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2,2,3,3-Tetramethylcyclopropanecarboxylic acid [3-(2-[11C]methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amide

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: January 27, 2011.

Chemical name:2,2,3,3-Tetramethylcyclopropanecarboxylic acid [3-(2-[11C]methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amideimage 104144353 in the ncbi pubchem database
Abbreviated name:[11C]A-836339
Agent category:Compound
Target:Cannabinoid CB2 receptors
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:11C
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.



There are two subtypes of cannabinoid receptors in mammalian tissues: CB1 and CB2 (1, 2). CB1 receptors are expressed abundantly in neuronal terminals in the central nervous system (CNS) and in some peripheral tissues to inhibit neurotransmitter release. CB1 receptors are found predominately in the striatum, hippocampus, substantia nigra, globus pallidus, and cerebellum. CB2 receptors are present mainly on immune cells in the blood and peripheral tissues (the spleen) to modulate cytokine release (3). However, CB2 receptors have been found in the CNS tissues (neurons and glial cells) at very low levels (4). Both receptor subtypes are coupled through Gi/o proteins to inhibit adenylate cyclase and to modulate potassium and calcium channels. CB1 receptors have been demonstrated to be involved in analgesia, regulation of food intake, and control of movement in normal subjects (3). Alteration of CB1 receptor function has been implicated in a number of human diseases such as depression, schizophrenia, and obesity (5-7). Upregulation of CB2 receptors in the brain is associated with neuroinflammation in disorders such as Alzheimer’s disease (AD), multiple sclerosis, encephalitis, and Down’s syndrome (8). CB2 receptors are also involved in inflammation associated with pain, osteoporosis, cancer, and liver diseases (9).

Δ9-Tetrahydrocannabinol (THC) is a major active cannabinoid found in marijuana, and it activates CB1 receptors (10). Various radioligands have been developed for imaging of CB1 receptors (11). However, only a few CB2 radioligands have been evaluated in animals as potential positron emission tomography (12) tracers (13-17). 2,2,3,3-Tetramethylcyclopropanecarboxylic acid [3-(2-[11C]methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amide ([11C]A-836339) has been evaluated for use as a CB2 radioligand for brain imaging of neuroinflammation and AD (18). A-836339 is a selective CB2 agonist with high binding (inhibition constant (Ki), 0.64 nM) (19).



Horti et al. (18) reported the synthesis of [11C]A-836339 by reaction of the O-desmethyl precursor with [11C]methyl triflate for 5 min in the presence of potassium hydroxide in dimethylformamide. The average radiochemical yield was 26 ± 2% (non–decay-corrected) at the end of synthesis (EOS), with a total synthesis time of 40 min from the end of bombardment. Specific radioactivity was 304 ± 62 GBq/μmol (8.2 ± 1.7 Ci/μmol; n = 7) at EOS with a radiochemical purity of >99% after purification.

In Vitro Studies: Testing in Cells and Tissues


Yao et al. (19) reported that A-836339 had Ki values of 0.64 nM and 270 nM for human CB2 and CB1, respectively. A-836339 exhibited Ki values of 0.76 nM and 143 nM for rat CB2 and CB1, respectively.

Animal Studies



Horti et al. (18) performed ex vivo biodistribution studies of [11C]A-836339 in normal mice (n = 3/group) at 30, 60, and 90 min after injection. The brain accumulation of radioactivity (0.3% injected dose/gram (ID/g)) at 30 min after injection was lower than that of the liver (4.9% ID/g), kidney (2.2% ID/g), intestine (1.5% ID/g), spleen (1.3% ID/g), and heart (0.7% ID/g). The selective CB2 antagonist AM630 (3 mg/kg, intravenous) significantly (P < 0.05) blocked radioactivity in the spleen when administered 30 min before injection of [11C]A-836339 in mice but had little effect on the binding in all other organs including the brain. Mice treated with lipopolysaccharide (LPS) for 5 days exhibited increased accumulation of [11C]A-836339 in the brainstem (+110%), hippocampus (+90%), cerebellum (+80%), and cortex (+70%) as compared with the control mice (P < 0.05). AM630 significantly (P < 0.05) reduced binding in the brainstem and hippocampus in the LPS-treated mice. Blocking experiments with AM630 showed little effect on the accumulation in the whole brain in control mice, whereas binding was reduced by 78% (P < 0.05) in the whole brain of LPS-treated mice.

PET imaging showed that the radioactivity in the whole brain of LPS-treated mice peaked (standard uptake value (SUV) = 2.3) at 3 min after [11C]A-836339 injection with washout. The cerebral SUV of the control mice was 0.5 at 3 min after injection with little washout. In a mouse model of AD (APPswe/PS1dE9 bigenic mice), [11C]A-836339 showed 29%–36% specific binding (AM630 blocking) in the cerebellum, brainstem, and cortex. The authors concluded that there is a need to develop tracers for CB2 PET imaging with lower lipophilicity and greater specific binding than [11C]A-836339.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.

NIH Support



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Yao B.B., Hsieh G., Daza A.V., Fan Y., Grayson G.K., Garrison T.R., El Kouhen O., Hooker B.A., Pai M., Wensink E.J., Salyers A.K., Chandran P., Zhu C.Z., Zhong C., Ryther K., Gallagher M.E., Chin C.L., Tovcimak A.E., Hradil V.P., Fox G.B., Dart M.J., Honore P., Meyer M.D. Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging. J Pharmacol Exp Ther. 2009;328(1):141–51. [PubMed: 18931146]
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