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Eur J Med Chem. 2015 Mar 6;92:554-64. doi: 10.1016/j.ejmech.2015.01.028. Epub 2015 Jan 13.

Synthesis, radiolabeling and evaluation of novel 4-oxo-quinoline derivatives as PET tracers for imaging cannabinoid type 2 receptor.

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Institute of Pharmaceutical Sciences, ETH Zürich, 8093, Zürich, Switzerland.
Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.
Institute of Pharmaceutical Sciences, ETH Zürich, 8093, Zürich, Switzerland. Electronic address:
Department of Nuclear Medicine, University Hospital Zürich, 8091, Zürich, Switzerland. Electronic address:


Our goal is to develop a highly specific and selective PET brain tracer for imaging CB2 expression in patients with neuroinflammatory diseases. Based on our previous findings on a carbon-11 labeled 4-oxo-quinoline structure, designated KD2, further structural optimizations were performed, which led to the discovery of N-(1-adamantyl)-1-(2-ethoxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-016). Compared to KD2, RS-016 exhibits a higher binding affinity towards CB2 (Ki = 0.7 nM) with a selectivity over CB1 of >10,000 and lower lipophilicity (logD7.4 = 2.78). [(11)C]RS-016 was obtained in ≥99% radiochemical purity and up to 850GBq/μmol specific radioactivity at the end of synthesis. In vitro autoradiography on rodent spleen tissue showed high specific binding to CB2. [(11)C]RS-016 was stable in vitro in rodent and human plasma over 40 min, whereas 47% intact compound was found in vivo in rat blood plasma 20 min post injection (p.i.). High specific binding to CB2 was observed in murine spleen tissues and postmortem ALS patient spinal cord tissues in vitro autoradiography, ex vivo biodistribution data confirmed the high and specific uptake of [(11)C]RS-016 in spleen region in rats. In vivo specificity of [(11)C]RS-016 could also be shown in brain by PET imaging using a murine neuroinflammation model, which has higher CB2 receptor expression level in the brain induced by lipopolysaccharide (LPS) application.


Autoradiography; Cannabinoid receptor type 2; Neuroinflammation; Positron emission tomography; Radiolabeling

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