NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

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

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

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

Show details

(3R,5R)-5-(3-(2-[18F]Fluoroethoxy)phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one

[18F]FEPEP

, PhD and , PhD.

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

Created: ; Last Update: October 7, 2010.

Chemical name:(3R,5R)-5-(3-(2-[18F]Fluoroethoxy)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-oneimage 99303193 in the ncbi pubchem database
Abbreviated name:[18F]FEPEP
Synonym:
Agent category:Compound
Target:Cannabinoid CB1 receptors
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • 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 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 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). 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 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 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). -5-(3-(2-[18F]Fluoroethoxy)phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one ([18F]FEPEP) is being evaluated for use as a CB1 tracer (9, 10).

Synthesis

[PubMed]

Donohue et al. (9) reported the synthesis of [18F]FEPEP by reaction of the O-desmethyl precursor with [18F]-2-fluoroethyl bromide, which itself was prepared from [18F]fluoride ion and bromoethyl tosylate, for 5 min at 110°C. An average radiochemical yield was 7.92 ± 2.16% (n = 6) with a total synthesis time of ~120 min. Specific activities were >86 GBq/μmol (2.32 Ci/μmol,) at the end of synthesis with a radiochemical purity of >95%. cLog D7.4 of FEPEP was calculated to be 5.8.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Donohue et al. (9) reported that FEPEP inhibited functional [γ-35S]GTP binding at the human recombinant CB1 receptor with high potency (Kb=0.424 ± 0.021 nM) compared to rimonabant (Kb = 0.698 ± 0.200 nM). FEPEP was significantly less potent at the human recombinant CB2 receptor (Kb >8,260 nM for FEPEP and Kb > 1,977 nM for rimonabant at CB2).

Animal Studies

Rodents

[PubMed]

Donohue et al. (9) performed ex vivo biodistribution studies in rats (n = 3) at 0.25, 0.5, 1, 2, 4, and 8 h after injection of FEPEP (0.03 mg/kg) using mass spectroscopy for determination of concentration in the frontal cerebral cortex. Peak concentration (~22 ng/g tissue or 0.29% ID/g) was achieved with 15-30 min after injection. The level was reduced to 0.7 ng/g (0.01% ID/g) at 8 h. Pretreatment with rimonabant (3.0 mg/kg) (15 min before FEPEP injection) reduced the level by ~70% at 30 min after injection.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Terry et al. (10) performed PET imaging in five rhesus monkeys with injection of [18F]FEPEP. Brain radioactivity increased to high levels (2.0-3.5 standardized uptake value (SUV) in the striatum) within 20 min after injection. Total distribution volume (VT) values determined using two-tissue compartment model were 21.6 and 25.0 mL/cm3 for the striatum and pons, respectively. Pretreatment with rimonabant (3.0 mg/kg) 30 min before the tracer injection reduced the radioactivity by 71% in the striatum and ~47% in the pons. SUV in the mandible increased from ~0.4 at <10 min to ~1 at 180 min.

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., 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]
10.
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.

PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (800K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:


Related information

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...