Volume 6 Supplement 1

9th German Conference on Chemoinformatics

Open Access

Development of cannabinoid receptor (CB 2 R) ligands for application in PET studies - where to attach the radiolabel?

  • Robert Günther1Email author,
  • Rareş Moldovan1,
  • Corinna Lueg2,
  • Winnie Deuther-Conrad1,
  • Bernhard Wünsch2 and
  • Peter Brust1
Journal of Cheminformatics20146(Suppl 1):O9

DOI: 10.1186/1758-2946-6-S1-O9

Published: 11 March 2014

The cannabinoid receptors type 2 (CB2R) are involved in many physiological processes but their expression level in healthy and diseased brain has not been unravelled. With positron emission tomography (PET) it is possible to monitor quantitatively very low amounts of compounds labelled with positron emitting isotopes like 18F in living organisms at high spatial resolution. For application in clinical research, such radiotracers have to show high selectivity and affinity to the target protein.

A series of fluorinated N-carbazolyl-oxadiazolyl-propionamides [1] was synthesised and the affinity towards the human CB2R was measured in receptor binding studies. Here, we combine our CB2R receptor model with 3D-QSAR data [2] to support molecular docking studies employing the MOE software (Version 2012.12 Chemical Computing Group Inc. Montreal. http://www.chemcomp.com). The studies revealed that both the primarily investigated compound 2 and the 2-fluoroethyl substituted carbazole derivative 1 (K i = 3.6 nM) fits well into the binding pocket. Attachment of the fluorine at different positions of the structure does not lead to significantly different poses in accordance with the experimental data. Organ distribution studies on CD1-mice verified our prediction, [3] that [18F]1 and [18F]2 can cross the blood-brain barrier.
Figure 1

Compounds 1 and 2 fitted into the binding pocket of the CB2R receptor model.

Authors’ Affiliations

(1)
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig
(2)
Department of Pharmaceutical and Medicinal Chemistry, University of Münster

References

  1. Rühl T, Deuther-Conrad W, Fischer S, Günther R, Hennig L, Krautscheid L, Brust P: Cannabinoid Receptor Type 2 (CB2)-Selective N-Aryl-Oxadiazolyl-Propionamides: Synthesis, Radiolabelling, Molecular Modelling and Biological Evaluation. Org Med Chem Lett. 2012, 2: 32-10.1186/2191-2858-2-32.View ArticleGoogle Scholar
  2. Günther R, Brust P: Synergistic approach of structure- based and ligand-based drug design for the development of selective cannabinoid receptor ligands. J Cheminform. 2012, 4 (Suppl 1): P11-10.1186/1758-2946-4-S1-O11.View ArticleGoogle Scholar
  3. Gerebtzoff G, Seelig A: In Silico Prediction of Blood-Brain Barrier Permeation Using the Calculated Molecular Cross-Sectional Area as Main Parameter. J Chem Inf Model. 2006, 6: 2638-2650.View ArticleGoogle Scholar

Copyright

© Günther et al; licensee Chemistry Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.