Preliminary studies of (99m)Tc-memantine derivatives for NMDA receptor imaging.

Introduction: Novel technetium-labeled ligands, (99m)Tc-NCAM and (99m)Tc-NHAM were developed from the N-methyl-d-aspartate (NMDA) receptor agonist memantine as a lead compound by coupling with N(2)S(2). This study evaluated the binding affinity and specificity of the ligands for the NMDA receptor.

Methods: Ligand biodistribution and uptake specificity in the brain were investigated in mice. Binding affinity and specificity were determined by radioligand receptor binding assay. Three antagonists were used for competitive binding analysis. In addition, uptake of the complexes into SH-SY5Y nerve cells was evaluated.

Results: The radiochemical purity of (99m)Tc-labeled ligands was more than 95%. Analysis of brain regional uptake showed higher concentration in the frontal lobe and specific uptake in the hippocampus. (99m)Tc-NCAM reached a higher target to nontarget ratio than (99m)Tc-NHAM. The results indicated that (99m)Tc-NCAM bound to a single site on the NMDA receptor with a K(d) of 701.21 nmol/l and a B(max) of 62.47 nmol/mg. Specific inhibitors of the NMDA receptor, ketamine and dizocilpine, but not the dopamine D(2) and 5HT(1A) receptor partial agonist aripiprazole, inhibited specific binding of (99m)Tc-NCAM to the NMDA receptor. Cell physiology experiments showed that NCAM can increase the viability of SH-SY5Y cells after glutamate-induced injury.

Conclusions: The new radioligand (99m)Tc-NCAM has good affinity for and specific binding to the NMDA receptor, and easily crosses the blood-brain barrier; suggesting that it might be a potentially useful tracer for NMDA receptor expression.