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.

Chelate oxorhenium to assemble new integrin antagonists

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Dynamic Combinatorial Self‐Assembly of Cyclophilin hCyp‐18 Ligands through Oxorhenium Coordination

“…[4,5] It would therefore be anticipated that all complexes should dissociate readily through GSH-mediated substitution [Eq. (2)], [4,6] whereas complexes that interact with the protein (i.e., hCyp-18) should be protected against thiol exchange. A thermodynamic step is thus combined with the kinetically controlled coordination process [5] in order to introduce partial reversibility and, therefore, to select high-affinity cyclophilin ligands.…”

Cyclopentadienyl tricarbonyl complexes of 99mTc for the in vivo imaging of the serotonin 5-HT1A receptor in the brain

“…However, the in vivo behaviour of such complexes may be influenced by the Tc@O unit offering a free position trans to the oxo ligand for further reaction in vivo as observed especially for the Ô3+1Õ complexes [4,5]. To reduce this in vivo reactivity, we consider oxo-free Tc complexes containing the metal in lower oxidation states to be interesting alternatives.…”