Synthesis and Receptor Binding Studies of ( ± )l-Iodo-MK-801

Abstract

The glutamate analogue N -methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (±)l-iodo-MK-801 and (±)l-[ 125 I]iodo-MK-801. The effect of (±)l-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (±)l-Iodo-MK-801 displaced the dissociative anesthetic ligand [ 3 H] N -[l-(2-thienyl)cyclohexyl]piperidine ([ 3 H]TCP) binding with an IC 50 of 1 µ M , which is a 10-fold lower binding affinity than that of (±)MK-801. In in vivo autoradiographic studies, (±)MK-801 failed to block selective uptake of (±)l-iodo-MK-801 in rat brain. These results suggest that (±)l-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels.