Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors

Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus

doi:10.1021/acs.jmedchem.0c00778

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Haider, A., Gobbi, L., Kretz, J., Ullmer, C., Brink, A., Honer, M., Woltering, T. J., Muri, D., Iding, H., Bürkler, M., Binder, M., Bartelmus, C., Knuesel, I., Pacher, P., Herde, A. M., Spinelli, F., Ahmed, H., Atz, K., Keller, C., … Ametamey, S. M. (2020). Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors. Journal of Medicinal Chemistry, 63(18), 10287–10306. https://doi.org/10.1021/acs.jmedchem.0c00778

Abstract

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Ki for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield o