m (r Re-188) chelates with a spectrum of physico-chemical properties will be conjugated at selected sites on BBN peptide analogues to determine which site-specific modifications will produce Tc-99m or Re-188 BBN analogues with optimal in vitro and in vivo properties. The results of these studies should provide radiolabeled BBN analogues that could be developed (via future clinical trials) into effective radiopharmaceuticals for treatment of patients with GRP-expressing neoplasms.
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