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N-[(1s)-1-[4-[[4-methoxy-2-[(4-[11C]methoxyphenyl)sulfonyl]-phenyl]sulfonyl]phenyl]ethyl]methanesulfonamide

[11C]Methoxy-Sch225336
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: June 3, 2010.

Chemical name:N-[(1s)-1-[4-[[4-methoxy-2-[(4-[11C]methoxyphenyl)sulfonyl]-phenyl]sulfonyl]phenyl]ethyl]methanesulfonamide
image 92764974 in the ncbi pubchem database
Abbreviated name:[11C]Methoxy-Sch225336
Synonym:
Agent Category:Compound
Target:Cannabinoid
Target Category:Cannabinoid CB2 receptor (CB2R)
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structure of [11C]methoxy-Sch225336. Click on the above structure for additional information in PubChem.

Background

[PubMed]

There are two known sub-types of the G-protein–coupled cannabinoid receptors, CB1R and CB2R, and they are believed to participate in many physiological processes such as neurotransmission, energy homeostasis, and the control of immune cell function (1). The CB1R are found primarily in the brain, whereas the CB2R are expressed predominantly on immune cells (2). However, the CB2R were shown recently to be expressed on brain neurons as well and were reported to have a role in the development of conditions such as drug abuse and depression (3). The modulation of CB2R expression has been reported in astrocytic tumors, atherosclerotic and amyloid plaques, and demyelination plaques observed in multiple sclerosis (4). A variety of CB2R antagonists and agonists are commercially available, and some agonists have been shown to induce apoptosis in various tumor cell types and are used to treat pain and inflammation observed during neuropathy, cancer, multiple sclerosis, etc (5). In addition, some agonists have been used for the management of depression, attention-deficit hyperactivity, and anxiety disorders (5).

A few tritiated ligands have been used to investigate the CB2R under in vitro conditions; however, due to low specific activity and a lack of receptor selectivity, these radioligands are not considered entirely suitable to study CB1R and CB2R (4). Recently, the 35S-labeled compound [35S]Sch225336 (N-[(1s)-1-[4-[[4-methoxy-2-[(4-[35S]methoxyphenyl)sulfonyl]-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide), with a high specific activity, was shown to specifically bind and act as a reverse agonist for the human CB2R (hCB2R) in in vitro binding studies (6). A near-infrared (NIR)–labeled dye that specifically bound to the CB2R was developed by Bai et al. for in vitro fluorescence imaging of the receptor (7). In addition, several clinical trials approved by the United States Food and Drug Administration are in progress to evaluate the use of positron emission tomography (PET) for the imaging of CB1R. Because no suitable radiolabeled ligand is available for the noninvasive study and investigation of the CB2R, the 11C-labeled compound [11C]methoxy-Sch225336 was synthesized and evaluated by Evens et al. (4) in miceas a potential PET imaging agent.

Other Sources of Information

Cannabinoid receptors in Online Mendelian Inheritance in Man (OMIM) database

Protein and mRNA reference sequences of human brain CB1R (GeneID: 1268)

Protein and mRNA reference sequences of mouse macrophage CB2R (GeneID: 12802)

Human brain CB1R in Genetic Association Database

Clinical trials with unlabeled cannabinoid receptor agonists.

Synthesis

[PubMed]

The synthesis and 11C-labeling of methoxy-Sch225336 was performed as described by Evens et al. (4). The radiochemical yield was reported to be ~35% with a purity of >99% (confirmed by co-elution with an authentic non-radioactive reference with high-performance liquid chromatography (HPLC)). The average specific activity of the labeled compound, from five labeling reactions, was 88.8 GBq/μmol (2.4 Ci/μmol) at the end of synthesis, but the total time required for the synthesis was not reported (4).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In a study to determine the partitioning coefficient of [11C]methoxy-Sch225336 with 1-octanol and 0.025 M phosphate buffer (pH 7.4), the log P value of the radiochemical was reported to be 2.15 (4).

In a competition binding assay using Chinese hamster ovary cells transfected with hCB1R or hCB2R with either [3H]-SR141716A or [3H]-CP55940 as radioligands, the affinity of Sch225336 was determined to be 78.5 ± 10.4 nM for hCB1R and 4.54 ± 0.48 nM for hCB2R (4). In another study using the [35S]-GTPγS assay, Sch225336 was shown to be a potential inverse agonist of hCB2R (see Milligan et al. (8) to read more about inverse agonists) (4).

