Evaluation of [11C]Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy and receptor crosstalk

Clinical and preclinical research with modulators binding to the NMDA receptor GluN2B N-terminal domain (NTD) aim for the treatment of various neurological diseases. However, the interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of candidate drugs. We have developed [¹¹C]Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator. Methods: [¹¹C]Me-NB1 was synthesized and characterized by in vitro displacement binding experiments with rat brain membranes, in vitro autoradiography, blocking and displacement experiments by PET and PET kinetic modeling with an arterial input function. Receptor occupancy by eliprodil was studied in vivo by PET with [¹¹C]Me-NB1. Results: [¹¹C]Me-NB1 was synthesized at 290±90 GBq/µmol specific activity, 7.4±1.9 GBq total activity at the end of synthesis and >99% radiochemical purity. [¹¹C]Me-NB1 binding in rat brain was blocked in vitro and in vivo by the NTD modulators Ro-25-6981 and eliprodil. In vivo, half maximal receptor occupancy by eliprodil occurred at 1.5 μg/kg. At 1 mg/kg eliprodil, a dose with reported neuroprotective effects, >99.5% binding sites were occupied. In vitro, [¹¹C]Me-NB1 binding was independent of sigma 1 receptor (Sigma1R) and the Sigma1R agonist (+)-pentazocine did not compete for high affinity binding. In vivo, 2.5 mg/kg (+)-pentazocine abolished [¹¹C]Me-NB1 specific binding, indicating an indirect effect of Sigma1R on [¹¹C]Me-NB1 binding. Conclusion: [¹¹C]Me-NB1 is suitable for the in vivo imaging of NMDA GluN1/GluN2B receptors and the assessment of the receptor occupancy by NTD modulators. GluN1/GluN2B NMDA receptors are fully occupied at neuroprotective doses of eliprodil. Furthermore, [¹¹C]Me-NB1 enables imaging of GluN1/GluN2B NMDA receptor crosstalk.

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