Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2

The cannabinoid receptor type 2 (CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [F-18]RS-126 was obtained in 99% radiochemical purity with an average specific radioactivity of 98 GBq/mol at the end of the radiosynthesis. [F-18]RS-126 showed a logD(7.4) value of 1.99 and is stable invitro in rat and human plasma over 120min, whereas 55% intact parent compound was found invivo in rat blood plasma at 10min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in invivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [F-18]RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [F-18]RS-126 using PET imaging. In summary, [F-18]RS-126 demonstrated high specificity toward CB2 receptor invitro and invivo and is a promising radioligand for imaging CB2 receptor expression. hic> Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [F-18]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in invivo displacement experiments with rats. Time activity curve of [F-18]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).