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

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(-)-3-(4-Chlorophenyl)-N'-[(4-[11C]cyanophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

[11C]CB1-(-)-12a
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: January 2, 2009.

Chemical name:(-)-3-(4-Chlorophenyl)-N'-[(4-[11C]cyanophenyl)sulfonyl]-4-phenyl- 4,5-dihydro-1H-pyrazole-1-carboxamidineimage 56431712 in the ncbi pubchem database
Abbreviated name:[11C]CB1-(-)-12a
Synonym:
Agent category:Compound
Target:Cannabinoid CB1 receptors
Target category:Receptor
Method of detection:PET
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Non-human primates
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 some peripheral tissues to inhibit neurotransmitter release. CB1 receptors are found predominantly in the striatum, hippocampus, substantia nigra, globus pallidus, and cerebellum. The 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). THC has a very high lipophilicity (log D7.4 value of 7), which causes imaging studies using radiolabeled THC to be unsuccessful because of slow entry into the brain and high nonspecific binding in the brain. However, a high lipophilicity is essential for binding to CB1 receptors, and an optimal lipophilicity (log D7.4 1–4) 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, which also exhibit high nonspecific binding and lipophilicity, limiting their application in imaging (8). Therefore, there is a need to lower the lipophilicity of the CB1 radioligands with little effect on binding affinity and ability to cross the BBB. (-)-3-(4-chlorophenyl)-N'-[(4-[11C]cyanophenyl)sulfonyl]-4-phenyl- 4,5-dihydro-1H-pyrazole-1-carboxamidine ([11C]CB1-(-)-12a) is a potent and selective CB1 antagonist with nanomolar affinity and lower lipophilicity than SR141716A (9). [11C]CB1-(-)-12a is being developed as a positron emission tomography (PET) agent for the non-invasive study of CB1 receptors in the brain.

Synthesis

[PubMed]

Donohue et al. (9) reported synthesis of [11C]CB1-(+/-)-12a by reaction of the bromo precursor (-)-3-(4-chlorophenyl)-N'-[(4-bromophenyl)sulfonyl]-4-phenyl- 4,5-dihydro-1H-pyrazole-1-carboxamidine with [11C]HCN in DMSO in the presence of KOH, Pd(PPh3)4 and K2.2.2 at 135°C for 5 min. An average radiochemical yield was 36% with a total synthesis time of 30 min after purification by high-performance liquid chromatography. The specific activity was 56 GBq/μmol (1.51 Ci/μmol; n = 2) at the end of synthesis with a radiochemical purity of >97%. Using NaHCO3 instead of KOH gave [11C]CB1-(-)-12a to [11C]CB1-(+)-12a in a 9:1 ratio. Using the (+)-iodo precursor and KH2PO4 gave [11C]CB1-(+)-12a to [11C]CB1-(-)-12a in a 9.7: 0.3 ratio. [11C]CB1-(+)-12a and [11C]CB1-(-)-12a were obtained in >94% chiral purity.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Donohue et al. (9) reported that CB1-(-)-12a had inhibition constant (Ki) values of 0.5 ± 0.1 nM for CB1 and >5,000 nM for CB2. [11C]CB1-(+)-12a showed Ki values of 16.9 ± 2.0 nM for CB1 and >5,000 nM for CB2. Each enantiomer exhibited a Clog D7.4 (lipophilicity) value of 3.85.

Animal Studies

Rodents

[PubMed]

No publication is currently available.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Donohue et al. (9) performed a biodistribution PET study in two anesthetized cynomolgus monkeys injected with [11C]CB1-(+/-)-12a, which showed a rapid accumulation of radioactivity in the brain. Selective maximal uptake was observed in the striatum, followed by the cortex, cerebellum, thalamus and pons. The thalamus and pons exhibited lower binding than the other brain regions. The peak level of 220% standardized uptake value (SUV) was reached in the striatum at 30 min after injection and decreased to 180% SUV at 90 min. The lowest peak accumulation was in the pons with 150% SUV at 30 min and 124% SUV at 90 min. Administration of a high potency cannabinoid subtype-1 receptor ligand, N-(4-fluoro-benzyl)-4-(3-(piperidin-1-yl)-indole-1-sulfonyl)benzamide (PipISB), 20 min before or 25 min after tracer injection reduced the radioactivity in the brain to homogeneity with 85% SUV and 95% SUV at 90 min, respectively. Injection of the higher affinity enantiomer [11C]CB1-(-)-12a exhibited a similar accumulation pattern in the brain as [11C]CB1-(+/-)-12a. On the other hand, injection of the lower affinity enantiomer [11C]CB1-(+)-12a showed the peak brain accumulation was 280% SUV at 1.5 min and decreased to 95% SUV at 90 min after injection.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

Intramural research program

References

1.
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, 2005(168): p. 1-51. [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]
5.
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.
Donohue S.R., Pike V.W., Finnema S.J., Truong P., Andersson J., Gulyas B., Halldin C. Discovery and labeling of high-affinity 3,4-diarylpyrazolines as candidate radioligands for in vivo imaging of cannabinoid subtype-1 (CB1) receptors. J Med Chem. 2008;51(18):5608–16. [PMC free article: PMC4182912] [PubMed: 18754613]
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