Radiochemical Synthesis And Research Of ^99mTc-NCAM As A Potential NMDA Receptor Imaging Agent

In recent years it has more and more study evidence indicated that the excess activation of NMDA receptor has shown an important role during the occurrence and the development of the neurodegenerative diseases. By showing those changes of density and quantity of the NMDA receptor in the special brain region, the NMDA receptor tracer could play very significant roles in researching the relationship between NMDA receptor and neurodegenerative diseases, as well as in the diagnosis and treatment in these diseases. So a new radioligand ^99mTc-NCAM by labelling a derivater of memantine N₂S₂-memantine (N-[2-(N-(2-mercapotoethyl))aminoformylmethyl]-N-(2-mercapotoethyl)-3,5-dimethyladamantyl aminoacetamide, NCAM) with ^99mTc was synthesised.On the role of reductor SnF2, a new radioligand ^99mTc-NCAM was directly synthesised by labelling N₂S₂-memantine which retented the pharmacophore of menmantine, and its radiochemical purity was greater than 95% determined by TLC and HPLC with optimizating the condition of labelling.It is an ideal NMDA receptor imaging agent to have the character of specific binding and targeting to NMDA receptor. The Radio-Ligand Receptor Binding Assay was shown that the binding of radioligand ^99mTc-NCAM to NMDA receptor was saturable with an equilibrium Kd of 706.3nmol/L and a Bmax of 56.8pmol/μg calculated by computer program of receptor theory in B region, which was similar to the results of menmantine binding to NMDA receptor reported in literature. The competitive analysis showed that such specific binding could be inhibited by ketamine and MK-801 which were the specific inhibitors of NMDA receptor. However, haloperidol which was the noninhibitor of NMDA receptor could not inhibit it. The fact confirmed that ^99mTc-NCAM had a targeted binding to NMDA receptor.Not only the specific binding and targeting to NMDA receptor is the key as a NMDA receptor imaging agent, but the ability to easily pass through the blood-brain barrier to definite brain region is also play a important role for a NMDA receptor imaging agent. The oil/water partition coefficient, the character of electric charge and other aspects of the radioligand are the key factors to determine it passing through the blood-brain barrier. ^99mTc-NCAM was of oil/water partition coefficient 1.9, electroneutral. The biodistribution of mice indicated that the brain had some distribution, especially in the cerebral cortex and hippocampus where the NMDA receptors was very abundant. The uptake of nerve cell HS-HY5Y to ^99mTc-NCAM had significant discrepancy compared to that of nerve cell HS-HY5Y to ^99mTc. In conclusion, ^99mTc-NCAM can easily pass through the brain-blood barrier to the definite brain domain.This study provided a few of basis evidences to the new radioligand ^99mTc-NCAM whether or not it could be continuely studied and be used as a NMDA receptor imaging agent in future. Furthermore, it could provide some methods and ideas for the study of receptor imaging agent.