N-methyl-D-aspartate (NMDA) receptors are crucial ionotropic glutamate receptors involved in synaptic transmission, learning, memory, and plasticity. They are heteromeric complexes composed of GluN1 and GluN2/GluN3 subunits, with GluN1 subunits being essential for function. NMDA receptors are distributed in the brain and play a key role in excitatory neurotransmission. Their activity is regulated by various factors, including co-agonists like glycine and D-serine, and they are involved in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus. In neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's, excessive glutamate release leads to increased intracellular calcium influx, causing excitotoxicity and neuronal damage. NMDA antagonists, particularly uncompetitive antagonists targeting the PCP site, have shown therapeutic potential in these conditions. Fluoroethylnormemantine (FENM), a novel NMDA antagonist, has demonstrated promising neuroprotective effects in Alzheimer's disease models and anxiolytic properties in post-traumatic stress disorder (PTSD) models. FENM is also a potential PET radiotracer for NMDA receptors. This review highlights the role of NMDA receptors in neurodegenerative diseases, their regulation, and the therapeutic potential of NMDA antagonists, with a focus on FENM.N-methyl-D-aspartate (NMDA) receptors are crucial ionotropic glutamate receptors involved in synaptic transmission, learning, memory, and plasticity. They are heteromeric complexes composed of GluN1 and GluN2/GluN3 subunits, with GluN1 subunits being essential for function. NMDA receptors are distributed in the brain and play a key role in excitatory neurotransmission. Their activity is regulated by various factors, including co-agonists like glycine and D-serine, and they are involved in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus. In neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's, excessive glutamate release leads to increased intracellular calcium influx, causing excitotoxicity and neuronal damage. NMDA antagonists, particularly uncompetitive antagonists targeting the PCP site, have shown therapeutic potential in these conditions. Fluoroethylnormemantine (FENM), a novel NMDA antagonist, has demonstrated promising neuroprotective effects in Alzheimer's disease models and anxiolytic properties in post-traumatic stress disorder (PTSD) models. FENM is also a potential PET radiotracer for NMDA receptors. This review highlights the role of NMDA receptors in neurodegenerative diseases, their regulation, and the therapeutic potential of NMDA antagonists, with a focus on FENM.