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Open Access Highly Accessed Original article

Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation

Thomas Rühl1, Winnie Deuther-Conrad1, Steffen Fischer1, Robert Günther1, Lothar Hennig2, Harald Krautscheid3 and Peter Brust1*

Author Affiliations

1 Department of Neuroradiopharmaceuticals, Institute of Radiopharmacy, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf e.V., Permoserstr. 15, Leipzig, 04318, Germany

2 Institute of Organic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, Leipzig, 04103, Germany

3 Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, Leipzig, 04103, Germany

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Organic and Medicinal Chemistry Letters 2012, 2:32  doi:10.1186/2191-2858-2-32

Published: 15 October 2012

Abstract

Background

The endocannabinoid system is involved in many physiological and pathological processes. Two receptors (cannabinoid receptor type 1 (CB1) and type 2 (CB2)) are known so far. Many unwanted psychotic side effects of inhibitors of this system can be addressed to the interaction with CB1. While CB1 is one of the most abundant neuroreceptors, CB2 is expressed in the brain only at very low levels. Thus, highly potent and selective compounds for CB2 are desired. N-aryl-((hetero)aromatic)-oxadiazolyl-propionamides represent a promising class of such selective ligands for the human CB2. Here, a library of various derivatives is studied for suitable routes for labelling with 18F. Such 18F-labelled compounds can then be employed as CB2-selective radiotracers for molecular imaging studies employing positron emission tomography (PET).

Results

By varying the N-arylamide substructure, we explored the binding pocket of the human CB2 receptor and identified 9-ethyl-9H-carbazole amide as the group with optimal size. Radioligand replacement experiments revealed that the modification of the (hetero)aromatic moiety in 3-position of the 1,2,4-oxadiazoles shows only moderate impact on affinity to CB2 but high impact on selectivity towards CB2 with respect to CB1. Further, we could show by autoradiography studies that the most promising compounds bind selectively on CB2 receptors in mouse spleen tissue. Molecular docking studies based on a novel three-dimensional structural model of the human CB2 receptor in its activated form indicate that the compounds bind with the N-arylamide substructure in the binding pocket. 18F labelling at the (hetero)aromatic moiety at the opposite site of the compounds via radiochemistry was carried out.

Conclusions

The synthesized CB2-selective compounds have high affinity towards CB2 and good selectivity against CB1. The introduction of labelling groups at the (hetero)aromatic moiety shows only moderate impact on CB2 affinity, indicating the introduction of potential labelling groups at this position as a promising approach to develop CB2-selective ligands suitable for molecular imaging with PET. The high affinity for human CB2 and selectivity against human CB1 of the herein presented compounds renders them as suitable candidates for molecular imaging studies.

Keywords:
Cannabinoid receptors; Molecular modelling; Autoradiography; 18F labelling; Molecular imaging; PET; Neuroimaging

Graphical abstract