Nock B A, Maina T, Yannoukakos D, Pirmettis I C, Papadopoulos M S, Chiotellis E
Institute of Radioisotopes - Radiodiagnostic Products, NCSR "Demokritos", P.O. Box 60228, 153 10 Aghia Paraskevi, Athens, Greece.
J Med Chem. 1999 Mar 25;42(6):1066-75. doi: 10.1021/jm980174f.
Two series of 99mTc mixed ligand complexes each carrying the N-diethylaminoethyl or the N-ethyl-substituted bis(2-mercaptoethyl)amine ligand (SNS) are produced at tracer level using tin chloride as reductant and glucoheptonate as transfer ligand. The identity of 99mTc complexes is established by high-performance liquid chromatographic (HPLC) comparison with authentic rhenium samples. The para substituent R on the phenylthiolate coligand (S) ranges from electron-donating (-NH2) to electron-withdrawing (-NO2) groups, to study complex stability against nucleophiles as a result of N- and R-substitution. The relative resistance of 99mTc complexes against nucleophilic attack of glutathione (GSH), a native nucleophilic thiol of 2 mM intracerebral concentration, is investigated in vitro by HPLC. The reaction of 99mTc complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic 99mTc daughter compound. The N-diethylaminoethyl complexes are found to be more reactive against GSH as compared to the N-ethyl ones. Complex reactivity as a result of R-substitution follows the sequence -NO2 >> -H > -NH2. These in vitro findings correlate well with in vivo distribution data in mice. Thus, brain retention parallels complex susceptibility to GSH attack. Furthermore, isolation of the hydrophilic 99mTc metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of 99mTc complexes is GSH-mediated.
