Synthesis and biological evaluation of carbon-11- and fluorine-18-labeled 2-oxoquinoline derivatives for type 2 cannabinoid receptor positron emission tomography imaging

Abstract

We synthesized two novel CB(2) receptor PET tracers that show high affinity/selectivity for CB(2) receptors. Both tracers show favourable characteristics as radioligands for central and peripheral in vivo visualization of the CB(2) receptor and are promising candidates for primate and human CB(2) PET imaging.

Non-Invasive Imaging of the Type 2 Cannabinoid Receptor, Focus on Positron Emission Tomography

“…However, these radioligands showed the highest brain uptake in mice (1.7 and 1.8 % ID at 2 minutes p.i., respectively) of the studied compounds [124].…”

“…The 2-oxoquinoline derivatives (NE40 (21) and 22) also showed CB 2 R specific binding in mouse and rat spleen [124]. However, in vivo human CB 2 R binding was demonstrated for both [ 11 C]GW405833 (9) and [ 11 C]NE40 (21) 2 .…”

“…In summary, quinoline derivative 21 seems to exhibit the most promising tracer characteristics, due to a combination of specific CB 2 R binding to mouse and rat spleen, high brain uptake and in vivo binding to human CB 2 R. The preliminary biological evaluation of 22 was also promising, however major drawbacks were a low radiochemical yield, a high bone uptake and a relatively low affinity compared to NE40 (21) [124]. The triaryl bis-sulfone, [ 11 C]Sch225336 (7c) has the highest in vitro affinity for human CB 2 R among the tested compounds, but is least selective and shows no brain uptake or in vivo spleen CB 2 R binding in mice.…”

“…We synthesized 2-oxo-7-[ 11 C]methoxy-8-butyloxy-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide (NE40, 21) and 2-oxo-7-[ 18 F]fluoroethoxy-8-butyloxy-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide (22) based on 2-oxo-7-methoxy-8-pentoxy-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide (23) (Fig. (9)) [124]. We shortened the lipophilic carbon tail from a pentoxy to a butoxy group with the aim to decrease non-specific binding related to the lipophilicity of the tracer.…”

Effects of Aerobic Exercise on Mood and Human Opioidergic Activation Measured by Positron Emission Tomography

“…is that the tracer binds to the entire opioidergic system, thus providing a rather composite view of opioidergic neurotransmission evoked by exercise challenges. As the endocannabinoid system is also of great interest in the context of exercise research (Dietrich and McDaniel 2004 ;Sparling et al 2003 ) , future applications are awaited using novel compounds that label endocannabinoid receptors (Evens et al 2009 ;Terry et al 2008 ;Van Laere et al 2008 ) . For a detailed summary of the available opioidergic tracers, we refer to a recent review article from our group (Boecker et al 2008a ) .…”