The synthesis and evaluation of bifunctional chelating agents designed to sequester Ga(III) isotopes define the general scope of the project. Taking advantage of extensive chemical literature elucidating the coordination chemistry of Ga(III), investigation into a new class of hexadentate ligands was initiated. These novel chelating agents are based on the cis,cis-1,3,5-triaminocyclohexane (TACH) system which functions as a platform for introducing a potentially wide variety of metal binding functional groups. Two novel chelating agents were synthesized and characterized and were found to form metal complexes with a variety of metal ions. The tris(pyridyl) triamine derivative was shown to form a Ga(III) complex of potentially useful stability justifying further in vivo evaluation. This complex has also received some preliminary investigation as a chemotherapeutic agent, replacing Gallium nitrate in a bladder cancer application. Evaluation of this complex and related analogues continues to proceed. Additionally, a novel series of alkyl substituted ethylene hexamine chelating agents were prepared and characterized. All formed complexes with both divalent and trivalent metals. Of particular interest has been the ability to alter lipophilicity by virtue of the alkyl groups that were introduced stereospecifically. As these ligands also possess a potentially oxidation prone secondary amine, efforts are being expanded to obviate this by introduction of a variety of alkyl substituents. A series of experiments employing a C-functionalized 1,4,7- triazacyclobobane triacetic acid (NOTA) as a sequestering agent for 66Ga has shown this ligand to be stable exceptionally in vivo. Catabolism studies have shown that the complex remains intact and is excreted as a amino acid conjugate. These studies imply that the renal clearance patterns of radiolabeled immunoprotein fragments or constructs may be manipulated by controlling the conjugation site(s) of the chelating agent. Further studies are planned to thoroughly explore this possibility.
