Novel 99mTc Aminobisthiolato/Monothiolato “3 + 1” Mixed Ligand Complexes: Structure−Activity Relationships and Preliminary in Vivo Validation as Brain Blood Flow Imaging Agents

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Abstract
A series of neutral, lipophilic 99mTc mixed-ligand complexes of the general formula 99mTcOL 1L 2, where L1H2 is an N-substituted bis-(2-mercaptoethyl)amine, [X-CH2CH2N(CH2CH2SH)2], [SNS], and L2H 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 99mTc(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 complexessyn and antiwas expected, since the N-substituent (X-CH2CH2N) can assume syn or anti configuration with respect to the 99mTcO3+ core during complexation. One anti and all syn isomers were isolated by HPLC. Their identity was confirmed by comparative HPLC studies with the analogous 99Tc complexes of established structure. In vivo distribution, in particular brain uptake and retention, greatly depended on the type of either tridentate (L1H2) or monodentate (L2H) ligand. All 99mTc 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 99mTc(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 99mTc−d,l-HMPAO, and sufficient retention 60 min postinjection were provided with complex 18 [X = (C2H5)2N and R = p-CH3OC6H4CH2].

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