The synthesis and evaluation of novel bifunctional chelating agents designed to sequester Ga(III) isotopes define the general scope of the project. Use of a bifunctional 1,4,7-triazacyclononane-N,N,N- triacetic acid (NOTA) as a sequestering agent for Ga-66 has shown this complex to be exceptionally stable in vivo. Evaluation of a C-functionalized NOTA continues to proceed. The extensive chemical literature of the coordination chemistry and the attractive physical characteristics of the isotopes of Ga(III) continue to stimulate investigation into the development of new ligands. Novel chelating agents, based on cis,cis- 1,3,5-triaminocyclohexane (TACH) functioning as a platform for introducing a potentially wide variety of metal binding functional groups, continue to be synthesized, characterized, and evaluated for forming metal complexes with Ga(III) and with a variety of transition metal ions. The tris(pyridyl)triamine derivative (TACHpyr) continues to be investigated as a chemotherapeutic agent for a bladder cancer application. The continuing investigation in the mode of action has indicated that the associated cytotoxicity occurs 100% by apoptosis. Involvement with cellular iron transport and storage mechanisms are clearly a pathway for this action and studies of the Fe(II) TACHpyr complex have demonstrated the reactive oxidative nature of the ligand towards Fe(III) to form the Fe(II) complex and then cycling through a redox cycle. Studies into tuning the lipophilicy and electronic nature of the pyridine donors of TACHpyr have been initiated through the introduction of substituents onto the aromatic ring and ongoing studies on the fundamental structure and stability of the complexes formed by such ligands continues. Copper complexes of several TACH ligands have also demonstrated their ability to hydrolytically cleave DNA phosphate ester bonds in model compounds, to cleave plasmid DNA, and exert significant cytotoxicity in vitro that appears to be effective against an adriamycin resistant cell line. This effect also appears to be enhanced under hypoxia and also appears in preliminary experiements to possess a radiosensitization component as well. These complexes also hydrolyse peptide bonds in model compounds. Current preliminary studies have demonstrated a maximum tolerated dose in murine systems and a tumor response to repeated treatments with the Cu(II) complex. Further studies are being planned to expand these results and increase the reproducibility of these preliminary results and to define the potential of these metal complexes as chemotherapeutics. - metal chelates, chemotherapeutics, radioimmunotherapy, imaging,
