SBIR Phase II: Novel macrocyclic chelating groups for use in targeted radioisotope diagnostic and companion diagnostic/therapeutic applications

This Small Business Innovation Research (SBIR) Phase II project proposes to develop novel "caged" macrocyclic chelating groups that display faster and more stable binding as compared to acyclic and mono-macrocyclic chelators currently used. Metallic radioisotopes offer versatile imaging and therapeutic properties, but loss of metallic radioisotopes from their site-directing molecules can lead to deleterious side-effects or reduced contrast and efficacy. There is a recognized, compelling need for improved chelating groups for use in radiopharmaceuticals. Such chelating groups must rapidly bind radioisotopes, so that they are compatible with the practicalities of clinical laboratory preparation. They must also stably bind the cation so that none is released in vivo, at least prior to its decay. The optimized chelating groups to be developed under this project will stably coordinate metal cations currently used for radioisotope-based diagnosis and therapy, display facile complexation kinetics, and provide a convenient synthetic handle for attachment to targeting moieties. By means of this approach, the novel chelators will both improve the utility of existing radiopharmaceuticals and permit the use of radionuclides that are at present underdeveloped in the clinic. The broader impact/commercial potential of this project, if successful, will be that aromatic macrocyclic bifunctional chelators (AMBFCs) will be developed that will potentially change the landscape in the way cancer is detected and treated. Because the AMBFCs can be used in cancer imaging, the physician benefits from an effective feedback loop on therapeutic progress, remission, and prognosis that could further shorten the time of treatment. AMBFCs in companion radiodiagnostics also could reduce the cost of ineffectual medication, which is a strategic goal of the FDA. Plus, by employing novel radionuclides in the AMBFCs to kill tumors and their metastases, the benefit could materially cut down the time and cost of therapy. All of these features could promote better clinical outcomes and reduce the overall cost of healthcare by saving lives with earlier intervention. Through improved clinical outcomes from this unique science, AMBFCs will advance the national health, prosperity and welfare of others.