The current paradigm in therapeutic nuclear medicine is to optimize receptor binding molecules and then add on a moiety capable of carrying a radioisotope. This """"""""afterthought"""""""" modification process results in suboptimum performance for such agents when dealing with molecules smaller than monoclonal antibodies. A new concept proposed here is to utilize the properties of chelating agents to build in the desired recognition functionalities. The conformationally restricted metal-ligand complexes proposed herein offer the opportunity to attach molecular recognition units in a certain three-dimensional spatial arrangement that will allow the molecule to mimic protein-protein (or peptide-receptor) binding interactions such as those found in antibody-antigen recognition. Synthetic molecules that mimic antibody-antigen recognition are known as chemobodies. The new approach in this proposal gives rise to a subset of chemobody molecules hereby termed chelabodies to reflect the critical role that the conformationally restricted metal-ligand complex plays in creating the molecular recognition event. This concept presented here is broadly applicable to receptors in general but will focus on designing (molecular modeling), synthesizing (through combinatorial methodology), screening (in vitro, in vivo in tumor-bearing mice) and optimizing metal-ligand complex-based antagonists of the alpha-v/beta-3 receptor that will deliver therapeutic radioactive metal ions to the neovasculature of alpha-v/beta-3 receptor-positive cancers.
The proposed work is aimed at the discovery, optimization and initial development of a tumor localizing therapeutic radiopharmaceutical drug that targets alpha-v/beta-3 receptors in new blood vessels required for tumor growth. The methodology proposed (combinatorial chelating agent synthesis methodology) is likely to be broadly applicable to address other target receptors.
