Glutamatergic Receptor NMDA PET Imaging via Specific (R)-¹¹C-Me-NB1 Radiotracers

Take-Away Points

• ■ Major Focus: Testing the efficacy of carbon 11 (¹¹C)-Me-NB1 S- and R-enantiomers as radiotracers in PET imaging for glutamatergic receptor N-methyl-d-aspartate (NMDA) subunit GluN2B.

• ■ Key Results: (R)-¹¹C-Me-NB1 demonstrated high selectivity and specificity for GluN2B subunits, whereas (S)-¹¹C-Me-NB1 exhibited greater specificity for off-target nonglutamatergic σ₁ receptors.

• ■ Impact: With further clinical testing, (R)-¹¹C-Me-NB1 may permit easier imaging and identification of nervous system disorders stemming from NMDA glutamatergic receptors.

Several processes necessary for nervous system function and maintenance are controlled by N-methyl-d-aspartate (NMDA). Overstimulation or malfunction of these glutamatergic receptors often results in apoptosis of neurons, which leads to psychiatric and neuronal disorders. Efforts to produce antagonists for the NMDA receptor have experienced limited success due to complete blocking of NMDA processes or an inability to specifically bind to the NMDA subunit responsible for excitotoxicity-induced apoptosis, GluN2B. To better view molecular interactions of introduced ligands with GluN2B receptors, Haider et al used PET imaging techniques. Their selected radiotracers were enantiomers of carbon 11 (¹¹C)-Me-NB1, a large molecule that previously detailed its selectivity for GluN2B and favorable pharmacokinetics. R- and S-enantiomers of ¹¹C-Me-NB1 were introduced separately into brain tissue samples from CD1 mice, Wistar rats, and postmortem humans for in vitro testing. Both R- and S-enantiomers were also tail-vein injected into live Wistar rats for in vivo and ex vivo testing. After radiotracer introduction, several inhibitors of GluN2B, including CP101,606, were applied to test the specificity of the radiotracers for the target receptors. PET images revealed location of enantiomers where (S)-¹¹C-Me-NB1 was found equally distributed throughout tissues with greater affinity for off-target nonglutamatergic σ₁ receptor sites. Alternatively, (R)-¹¹C-Me-NB1 exhibited highly selective binding to GluN2B-rich sites, specifically the cortex. (R)-¹¹C-Me-NB1 also possessed high specificity for GluN2B, competing with known GluN2B blockers in a dose-dependent manner. Haider et al’s research also included an ex vivo radiometabolite study and molecular dynamics analysis of (R)-¹¹C-Me-NB1 binding to GluN2B, which respectively revealed an absence of radiometabolites from (R)-¹¹C-Me-NB1 and favorable interactions with the N-terminal binding domain of GluN2B. The evidence presented in the study suggests that (R)-¹¹C-Me-NB1 is a viable PET imaging tool for current brain disease imaging practices in both preclinical and clinical studies centered around candidate therapeutics for GluN2B binding.

Highlighted Article

• Haider A, Herde AM, Krämer SD, et al. Preclinical evaluation of benzazepine-based PET radioligands (R)- and (S)-¹¹C-Me-NB1 reveals distinct enantiomeric binding patterns and a tightrope walk between GluN2B- and σ₁-receptor–targeted PET imaging. J Nucl Med 2019;60:1167–1173. doi: 10.2967/jnumed.118.221051.