RT Journal Article
SR Electronic
T1 Preclinical Evaluation of Benzazepine-Based PET Radioligands (<em>R</em>)- and (<em>S</em>)-<sup>11</sup>C-Me-NB1 Reveals Distinct Enantiomeric Binding Patterns and a Tightrope Walk Between GluN2B- and σ<sub>1</sub>-Receptor–Targeted PET Imaging
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1167
OP 1173
DO 10.2967/jnumed.118.221051
VO 60
IS 8
A1 Haider, Achi
A1 Herde, Adrienne Müller
A1 Krämer, Stefanie D.
A1 Varisco, Jasmine
A1 Keller, Claudia
A1 Frauenknecht, Katrin
A1 Auberson, Yves P.
A1 Temme, Louisa
A1 Robaa, Dina
A1 Sippl, Wolfgang
A1 Schibli, Roger
A1 Wünsch, Bernhard
A1 Mu, Linjing
A1 Ametamey, Simon M.
YR 2019
UL http://jnm.snmjournals.org/content/60/8/1167.abstract
AB The study aims to investigate the performance characteristics of the enantiomers of 11C-Me-NB1, a recently reported PET imaging probe that targets the GluN2B subunit of N-methyl-d-aspartate (NMDA) receptors. Methods: Reference compound Me-NB1 (inhibition constant for hGluN1/GluN2B, 5.4 nM) and the phenolic precursor were prepared via multistep synthesis. Following chiral resolution by high-performance liquid chromatography, enantiopure precursor compounds, (R)-NB1 and (S)-NB1, were labeled with 11C and validated in rodents using in vitro/ex vivo autoradiography, PET experiments, and dose–response studies. To illustrate the translational relevance, (R)-11C-Me-NB1 was validated in autoradiographic studies using postmortem human GluN2B-rich cortical and GluN2B-deficient cerebellar brain slices. To determine target engagement, receptor occupancy was assessed at different plasma concentrations of CP101,606, a GluN2B receptor antagonist. Results: The radiosynthesis of (R)- and (S)-11C-Me-NB1 was accomplished in 42% ± 9% (decay-corrected) radiochemical yields. Molar activity ranged from 40 to 336 GBq/μmol, and an excellent radiochemical purity of greater than 99% was achieved. Although (R)-11C-Me-NB1 displayed heterogeneous accumulation with high selectivity for the GluN2B-rich forebrain, (S)-11C-Me-NB1 revealed a homogeneous distribution across all brain regions in rodent brain autoradiograms and predominantly exhibited σ1-receptor binding. Similar to rodent brain, (R)-11C-Me-NB1 showed in postmortem human brain tissues higher binding in the cortex than in the cerebellum. Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of (R)-11C-Me-NB1 binding to the human GluN2B-containing NMDA receptor. In vivo specificity of (R)-11C-Me-NB1 in the GluN2B-expressing cortex, striatum, thalamus, and hippocampus was demonstrated by PET imaging in rodents. Applying GluN2B-antagonist eliprodil, an evident dose–response behavior was observed with (R)-11C-Me-NB1 but not with (S)-11C-Me-NB1. Our findings further underline the tightrope walk between GluN2B- and σ1-receptor–targeted imaging, illustrated by the entirely different receptor binding behavior of the 2 radioligand enantiomers. Conclusion: (R)-11C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the NMDA receptor. The entirely different receptor binding behavior of (R)-11C-Me-NB1 and (S)-11C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2B-carrying NMDA or σ1-receptors.