title: Glutathione-mediated metabolism of technetium-99m SNS/S mixed ligand complexes: a proposed mechanism of brain retention.
abstract: Two series of [99mTc](SNS/S) 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](SNS/S) 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](SNS/S) 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](SNS/S) complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic [99mTc](SNS/GS) 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](SNS/GS) metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of [99mTc](SNS/S) complexes is GSH-mediated.
authors: Institute of Radioisotopes - Radiodiagnostic Products, NCSR "Demokritos", P.O. Box 60228, 153 10 Aghia Paraskevi, Athens, Greece.
authors: B A
authors: BA
authors: Nock
authors: T
authors: T
authors: Maina
authors: D
authors: D
authors: Yannoukakos
authors: I C
authors: IC
authors: Pirmettis
authors: M S
authors: MS
authors: Papadopoulos
authors: E
authors: E
authors: Chiotellis
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003545:Cysteine / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D012211:Rhenium / Q000737:chemistry; D013237:Stereoisomerism; D019690:Technetium Tc 99m Exametazime / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D009942:Organometallic Compounds; D015609:Organotechnetium Compounds; D019690:Technetium Tc 99m Exametazime; D003543:Cysteamine; D012211:Rhenium; D005978:Glutathione; D003545:Cysteine