Developing PET Imaging Agents to Measure NR2B within NMDA Complexes

Science Center, Bent Corridor

N-methyl D-aspartate (NMDA) is a protein found in neurons that acts as both a receptor complex and a channel for transporting cations across the cell membrane. NMDA is partially responsible for neurogenesis and neuroprotection in the brain and spinal cord, and when operating below its typical range of function, it is also associated with neurodegeneration. NMDA is composed of a combination of seven subunits: NR1, NR2A-D, and NR3A-B. The inclusion of these subunits in an NMDA complex varies depending on location in the brain. NR2B, one subunit of NMDA, binds to glutamate. This subunit alters NMDA channel kinetics and influences the binding affinities of other NMDA receptors. NR2B is a promising candidate for targeting with radioligands for PET imaging due to its distinct presence in the forebrain of healthy individuals. One previously synthesized radioligand that targets the NR2B glutamate receptor is NB1, a tertiary amine bound to a benzene ring via a 4-carbon chain. The compound’s phenylbutyl group has hundreds of analogous structures that have not yet been synthesized and tested. This untouched stock of ligands could contain a number of labeling and therapeutic agents for NR2B. The objective of this project was to synthesize novel ligands to be tested in a binding assay, followed by use in PET studies of neurodegeneration. These ligands were primarily synthesized through aromatic substitution, tosylation, and amination. By the end of the summer, thirteen products were synthesized and sent to an external lab for assay, pending viability as imaging agents.