A new, versatile synthetic route to a variety of tetradentate N2S2 and hexadentate N3S3 ligands for use in technetium-99m radiopharmaceuticals has been developed. The key reaction employs 1-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline (EEDQ) for coupling an appropriate di- or triamine with S-protected thioglycolic acid. Selected DADS (diamido disulfur) and DADT (diamino dithiol) and analogues derived from ethanediamine-1,2 and butanediamine-1,4, as well as a tripodal N3S3 analogue, were synthesized in high yield. The labeling of DADS analogue ligands derived from butanediamine-1,4 (DADS-bn) with Tc-99m results in a single radiochemical product, or the expected number of stereoisomeric products. FAB MS analysis, using Tc-99, indicates that DADS-bn ligands form a tetradentate 5,7,5-membered ring chelate system with the monooxo Tc(V) core: [TcO-DAD-bn]. In rat biodistribution studies the DADS-en and DADS-bn complexes show very similar biological activity. Phenyl substitutents on the 7-membered ring give rise to a Tc-99m complex of increased lipophilicity, increased liver uptake, and minimal hepatobillary clearance. Thus, new classes of DADS ligand analogues which contain a 5,7,5-membered chelate ring system are readily synthesized and labeled with Tc-99m to form stable complexes. The presence of the 7-membered chelate ring allows for facile introduction of pendant groups into the ligand system, and thus for a ready route to control the biodistribution of the resulting Tc-99m radiopharmaceutical. The Tc-99m labeling of the DADT analgoues derived from butanediamine-1,4 provided to be erratic, despite the use of a variety of labeling techniques; the larger ring system of DADT-bn apparently does not favor the monooxo Tc(V) core and appears to generate a mixture of mono- and dioxo Tc(V) cores.