Preliminary studies of99m Tc-memantine derivatives for NMDA receptor imaging

Abstract Introduction Novel technetium-labeled ligands,99m Tc-NCAM and99m Tc-NHAM were developed from the N -methyl- d -aspartate (NMDA) receptor agonist memantine as a lead compound by coupling with N2 S2 . 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 of99m 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 than99m Tc-NHAM. The results indicated that99m Tc-NCAM bound to a single site on the NMDA receptor with a Kd of 701.21 nmol/l and a Bmax of 62.47 nmol/mg. Specific inhibitors of the NMDA receptor, ketamine and dizocilpine, but not the dopamine D2 and 5HT1A receptor partial agonist aripiprazole, inhibited specific binding of99m 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 radioligand99m 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.