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

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.