Labelling and biological evaluation of [11C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor

Evens, Nele; Bosier, Barbara; Lavey, Brian J.; Kozlowski, Joseph A.; Vermaelen, Peter; Baudemprez, Luc; Busson, Roger; Lambert, Didier M.; Van Laere, Koen; Verbruggen, Alfons M.; Bormans, Guy M.

doi:10.1016/j.nucmedbio.2008.07.004

« Previous Next »Nuclear Medicine and Biology
Volume 35, Issue 7 , Pages 793-800, October 2008

Labelling and biological evaluation of [¹¹C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor

Nele Evens
- Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000, Belgium
Barbara Bosier
- Department of Pharmaceutical Chemistry and Radiopharmacy, U.C.L., Brussels 1200, Belgium
Brian J. Lavey
- Schering Plough Research Institute, Kenilworth, NJ 07033, USA
Joseph A. Kozlowski
- Schering Plough Research Institute, Kenilworth, NJ 07033, USA
Peter Vermaelen
- Division of Nuclear Medicine, K.U.Leuven, Leuven 3000, Belgium
Luc Baudemprez
- Laboratory of Medicinal Chemistry, K.U.Leuven, Leuven 3000, Belgium
Roger Busson
- Laboratory of Medicinal Chemistry, K.U.Leuven, Leuven 3000, Belgium
Didier M. Lambert
- Department of Pharmaceutical Chemistry and Radiopharmacy, U.C.L., Brussels 1200, Belgium
Koen Van Laere
- Division of Nuclear Medicine, K.U.Leuven, Leuven 3000, Belgium
Alfons M. Verbruggen
- Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000, Belgium
Guy M. Bormans
- Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000, Belgium
- Corresponding author. Onderwijs & Navorsing 2, Herestraat 49, bus 821, BE-3000 Leuven, Belgium. Tel.: +32 16 330447; fax: +32 16 330449.

Received 4 June 2008; received in revised form 3 July 2008; accepted 10 July 2008.

Abstract

Introduction

The cannabinoid type 2 receptor (CB₂ 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-[¹¹C]methoxyphenyl)sulfonyl)-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([¹¹C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB₂ receptors.

Methods

Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [¹¹C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [¹¹C]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

[¹¹C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/μmol (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.

Conclusion

[¹¹C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB₂ receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.

Keywords: Cannabinoids, CB₂ receptor, PET, Carbon-11, Sch225336