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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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R-2-[131I]Iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanone

R-[131I]AM2233
, PhD
National Center for Biotechnology Information, NLM, NIH, vog.hin.mln.ibcn@dacim

Created: ; Last Update: February 12, 2008.

Chemical name:R-2-[131I]Iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanoneimage 17422992 in the ncbi pubchem database
Abbreviated name:R-[131I]AM2233
Synonym:
Agent Category:Compound
Target:Cannabinoid CB1receptors
Target Category:Receptor binding
Method of detection:SPECT, gamma planar
Source of signal:131I
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

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 peripheral tissues to inhibit neurotransmitter release. CB1 receptors are found predominantly in the striatum, hippocampus, substantia nigra, globus pallidus, and cerebellum. CB2 receptors are present mainly on immune cells to modulate cytokine release. 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 (4-6).

Δ9-Tetrahydrocannabinol (THC) is a major active cannabinoid that is found in marijuana and activates CB1 receptors (7). However, high lipophilicity is essential for binding to CB1 receptors, and moderate lipophilicity is required for crossing the blood–brain barrier (BBB). Existing radiolabeled ligands are mainly analogs of the antagonist rimonabant (SR141716A) and the agonist WIN 55,212-2; however, these ligands also exhibit high nonspecific binding, which limits their application in imaging (8). R-2-Iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanone (R-AM2233) is a potent CB agonist with ~8-fold higher affinity than WIN 55,212-2 (9). R-2-[131I]Iodophenyl-(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanone (R- [131I]AM2233) is being developed as a single photon emission computed tomography agent for the noninvasive study of CB1 receptors in the brain (9, 10).

Synthesis

[PubMed]

Deng et al. (9) reported synthesis of R-[131I]AM2233 by radioiododestannylation of the tributyltin precursor R-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]-2-(tributylstannylphenyl)methanone with 131I-labeled iodide in the presence of HCl and chloramine-T. Radiochemical yields were 62% after high-performance liquid chromatography purification. Specific activities were >18.5 GBq/μmol (>0.5 Ci/μmol) with a radiochemical purity of >97%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Deng et al. (9) reported R/S-AM2233 had an inhibitory constant (Ki) value of 2.8 nM for CB1 receptors in rat forebrain membranes and a Ki value of 2.9 nM for CB2 receptors in mouse spleen membranes. The R-enantiomer is 300-fold more potent than the S-enantiomer. R/S-AM2233 and WIN 55,212-2 exhibited Ki values of 0.2 and 1.6 nM in displacing R-[131I]AM2233 in mouse hippocampus membranes. R/S-AM2233 and WIN 55,212-2 exhibited Ki values of 1.3 and 20 nM in displacing [3H]SR141716 in mouse hippocampus membranes. Therefore, R/S-AM2233 is 8- to 15-fold more potent than WIN 55,212-2. In vitro autoradiography of mouse brain sections showed that R-[131I]AM2233 gave images consistent with binding to brain CB1 receptor-rich areas, including the globus pallidus, substantia nigra, striatum, cerebellum, and hippocampus. Binding of S-[131I]AM2233 in these brain sections was much reduced compared with that of R/S-[131I]AM2233. Selective binding of R-[131I]AM2233 was not detected in sections prepared from a CB1 receptor knockout mouse, confirming that in vitro binding was caused by CB1 receptors.

Animal Studies

Rodents

[PubMed]

Dhawan et al. (10) showed there was a low uptake of radioactivity in the mouse whole brain after injection of R-[131I]AM2233, reaching a peak value of 1.3% injected dose per gram (% ID/g) at 5 min and declining to 0.6% ID/g at 30 min. The hippocampus exhibited higher uptake than the cerebellum, brain stem, and whole brain. Co-injection of 3 mg/kg of SR141716A with R-[131I]AM2233 reduced the radioactivity to nonspecific levels in the striatum, globus pallidus, and substantia nigra. However, the hippocampus exhibited only 69% reduction because of tentative binding to non-CB1 receptors in the region. Co-injection of 10 mg/Kg WIN 55,212-2 reduced R-[131I]AM2233 specific binding in CB1 receptor-rich areas by only 21–43%. Ex vivo autoradiography of rat brain showed the high levels of radioactivity in the substantia nigra, globus pallidus, hippocampus, and cerebellum, followed by the cortex, striatum, and thalamus at 15–30 min after R-[131I]AM2233 injection, consistent with the CB1 distribution in the brain.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

DA-112-01, DA-3801, DA-12412, DA-3801, DA-9158

References

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Howlett A.C. , Barth F. , Bonner T.I. , Cabral G. , Casellas P. , Devane W.A. , Felder C.C. , Herkenham M. , Mackie K. , Martin B.R. , Mechoulam R. , Pertwee R.G. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161–202. [PubMed: 12037135]
2.
Pertwee R.G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74(2):129–80. [PubMed: 9336020]
3.
Pertwee R.G. Pharmacological actions of cannabinoids. Handb Exp Pharmacol, (168): p. 1-51. 2005 [PubMed: 16596770]
4.
Gambi F. , De Berardis D. , Sepede G. , Quartesan R. , Calcagni E. , Salerno R.M. , Conti C.M. , Ferro F.M. Cannabinoid receptors and their relationships with neuropsychiatric disorders. Int J Immunopathol Pharmacol. 2005;18(1):15–9. [PubMed: 15698507]
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De Vries T.J. , Schoffelmeer A.N. Cannabinoid CB1 receptors control conditioned drug seeking. Trends Pharmacol Sci. 2005;26(8):420–6. [PubMed: 15992935]
6.
Guzman M. , Sanchez C. Effects of cannabinoids on energy metabolism. Life Sci. 1999;65(6-7):657–64. [PubMed: 10462066]
7.
Martin B.R. Cellular effects of cannabinoids. Pharmacol Rev. 1986;38(1):45–74. [PubMed: 2872689]
8.
Gifford A.N. , Makriyannis A. , Volkow N.D. , Gatley S.J. In vivo imaging of the brain cannabinoid receptor. Chem Phys Lipids. 2002;121(1-2):65–72. [PubMed: 12505691]
9.
Deng H. , Gifford A.N. , Zvonok A.M. , Cui G. , Li X. , Fan P. , Deschamps J.R. , Flippen-Anderson J.L. , Gatley S.J. , Makriyannis A. Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor. J Med Chem. 2005;48(20):6386–92. [PubMed: 16190764]
10.
Dhawan J. , Deng H. , Gatley S.J. , Makriyannis A. , Akinfeleye T. , Bruneus M. , Dimaio A.A. , Gifford A.N. Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233. Synapse. 2006;60(2):93–101. [PubMed: 16715483]

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