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].