New PET Radioligands for Imaging of Cannabinoid Receptors Type 2 (CB2) in the Human Brain
Cannabinoid receptors are involved in many physiological mechanisms. There is evidence that cannabinoid receptors type 2 (CB2) play a central role in neurodegenerative disorders, like Alzheimer‘s or Parkinson‘s disease as well as in cancerous diseases. Thus, a therapeutic role for cannabinoid receptor ligands has been suggested for brain diseases and tumor treatment. By means of neuroimaging with positron emission tomography (PET), a better understanding of the involvement of the cannabinoid system in these diseases in living humans will be achieved. Furthermore, neuroimaging with 18F-labelled CB receptor ligands will be useful for monitoring treatment effects. Thus, radioligands selective for CB2, which are suitable for PET imaging in humans, will be developed.
Employing molecular modeling methods, data were obtained by pharmacophore/3D-QSAR studies as additional constraints, which deliver valuable information on affinity and selectivity of the compounds towards CB1 and CB2.
Docking of various compounds on the 3D-model of the human CB2 receptor. The proposed binding pocket is shown in green view with the membrane indicated by a gray area.
Among the various compound classes investigated, N-Aryl-oxadiazolyl-propionamides proved to be highly selective and orally bio-available CB2 agonists. 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 selective CB2 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.
|Autoradiogram of representative coronal sections of CD-1 mouse spleen tissue together with affinity data obtained by competetive radioligand displacement studies against [1H]CP55,940 on CHO (Chinese Hamster Ovary) cells expressing human CB2|
PET images of a female CD-1 mouse 30 min p.i. of a specific CB2 radioligand. Left: Detailed view of the abdominal region (left: PET; middle: T1-weighted MR; right: PET/MR fusion) and whole body (summed 1 h p.i.) with main organs highlighted by arrows. Right: Whole body PET and MR image of a female CD-1 mouse.
Westfälische Wilhelms-Universität, Münster, Germany
- Johns Hopkins University, Baltimore, USA
- ETH Zurich, Zurich, Switzerland
- KU Leuven, Belgium
- Gündel, D.; Deuther-Conrad, W.; Ueberham, L.; Kaur, S.; Otikova, E.; Teodoro, R.; Lai, T. H.; Clauß, O.; Scheunemann, M.; Bormans, G.; Kopka, K.; Bachmann, M.; Brust, P., Moldovan R.-P. J. Med. Chem. ASAP https://doi.org/10.1021/acs.jmedchem.2c00256
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Financial Support by
- Deutsche Forschungsgemeinschaft - DFG