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J. Biol. Chem., Vol. 281, Issue 38, 28143-28151, September 22, 2006

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Characterization of Peripheral Human Cannabinoid Receptor (hCB2) Expression and Pharmacology Using a Novel Radioligand, [³⁵S]Sch225336^*

Waldemar Gonsiorek, David Hesk, Shu-Cheng Chen, David Kinsley, Jay S. Fine, James V. Jackson, Loretta A. Bober, Gregory Deno, Hong Bian, James Fossetta, Charles A. Lunn^¶, Joseph A. Kozlowski^||, Brian Lavey^||, John Piwinski^||, Satwant K. Narula, Daniel J. Lundell, and R. William Hipkin¹

From the Departments of Inflammation, Radiochemistry, ^||Chemistry, and ^¶High Throughput Screening, Schering-Plough Research Institute, Kenilworth, New Jersey 07033

Studies to characterize the endogenous expression and pharmacology of peripheral human cannabinoid receptor (hCB2) have been hampered by the dearth of authentic anti-hCB2 antibodies and the lack of radioligands with CB2 selectivity. We recently described a novel CB2 inverse agonist, N-[1(S)-[4-[[4-methoxy-2-[(4methoxyphenyl)sulfonyl] phenyl]sulfonyl] phenyl]ethyl]methane-sulfonamide (Sch225336), that binds hCB2 with high affinity and excellent selectivity versus hCB1. The precursor primary amine of Sch225336 was prepared and reacted directly with [³⁵S]mesyl chloride (synthesized from commercially obtained [³⁵S]methane sulfonic acid) to generate [³⁵S]Sch225336. [³⁵S]Sch225336 has high specific activity (>1400 Ci/mmol) and affinity for hCB2 (65 pM). Using [³⁵S]Sch225336, we assayed hemopoietic cells and cell lines to quantitate the expression and pharmacology of hCB2. Lastly, we used [³⁵S]Sch225336 for detailed autoradiographic analysis of CB2 in lymphoid tissues. Based on these data, we conclude that [³⁵S]Sch225336 represents a unique radioligand for the study of CB2 endogenously expressed in blood cells and tissues.

Received for publication, March 13, 2006 , and in revised form, May 25, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Inflammation, K15 E332C-3945, Schering-Plough Research Inst., Kenilworth, NJ 07033. Tel.: 908-740-3080; Fax: 908-740-3083; E-mail: william.hipkin{at}spcorp.com.

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