Labelling and biological evaluation of [(11)C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor.
BACKGROUND
The cannabinoid type 2 receptor (CB(2) receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[(11)C]methoxyphenyl)sulfonyl)-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([(11)C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB(2) receptors.


METHODS
Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [(11)C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [(11)C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined.


RESULTS
[(11)C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/mumol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps.


CONCLUSIONS
[(11)C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB(2) receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.
Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000, Belgium.
Nele
N
Evens
Barbara
B
Bosier
Brian J
BJ
Lavey
Joseph A
JA
Kozlowski
Peter
P
Vermaelen
Luc
L
Baudemprez
Roger
R
Busson
Didier M
DM
Lambert
Koen
K
Van Laere
Alfons M
AM
Verbruggen
Guy M
GM
Bormans
D000818:Animals; D001812:Blood-Brain Barrier; D016466:CHO Cells; D002250:Carbon Radioisotopes / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis*; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D043885:Receptor, Cannabinoid, CB2; C514445:Sch225336; D013449:Sulfonamides; D016244:Guanosine 5'-O-(3-Thiotriphosphate)