NOVEL TC-99M AMINOBISTHIOLATO MONOTHIOLATO 3+1-MIXED-LIGAND COMPLEXES- STRUCTURE-ACTIVITY-RELATIONSHIPS AND PRELIMINARY IN-VIVO VALIDATIONAS BRAIN BLOOD-FLOW IMAGING AGENTS/

A series of neutral, lipophilic Tc-99m mixed-ligand complexes of the g eneral formula (TcOLL2)-Tc-99m-L-1, where L(1)H2 is an N-substituted b is-(2-mercaptoethyl)amine, [X-CH2CH2N(CH2CH2SH)(2)], [SNS], and (LH)-H -2 is a monodentate thiol (RSH), [S], has been synthesized and evaluat ed in rodents for potential use in brain blood flow imaging. The compl exes were prepared by ligand exchange reaction using Tc-99m(V)O-glucoh eptonate 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 as sume syn or anti configuration with respect to the (TcO3+)-Tc-99m core during complexation. One anti and all syn isomers were isolated by HP LC. Their identity was confirmed by comparative HPLC studies with the analogous Tc-99 complexes of established structure. In vivo distributi on, in particular brain uptake and retention, greatly depended on the type of either tridentate (L(1)H2) or monodentate ((LH)-H-2) ligand. A ll 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 complexe s. Structure-activity relationships of novel Tc-99m(V)O SNS/S complexe s in mice are reported and discussed. Selected complexes were further studied in rats. High brain uptake, comparable to that of Tc-99m-d,l-H MPAO, and sufficient retention 60 min postinjection were provided with complex 18 [X = (C2H5)(2)N and R = p-CH3OC6H4CH2].