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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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

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, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
, PhD
ICF International, 9300 Lee Highway, Fairfax, VA 22031

Created: ; Last Update: October 28, 2010.

Chemical name:[Carbonyl-11C]-N-(4-fluorobenzyl)-4-(3-(piperidin-1-yl)indole-1-sulfonyl)benzamideimage 99376140 in the ncbi pubchem database
Abbreviated name:[11C]PipISB
Agent category:Compound
Target:Cannabinoid CB1 receptors
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:11C
  • Checkbox In vitro
  • Checkbox Non-human primates
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 and in some 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). 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. 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 inverse agonist 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. [Carbonyl-11C]-N-(4-fluorobenzyl)-4-(3-(piperidin-1-yl)indole-1-sulfonyl)benzamide ([11C]PipISB) is being evaluated for use as a CB1 receptor tracer (9, 10).



Donohue et al. (10) reported the synthesis of [11C]PipISB by reaction of 1-(4-iodo-benzenesulfonyl)-3-piperidin-1-yl-1H-indole and 4-fluorobenzylamine with [11C]CO in tetrahydrofuran containing tetrakis(triphenylphosphine) for 5 min at 150°C. Radiochemical yields were 3.1%–11.6% (decay-corrected) with a total synthesis time of ~44 min. Specific radioactivities were 21–67 GBq/μmol (0.57–1.81 Ci/μmol) at the end of synthesis with a radiochemical purity of >98%. cLog D7.4 of PipISB was calculated to be 5.1.

In Vitro Studies: Testing in Cells and Tissues


Donohue et al. (10) reported that PipISB inhibited functional [γ-35S]GTP binding at the human recombinant CB1 receptors with high potency (Kb = 1.5 nM). PipISB was significantly less potent at the human recombinant CB2 receptors (Kb > 7,000 nM).

Animal Studies



No publication is currently available.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


Finnema et al. (9) performed positron emission tomography imaging in two rhesus monkeys after injection of 141–191 MBq (3.8–5.2 mCi) [11C]PipISB (~0.28 nmol/kg). The radioactivity in the striatum and cerebellum exhibited ~120% standardized uptake value (SUV) at 25 min and increased to 150%–160% SUV at 120 min after injection. The thalamus and cortex showed moderate radioactivity (~140% SUV), whereas the pons showed the lowest radioactivity (~100% SUV) at 120 min after injection. Pretreatment with intravenous rimonabant (1.0 mg/kg) 20 min before tracer injection reduced the radioactivity of all brain regions to ~65% SUV at 120 min after injection. Administration of rimonabant at 100 min after tracer injection displaced the radioactivity from all brain regions to 70%–80% SUV at 180 min after tracer injection. [11C]PipISB was quickly metabolized with 20% intact in the plasma at 60 min after injection. Two less lipophilic radiometabolites were detected.

Human Studies


No publication is currently available.

NIH Support

Intramural research program


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]
Pertwee R.G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74(2):129–80. [PubMed: 9336020]
Pertwee, R.G., Pharmacological actions of cannabinoids. Handb Exp Pharmacol, 2005(168): p. 1-51. [PubMed: 16596770]
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]
De Vries T.J., Schoffelmeer A.N. Cannabinoid CB1 receptors control conditioned drug seeking. Trends Pharmacol Sci. 2005;26(8):420–6. [PubMed: 15992935]
Guzman M., Sanchez C. Effects of cannabinoids on energy metabolism. Life Sci. 1999;65(6-7):657–64. [PubMed: 10462066]
Martin B.R. Cellular effects of cannabinoids. Pharmacol Rev. 1986;38(1):45–74. [PubMed: 2872689]
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]
Finnema S.J., Donohue S.R., Zoghbi S.S., Brown A.K., Gulyas B., Innis R.B., Halldin C., Pike V.W. Evaluation of [11C]PipISB and [18F]PipISB in monkey as candidate radioligands for imaging brain cannabinoid type-1 receptors in vivo. Synapse. 2009;63(1):22–30. [PMC free article: PMC2587077] [PubMed: 18925657]
Donohue S.R., Halldin C., Schou M., Hong J., Phebus L., Chernet E., Hitchcock S.A., Gardinier K.M., Ruley K.M., Krushinski J.H., Schaus J.M., Pike V.W. Radiolabeling of a high affinity cannabinoid subtype-1 receptor inverse agonist, N-(4-fluoro-benzyl)-4-(3-(piperidin-1-yl-indole-1-sulfonyl)benzamide (PipISB), with carbon-11 or fluorine-18. J Label Compd Radiopharm. 2009;51:146–152.

This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.

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