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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
Author(s) -
Mu Linjing,
Bieri Daniel,
Slavik Roger,
Drandarov Konstantin,
Müller Adrienne,
Čermak Stjepko,
Weber Markus,
Schibli Roger,
Krämer Stefanie D.,
Ametamey Simon M.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12354
Subject(s) - in vivo , in vitro , chemistry , receptor , cannabinoid receptor agonists , amyotrophic lateral sclerosis , cannabinoid , pharmacology , microbiology and biotechnology , cannabinoid receptor , agonist , biochemistry , pathology , medicine , biology , disease
The cannabinoid type 2 (CB 2 ) 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 KD 2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB 2 . [ 11 C] KD 2 was obtained in 99% radiochemical purity. Moderate blood–brain barrier ( BBB ) passage was predicted for KD 2 from an in vitro transport assay with P‐glycoprotein‐transfected Madin Darby canine kidney cells. No efflux of KD 2 by P‐glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [ 11 C] KD 2 exhibits high specific binding towards CB 2 . High spleen uptake of [ 11 C] KD 2 was observed in dynamic positron emission tomography (PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB 2 agonist, GW 405833. A pilot autoradiography study with post‐mortem spinal cord slices from amyotrophic lateral sclerosis ( ALS ) patients with [ 11 C] KD 2 suggested the presence of CB 2 receptors under disease conditions. Specificity of [ 11 C] KD 2 binding could also be demonstrated on these human tissues. In conclusion, [ 11 C] KD 2 shows good in vitro and in vivo properties as a potential PET tracer for CB 2 .The cannabinoid type 2 receptor (CB 2 ) plays an important role in neuroinflammatory and neuro–degenerative diseases. [ 11 C]KD2, a new CB 2 radioligand, exhibits selectivity towards CB 2 receptor in vitro and in vivo in rat. A pilot autoradiography study with spinal cord slices from amyotrophic lateral sclerosis patients with [ 11 C]KD2 suggested the presence of CB 2 under disease conditions (Figure). Selective CB 2 agonist, GW405833.