Animal Studies

Rodents

[PubMed]

Evens et al. studied the biodistribution of [11C]methoxy-Sch225336 in normal National Murine Research Institute mice (4). The animals (n = 4 mice per time point) were injected with the radiochemical through the tail vein, and the mice were euthanized at 2 min and 60 min postinjection (p.i.). Subsequently, the major organs and tissues were removed from the animals and weighed to determine the amount of accumulated radioactivity. Data obtained from this study were presented as percent of injected dose per gram tissue (% ID/g). Little radioactivity was found to have accumulated in most organs except the liver (51.5 ± 9.1 and 10.8 ± 1.7% ID/g at 2 min and 60 min p.i., respectively) and the intestines (12.6 ± 3.0 and 71.2 ± 6.9% ID/g at 2 min and 60 min p.i., respectively). Although a high accumulation of radioactivity (8.0 ± 1.0% ID/g) was noticed in the kidneys at 2 min p.i., the level reduced to 1.1 ± 0.3% ID/g by 60 min p.i., indicating that the radioactivity was not excreted through the urine but was cleared primarily through the hepatobiliary route. Very low amounts of label were detected in the brain at both time points (0.1 ± 0.0% ID/g both at 2 min and 60 min p.i.).

The percentage of intact [11C]methoxy-Sch225336 in the plasma of animals at 2, 10, and 30 min p.i. was reported to be 93, 63, and 60%, respectively as determined with reverse-phase HPLC (4). From these results the investigators concluded that the radiolabeled compound was rapidly metabolized during circulation in the animals.

From these studies, the investigators concluded that, because a very low amount of [11C]methoxy-Sch225336 accumulated in the mouse brain, this radioligand is useful only to investigate the peripheral tissue CB2R (e. g. spleen, Peyer’s patches and bone marrow etc.) in these animals (4). Also, because it was metabolized rapidly in the plasma, [11C]methoxy-Sch225336 can be used only for short durations under in vivo conditions to study the peripheral CB2R.

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

No references are currently available.

References

1.
Graham E.S., Ashton J.C., Glass M. Cannabinoid receptors: a brief history and "what's hot". Front Biosci. 2009;14:944–57. [PubMed: 19273110]
2.
Takano A. The application of PET technique for the development and evaluation of novel antipsychotics. Curr Pharm Des. 2010;16(3):371–7. [PubMed: 20109145]
3.
Onaivi, E.S., H. Ishiguro, J.P. Gong, S. Patel, P.A. Meozzi, L. Myers, A. Perchuk, Z. Mora, P.A. Tagliaferro, E. Gardner, A. Brusco, B.E. Akinshola, B. Hope, J. Lujilde, T. Inada, S. Iwasaki, D. Macharia, L. Teasenfitz, T. Arinami, and G.R. Uhl, Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS One, 20083(2): p. e1640. [PMC free article: PMC2241668] [PubMed: 18286196]
4.
Evens N., Bosier B., Lavey B.J., Kozlowski J.A., Vermaelen P., Baudemprez L., Busson R., Lambert D.M., Van Laere K., Verbruggen A.M., Bormans G.M. Labelling and biological evaluation of [(11)C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor. Nucl Med Biol. 2008;35(7):793–800. [PubMed: 18848664]
5.
Pertwee R.G. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol. 2009;156(3):397–411. [PMC free article: PMC2697681] [PubMed: 19226257]
6.
Gonsiorek W., Hesk D., Chen S.C., Kinsley D., Fine J.S., Jackson J.V., Bober L.A., Deno G., Bian H., Fossetta J., Lunn C.A., Kozlowski J.A., Lavey B., Piwinski J., Narula S.K., Lundell D.J., Hipkin R.W. Characterization of peripheral human cannabinoid receptor (hCB2) expression and pharmacology using a novel radioligand, [35S]Sch225336. J Biol Chem. 2006;281(38):28143–51. [PubMed: 16754676]
7.
Bai M., Sexton M., Stella N., Bornhop D.J. MBC94, a conjugable ligand for cannabinoid CB 2 receptor imaging. Bioconjug Chem. 2008;19(5):988–92. [PMC free article: PMC4180707] [PubMed: 18444670]
8.
Milligan G. Constitutive activity and inverse agonists of G protein-coupled receptors: a current perspective. Mol Pharmacol. 2003;64(6):1271–6. [PubMed: 14645655]
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