Research ArticleRadiochemistry

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

Achi Haider, Adrienne Müller Herde, Stefanie D. Krämer, Jasmine Varisco, Claudia Keller, Katrin Frauenknecht, Yves P. Auberson, Louisa Temme, Dina Robaa, Wolfgang Sippl, Roger Schibli, Bernhard Wünsch, Linjing Mu and Simon M. Ametamey
Journal of Nuclear Medicine August 2019, 60 (8) 1167-1173; DOI: https://doi.org/10.2967/jnumed.118.221051

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Absolute configuration and binding behavior of (R)- and (S)-Me-NB1. (A) ORTEP view of (R)- and (S)-Me-NB1 in solid state. Me-NB1 exhibits one chiral center depicted at position C13. Thermal ellipsoids are set to 30% probability. For all nonhydrogen atoms, anisotropic displacement parameters were used. Hydrogen atoms were refined in idealized positions using riding model. (B) Representative in vitro autoradiograms of (R)/(S)-11C-Me-NB1 incubated with Wistar rat brain sections. Although (S)-enantiomer binds to virtually all brain regions, (R)-enantiomer exhibits selectivity for GluN2B-rich forebrain. Cx = cortex; CPu = corpus striatum; Hp = hippocampus; Th = thalamus; Cb = cerebellum.

  • FIGURE 2.
    FIGURE 2.

    Autoradiographic screening of clinically tested GluN2B ligands CERC-301, EVT-101, and CP101,606, as well as σ1R ligands SA4503, fluspidine, and (+)-pentazocine, as blocking agents for (R)-11C-Me-NB1 and (S)-11C-Me-NB1. (R)-11C-Me-NB1 showed heterogeneous binding behavior that was GluN2B-specific whereas (S)-11C-Me-NB1 exhibited considerable σ1R binding.

  • FIGURE 3.
    FIGURE 3.

    Whole-brain time–activity curves of racemic and enantiomerically pure 11C-Me-NB1 in Wistar rat brain are depicted as SUVs. GluN2B-specific (R)-form exhibited higher SUVs than (S)-form, whereas racemic mixture displayed time–activity curve that lies between the two enantiomers. For blockade experiment, 2 mg/kg dose of GluN2B antagonist eliprodil was used.

  • FIGURE 4.
    FIGURE 4.

    Dose–response curves of (R)-11C-Me-NB1 and (S)-11C-Me-NB1 with eliprodil in Wistar rat brain. Results are reported as SUVs calculated from PET experiments (0–60 min). (A) (R)-11C-Me-NB1 revealed consistent dose–response profile on stepwise dose escalation of eliprodil. (B) (S)-11C-Me-NB1 did not show dose-dependent blockade.

  • FIGURE 5.
    FIGURE 5.

    Representative ex vivo autoradiogram of Wistar rat brain at 15 min after injection of (R)-11C-Me-NB1. Selectivity for cortex, striatum, thalamus, and hippocampus over cerebellum was observed. Cb = cerebellum; CPu = corpus striatum; Cx = cortex; Hp = hippocampus; Th = thalamus.

  • FIGURE 6.
    FIGURE 6.

    Receptor occupancy by clinically tested GluN2B antagonist CP101,606 and GluN2B PET radioligand (R)-11C-Me-NB in Wistar rats (B), calculated from experimental SUV0–60 min (A), revealed plasma concentration of 158 nmol/L, or 52 ng/mL, required for 50% receptor occupancy. Clinically applied target plasma concentration of 200 ng/mL occupies 80% of GluN2B binding sites in our rat model. Rat brain PET images were superimposed on PMOD MRI template (C). Bs = brain stem; Cb = cerebellum; CPu = corpus striatum; Cx = cortex; Hp = hippocampus; Th = thalamus.

  • FIGURE 7.
    FIGURE 7.

    Representative autoradiograms on rodent and human brain tissue. (A) Ex vivo autoradiography at 15 min after injection of (R)-11C-Me-NB1 into Wistar rat and subsequent in vitro displacer screening with GluN2B ligands CERC-301, EVT-101, CP101,606, and σ1R ligands fluspidine, (+)-pentazocine, and (S)-Me-NB1. Displacement of (R)-11C-Me-NB1 binding is observed only for GluN2B antagonists. (B) Representative autoradiograms of (R)-11C-Me-NB1 incubated with human postmortem brain sections. GluN2B-specific binding was observed in temporal cortex (indicated by blockade experiment with GluN2B antagonist CERC-301), whereas cerebellum did not reveal any specific binding of radioligand.

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