Novel Tc-99m aminobisthiolato/monothiolato ''3+1'' mixed ligand complexes: Structure-activity relationships and preliminary in vivo validation as brain blood flow imaging agents

A series of neutral, lipophilic Tc-99m mixed-ligand complexes of the general formula (TcOLL2)-Tc-99m-L-1, where L(1)H2 is an N-substituted bis-(2-mercaptoethyl)amine, [X-CH2CH2N(CH2CH2SH)(2)], [SNS], and (LH)-H-2 is a monodentate thiol (RSH), [S], has been synthesized and evaluated in rodents for potential use in brain blood flow imaging. The complexes were prepared by ligand exchange reaction using Tc-99m(V)O-glucoheptonate as precursor and equimolar quantities of the two ligands. In all cases the syn isomer was formed in a high yield, whereas the anti isomer was not always present. The formation of two isomeric complexes-syn and anti-was expected, since the N-substituent (X-CH2CH2N) can assume syn or anti configuration with respect to the (TcO3+)-Tc-99m core during complexation. One anti and all syn isomers were isolated by HPLC. Their identity was confirmed by comparative HPLC studies with the analogous Tc-99 complexes of established structure. In vivo distribution, in particular brain uptake and retention, greatly depended on the type of either tridentate (L(1)H2) or monodentate ((LH)-H-2) ligand. All Tc-99m complexes showed significant brain uptake in mice (0.78-4.35% injected dose per organ at 5 min postinjection). This initial uptake remained nearly constant for at least 30 min for most of the complexes. Structure-activity relationships of novel Tc-99m(V)O SNS/S complexes in mice are reported and discussed. Selected complexes were further studied in rats. High brain uptake, comparable to that of Tc-99m-d,l-HMPAO, and sufficient retention 60 min postinjection were provided with complex 18 [X = (C2H5)(2)N and R = p-CH3OC6H4CH2].