Contact

Porträt Prof. Dr. Brust, Peter; FWPN

Prof. Dr. Peter Brust
Head
p.brustAthzdr.de
Phone: +49 351 260 - 4610
Fax: +49 351 260 - 4699

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 to 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 proofed 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.

CB2 Autoradiographs
​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

 

CB2 Moldovan

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.

 

Partner

  • Westfälische Wilhelms-Universität, Münster, Germany

  • Johns Hopkins University, Baltimore, USA
  • ETH Zurich, Zurich, Switzerland

Publications

  • Moldovan R, Hausmann K, Deuther-Conrad W, Brust P. Development of highly affine and selective fluorinated cannabinoid type 2 receptor ligands. ACS Med Chem Let. 2017,8, 566–571.
  • Moldovan R, Deuther-Conrad W, Horti A, Brust P. Synthesis and preliminary biological evaluation of indol-3-yl-oxoacetamides as potent cannabinoid receptor type 2 ligands. Molecules. 2017, 22, E77.
  • Moldovan R, Teodoro R, Deuther-Conrad W, Wang Y, Wenzel B, Fischer S, Pomper M, Wong DF, Dannals RF, Brust P, Horti A. [18F]JHU94620, a high affinity PET radioligand for imaging of cannabinoid subtype 2 receptors (CB2R). J Med Chem. 2016, 59, 7840-7855.
  • Donat CK, Fischer F, Walter B, Deuther-Conrad W,Bauer R, Brust P. Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet. Acta Neurbiologiae Experimentalis. 2014, 74, 197-210.
  • Teodoro R, Moldovan R, Lueg C, Günther R, Donat CK, Ludwig F-A, Fischer S, Deuther-Conrad W, Wünsch B, Brust P. Synthesis, 18F-labelling and first biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors.  Org Med Chem Lett. 2013, 3: 11, doi:10.1186/2191-2858-3-11.
  • Rühl T, Deuther-Conrad W, Fischer S, Günther R, Hennig L, Krautscheid H, 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.

Financial Support by

  • Deutsche Forschungsgemeinschaft - DFG

Contact

Prof. Dr. Peter Brust
Head
p.brustAthzdr.de
Phone: +49 351 260 - 4610
Fax: +49 351 260 - 4699