SBIR-STTR Award

This Small Business Innovative Research (SBIR) Phase I project describes the synthesis and evaluation of novel macrocyclic chelating groups intended for use in targeted radioisotope applications. Targeted radioisotopes are deployed as imaging agents in the context of single-photon emission computed tomography and positron emission tomography. Such diagnostic agents also are used as a companion in targeted radioisotope therapy wherein a radionuclide that emits therapeutically useful ionizing radiation is similarly localized within specific biological sites by attachment to an accessory molecule that imparts appropriate biodistribution and pharmacokinetic properties. 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, therefore, 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 also must stably bind the cation so that none is released in vivo, at least prior to its decay. The optimized chelating groups we propose 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. The broader impact/commercial potential of this project will be the development of novel "caged" macrocyclic chelating groups that display faster and more stable binding as compared to acyclic and mono-macrocyclic chelators currently used. These will coordinate not only In+3, but also more exotic cations such as Zr+4 whose isotopes have hitherto remained undeveloped but possess intriguing radiochemical characteristics, e.g., zirconium-89, positron emission half-life 78 hr. By means of this approach, the aim is both to improve the utility of existing radiopharmaceuticals, and to expand the scope of this technology to radionuclides that are, at present, underdeveloped in the clinic

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.