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(3R,5R)-5-(3-[11C]Methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one

[11C]MePPEP

, PhD and , PhD.

Author Information

Created: ; Last Update: October 7, 2010.

Chemical name:(3R,5R)-5-(3-[11C]Methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-oneimage 99303191 in the ncbi pubchem database
Abbreviated name:[11C]MePPEP
Synonym:
Agent category:Compound
Target:Cannabinoid CB1 receptors
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
  • Checkbox Humans
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-[11C]Methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one ([11C]MePPEP) is being evaluated for use as a CB1 tracer (9-14). MePPEP is a CB1 mixed inverse agonist and antagonist.

Synthesis

[PubMed]

Donohue et al. (9) and Yasuno et al. (12) reported the synthesis of [11C]MePPEP 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 2.5 ± 1.1% with a total synthesis time of ~35 min. Specific radioactivities were 78.1 ± 54.9 GBq/μmol (2.1 ± 1.5 Ci/μmol, n = 12) at the time of injection with a radiochemical purity of >99%. Log D7.4 of [11C]MePPEP was determined to be 4.8 ± 0.3 (n = 6).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Yasuno et al. (12) reported that MePPEP inhibited functional [γ-35S]GTP binding at the human recombinant CB1 receptor with high potency (Kb = 0.574 ± 0.207 nM) compared to rimonabant (Kb = 5.96 ± 0.21 nM). MePPEP was significantly less potent at the human recombinant CB2 receptor (Kb = 363 ± 78 nM for MePPEP and Kb > 10,000 nM for rimonabant at CB2).

Animal Studies

Rodents

[PubMed]

Terry et al. (11) performed various [11C]MePPEP PET imaging studies. A peaked brain accumulation of 182% standard uptake value (SUV) was observed at ~20 min after injection of [11C]MePPEP in mice (n = 4). Rimonabant (3 mg/kg, i.v.) blocked ~65% of radioactivity in the brain when administered 25 before or 30 min after [11C]MePPEP injection in mice. Displacement studies were performed in rats at 40 min after [11C]MePPEP injection. Direct acting agonists anandamide (10 mg/kg, i.v.), methanandamide (10 mg/kg, i.v.), CP 55,940 (1 mg/kg, i.v.), and indirect agonist URB597 (0.3 and 0.6 mg/kg, i.v.) showed little displacement of [11C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg, i.v.) showed >65% displacement of [11C]MePPEP. Radiometabolites were ~13% of total radioactivity in the excised brains between 30 and 120 min. Only 16% of radioactivity in the plasma represented intact [11C]MePPEP at 60 min after injection. Three hydrophilic radiometabolites were detected in the plasma with HPLC.

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 MePPEP (0.03 mg/kg) using mass spectroscopy for determination of concentration in the frontal cerebral cortex. Peak concentration (39 ng/g tissue or 0.52% ID/g) was achieved with 15-30 min after injection. The level was reduced to 9 ng/g (0.12% ID/g) at 8 h. Pretreatment with rimonabant (3.0 mg/kg, i.v.) (15 min before MePPEP injection) reduced the level by ~90% at 30 min after injection.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Yasuno et al. (12) performed PET imaging in four rhesus monkeys with injection of [11C]MePPEP (0.11 ± 0.06 μg/kg). Brain radioactivity increased to high levels (~6.0 SUV in the cerebellum) within 10–20 min after injection. High levels of radioactivity were observed in the striatum and cerebellum and low in the thalamus and pons. Pretreatment with rimonabant (3.0 mg/kg) 10 min before the tracer injection reduced the radioactivity by ~90% in the striatum and cerebellum and ~70% in the thalamus and pons. In addition, brain accumulation was rapidly displaced by 4-(3-cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide (ISPB) (1.5 mg/kg i.v.) at 60 min after tracer injection. [11C]MePPEP was quickly metabolized with 21% intact in the blood at 60 min after injection. Total distribution volume (VT) values determined using two-tissue compartment model were 54, 47, 43, 37, 33, 17, and 16 mL/cm3 for the prefrontal cortex, striatum, medial temporal region, lateral temporal cortex, cerebellum, thalamus, and pons, respectively. The coefficient of variance (COV) values were <5.5%.

Human Studies

[PubMed]

Terry et al. (13) performed [11C]MePPEP positron emission tomography (PET) scans in 17 healthy subjects. After injection of [11C]MePPEP, brain uptake of radioactivity was high (e.g., 3.6 SUV in putamen at approximately 60 min) and washed out very slowly. A two-tissue compartment model yielded VT values that were both well identified and stable between 60 and 210 min. The simple measure of brain accumulation (average concentration of radioactivity between 40 and 80 min) had good retest variability (~8%) and moderate inter-subject variability (~16% COV). In contrast, VT had two-fold greater retest variability (~15%). In addition, VT had three-fold greater inter-subject variability (~52% COV). The decreased precision of VT compared to brain accumulation was likely due to the slow washout of radioactivity from the brain and to noise in measurements of the low concentrations of [11C]MePPEP in plasma.

Terry et al. (14) performed human dosimetry of [11C]MePPEP from PET images in seven human subjects after intravenous injection of 340 MBq (9.2 mCi, 5.2 nmol) [11C]MePPEP. Uptake in the lungs, heart, spleen, kidneys, and liver peaked in 10-20 min and fell rapidly. Radioactivity slowly accumulated in the brain and intestine. The effective dose was 0.0046 mSv/MBq (17 mrem/mCi). The organ that received the highest dose was the liver (0.016 mGy/MBq (59 mrem/mCi)), followed by the small intestine (0.012 mGy/MBq (44 mrem/mCi)), lungs (0.011 mGy/MBq (41 mrem/mCi)), (0.010 mGy/MBq (37 mrem/mCi)), gallbladder wall (0.009 mGy/MBq (33 mrem/mCi)), and brain (0.008 mGy/MBq (30 mrem/mCi)). [11C]MePPEP showed hepatobiliary excretion only.

NIH Support

Intramural research program

References

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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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