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 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 G_i/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 D_7.4 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 D_7.4 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. N-(4-[¹⁸F]Fluorobenzyl)-4-(3-(piperidin-1-yl)indole-1-sulfonyl)benzamide ([¹⁸F]PipISB) is being evaluated for use as a CB1 receptor tracer (9, 10).

Synthesis

[PubMed]

Donohue et al. (10) reported the synthesis of [¹⁸F]PipISB by reaction of the carboxamide precursor with [¹⁸F]-4-fluorobenzyl bromide in dimethylformamide containing sodium hydride for 3 min at room temperature. Average radiochemical yield was 36% (n = 2) with a total synthesis time of ~115 min from the activated [¹⁸F]fluorine ion. Specific radioactivity was ~270 GBq/μmol (7.4 Ci/μmol) at the end of synthesis, with a radiochemical purity of >98%. cLog D_7.4 of PipISB was calculated to be 5.1.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

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

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

NIH Support

Intramural research program

References

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Pertwee, R.G., Pharmacological actions of cannabinoids. Handb Exp Pharmacol, 2005(168): p. 1-51. [PubMed: 16596770]

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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]

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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]

10.

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.