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 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 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). Alternation 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 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 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 (3R, 5R). -3-((R)-1-(4-Fluorophenyl)ethylamino)-5-(3-[¹¹C]methoxyphenyl)-1-(4-trifluoromethylphenyl)pyrrolidin-2-one trifluoromethyl-phenyl)-pyrrolidin-2-one ([¹¹C]FMePPEP) is being evaluated for use as a CB1 tracer (9, 10).

Synthesis

[PubMed]

Donohue et al. (9) reported the synthesis of [¹¹C]FMePPEP by reaction of the O-desmethyl precursor with [¹¹C]iodomethane for 5 min in presence of tetrabutylammonium hydroxide in dimethylformamide. An average radiochemical yield was 16.5% (decay-corrected) with a total synthesis time of ~40 min. Specific activity was >261 GBq/μmol (7.1 Ci/μmol) at end of synthesis with a radiochemical purity of >95%. cLog D_7.4 of FMePPEP was calculated to be 5.7.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Donohue et al. (9) reported that FMePPEP inhibited functional [γ-³⁵S]GTP binding at the human recombinant CB1 receptor with high potency (K_b=0.22 ± 0.01 nM) compared to rimonabant (K_b = 0.698 ± 0.200 nM). FMePPEP was significantly less potent at the human recombinant CB2 receptor (K_b = 466 ± 136 nM for FMePPEP and K_b > 1,977 nM for rimonabant at CB2).

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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9.

Donohue S.R., Krushinski J.H., Pike V.W., Chernet E., Phebus L., Chesterfield A.K., Felder C.C., Halldin C., Schaus J.M. Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging. J Med Chem. 2008;51(18):5833–42. [PMC free article: PMC2587418] [PubMed: 18800770]

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Terry G.E., Hirvonen J., Liow J.S., Zoghbi S.S., Gladding R., Tauscher J.T., Schaus J.M., Phebus L., Felder C.C., Morse C.L., Donohue S.R., Pike V.W., Halldin C., Innis R.B. Imaging and quantitation of cannabinoid CB1 receptors in human and monkey brains using (18)F-labeled inverse agonist radioligands. J Nucl Med. 2010;51(1):112–20. [PMC free article: PMC2997525] [PubMed: 20008988]

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.