Haider, Ahmed, Müller Herde, Adrienne, Krämer, Stefanie D., Varisco, Jasmine, Keller, Claudia, Frauenknech, Katrin, Auberson, Yves, Temme, Louisa, Robaa, Dina, Sippl, Wolfgang, Schibli, Roger, Wünsch, Bernhard, Mu, Linjing and Ametamey, Simon (2019) 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. Journal of nuclear medicine : JNM, 60 (8). pp. 1167-1173. ISSN 1535-5667; 0161-5505

Abstract

Our understanding of the NMDA receptor subunit composition, localization and function has dramatically improved and has led to the identification of the GluN2B-subunit as a key contributor to excitotoxicity-induced apoptosis. GluN2B antagonists have failed to demonstrate clinical efficacy and more are currently under clinical development. A suitable GluN2B-selective PET radioligand, which would facilitate target occupancy studies using imaging modalities such as positron emission tomography is lacking.
We have recently reported on (rac)-[11C]Me-NB1, a GluN2B-specific probe with high affinity (Ki to human GluN1/GluN2B of 5.4 nM) and excellent pharmacokinetic properties. The present study demonstrates that the enantiomeric pure forms of [11C]Me-NB1 show entirely different behavior as illustrated by distinct binding patterns in autoradiographic studies with rodent brain tissues, molecular dynamics studies as well as in vivo dose-response experiments. Whereas, the R-enantiomer, (R)-[11C]Me-NB1 revealed high selectivity for the GluN2B-rich forebrain, the S-enantiomer, (S)-[11C]Me-NB1, displayed a homogenous distribution pattern in autoradiograms of rodent brain and was found to predominantly bind to the σ1 receptor. (R)-[11C]Me-NB1 revealed outstanding characteristics as a GluN2B PET imaging agent as evidenced by in vitro and ex vivo autoradiography as well as dose-response experiments in rodents. Receptor occupancy studies with CP101,606, the only GluN2B-antagonist with well-documented clinical efficacy, showed that the currently applied therapeutic dose of 200 ng/mL exhibits 80 % receptor occupancy, demonstrating the utility of (R)-[11C]Me-NB1 for in vivo drug occupancy studies.. Finally, we validated (R)-[11C]Me-NB1 on post-mortem human brain tissue sections and showed that (R)-[11C]Me-NB1 binds specifically to the GluN2B-subunit of the NMDA receptor in humans.

Item Type:	Article
Date Deposited:	30 May 2023 00:46
Last Modified:	30 May 2023 00:46
URI:	https://oak.novartis.com/id/eprint/35626