Synthesis and biological evaluation of carbon-11- and fluorine-18-labeled 2-oxoquinoline derivatives for type 2 cannabinoid receptor positron emission tomography imaging.
BACKGROUND
The type 2 cannabinoid (CB(2)) receptor is part of the endocannabinoid system and has been suggested as a mediator of several central and peripheral inflammatory processes. Imaging of the CB(2) receptor has been unsuccessful so far. We synthesized and evaluated a carbon-11- and a fluorine-18-labeled 2-oxoquinoline derivative as new PET tracers with high specificity and affinity for the CB(2) receptor.


METHODS
Two 2-oxoquinoline derivatives were synthesized and radiolabeled with either carbon-11 or fluorine-18. Their affinity and selectivity for the human CB(2) receptor were determined. Biological evaluation was done by biodistribution, radiometabolite and autoradiography studies in mice.


RESULTS
In vitro studies showed that both compounds are high affinity CB(2)-specific inverse agonists. Biodistribution study of the tracers in mice showed a high in vivo initial brain uptake and fast brain washout, in accordance with the low CB(2) receptor expression levels in normal brain. A persistently high in vivo binding to the spleen was observed, which was inhibited by pretreatment with two structurally unrelated CB(2) selective inverse agonists. In vitro autoradiography studies with the radioligands confirmed CB(2)-specific binding to the mouse spleen.


CONCLUSIONS
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.
Evens
Nele
N
Laboratory for Radiopharmacy, K.U. Leuven, 3000 Leuven, Belgium.
Muccioli
Giulio G
GG
Houbrechts
Nele
N
Lambert
Didier M
DM
Verbruggen
Alfons M
AM
Van Laere
Koen
K
Bormans
Guy M
GM
D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes / Q000737:chemistry*; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D015363:Quinolones / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013194:Staining and Labeling; D013499:Surface Properties; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2