TRIDENTATE LIGANDS CONTAINING THE SNS DONOR ATOM SET AS A NOVEL BACKBONE FOR THE DEVELOPMENT OF TECHNETIUM BRAIN-IMAGING AGENTS

In developing Tc-99m complexes as potential brain-imaging agents, we i nvestigated the coordination chemistry of ligands containing sulfur an d nitrogen donor atoms with the general formula R-CH2CH2N(CH2CH2SH)(2) (R=C2H5S, (C2H5)(2)N). These ligands act as tridentate SNS chelates t o the TcO3+ core, leaving open one coordination site cis to the oxo gr oup. In reactions with the highly reactive [(TcOCl4)-Tc-99](-) precurs or, this vacancy was occupied by a chlorine atom. When the ligands rea cted in the presence of 4-methoxythiophenol, using Tc-99(V)-gluconate as precursor, the vacancy was filled with 4-methoxythiophenol, which a cted as coligand. Thus neutral mixed ligand complexes of the general f ormula [TcO((SCH2CH2)(2)NCH(2)CH(2)R)X], where X = Cl or 4-methoxythio phenol, were synthesized. The complexes were characterized by UV-vis, IR, H-1 NMR, crystallographic, and elemental analyses. The crystal str uctures of 3a (R = C2H5S, X = Cl) and 4b (R = (C2H5)(2)N, X = 4-methox ythiophenol) demonstrated that the coordination geometry is trigonal b ipyramidal with the N1 and Cl or S3 occupying the apical positions and the basal plane defined by the S1 and S2 of the tridentate ligand and the oxo group. The complexes 4a(Tc-99m) (R = C2H5S, X = 4-methoxythio phenol) and 4b(Tc-99m) were prepared using Tc-99m-glucoheptonate as pr ecursor and were purified by HPLC. Biodistribution in mice showed high initial brain uptake (3.68% and 3.56% dose/organ for 4a(Tc-99m) and 4 b(99m Tc), respectively). Complex 4b(Tc-99m) displayed significantly h igher brain/blood values and prolonged retention in brain as well. The results suggest that structural modifications based on configurations 4a,b may provide novel Tc-99m brain-imaging agents with improved biol ogical characteristics.