Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor
Article first published online: 19 JUL 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 126, Issue 5, pages 616–624, September 2013
How to Cite
J. Neurochem. (2013) 126, 616–624.
- Issue published online: 23 AUG 2013
- Article first published online: 19 JUL 2013
- Accepted manuscript online: 24 JUN 2013 07:03AM EST
- Manuscript Accepted: 19 JUN 2013
- Manuscript Revised: 12 JUN 2013
- Manuscript Received: 14 MAY 2013
- Swiss ALS Foundation
- cannabinoid receptor type 2 ligand;
- small-animal PET
The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline derivative (designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochemical purity. Moderate blood–brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was observed in dynamic positron emission tomography (PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiography study with post-mortem spinal cord slices from amyotrophic lateral sclerosis (ALS) patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2.
The cannabinoid type 2 receptor (CB2) plays an important role in neuroinflammatory and neuro–degenerative diseases. [11C]KD2, a new CB2 radioligand, exhibits selectivity towards CB2 receptor in vitro and in vivo in rat. A pilot autoradiography study with spinal cord slices from amyotrophic lateral sclerosis patients with [11C]KD2 suggested the presence of CB2 under disease conditions (Figure). Selective CB2 agonist, GW405833.