Development of PET and SPECT Radioligands for In Vivo Imaging of NMDA Receptors

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

“…Despite extensive efforts, no radioligands have been identified as potential in vivo imaging agents for NMDA receptors using PET imaging. This may be due to the complexity of NMDA receptors, which form systems with ligand-gated ion channels including two agonist binding sites, a transmembrane ion permeation pore, and various allosteric modulator binding sites, making it challenging to develop radioligands using strategies successful for other neurotransmitter receptors . Another perspective is that the brain localization of radioligands of NMDA receptors in vitro and in vivo may differ due to the dynamic plasticity of NMDA receptors.…”

“…This may be due to the complexity of NMDA receptors, which form systems with ligand-gated ion channels including two agonist binding sites, a transmembrane ion permeation pore, and various allosteric modulator binding sites, making it challenging to develop radioligands using strategies successful for other neurotransmitter receptors. 154 Another perspective is that the brain localization of radioligands of NMDA receptors in vitro and in vivo may differ due to the dynamic plasticity of NMDA receptors. Structural changes in NMDA receptors occur upon binding to endogenous agonists and exogenous ligands, 153 and the number of NMDA receptors on the cell surface can be altered by C-terminal tyrosine phosphorylation and/or cysteine palmitoylation of NMDA receptors, resulting in changes in subunit composition.…”

“…Despite numerous efforts since the late 1980s to develop radioligands for the NMDA receptor, there are no clinically available radiotracers currently. The target sites on NMDA receptors with their corresponding radioligands can be classified into four categories: 1) the PCP binding site (a channel blocker binding site) with [ 11 C] 16 ; 2) the glutamate binding site; 3) the glycine binding site with 5Et-[ 11 C]­4HQ ([ 11 C] 29 ) and 5I-[ 11 C]­4HQ ([ 11 C] 30 ); and 4) the ifenprodil binding site (a GluN2B negative regulator binding site) with 11 C-Me-NB1 ([ 11 C] 31 ), ( R )- 18 F-OF-Me-NB1 ([ 18 F] 32 ), and [ 18 F]­N2B-0518 ([ 18 F] 33 )) …”

“…Neurotransmitters and voltage-gated ion channels have been identified as the most likely molecular targets of general anesthesia, including NMDA receptors, GABA receptors, opioid receptors, α2-Ars, nACh receptors, potassium channels, and sodium channels. 154 Most competitive antagonists targeting the glutamate binding site have an acidic fraction, which may lead to low brain uptake and low selectivity for NMDA receptors over other glutamate receptors, resulting in few radioligands being published in the literature. 154 However, considerable effort has been invested in developing GluN1/2A-selective NMDA receptor ligands that target the glutamate binding site.…”

The role of neuroimaging in Parkinson’s disease

“…NMDARs are a family of ionotropic receptors (ion channels) activated by glutamate-the principal excitatory neurotransmitter in the brain (Fuchigami et al, 2021). Overactive glutamatergic neurotransmission is thought to underlie LID, and inhibition of NMDARs reduces LID in preclinical PD models (Niccolini et al, 2015; Table 1, row 21).…”