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

(-)-4-[11C]Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine

[11C]GR103545
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: March 21, 2012.

Chemical name:(-)-4-[11C]Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidineimage 11114622 in the ncbi pubchem database
Abbreviated name:[11C]GR103545, (-)-[11C]GR89696
Synonym:
Agent category:Compound
Target:Kappa opioid (κ) receptor
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
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Opioids such as morphine are commonly used analgesics in clinical practice. Three opioid receptors (mu, µ; delta, δ; and kappa, κ) that mediate opioid effects have been identified by molecular cloning: δ (enkephalin-preferring), κ (dynorphin-preferring), and µ (ß-endorphin-preferring) (1). Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies (2, 3). Their specificity and ubiquitous location are present in both the central and peripheral nervous system. The opioid receptors (G-protein coupled, resulting in decrease in adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, cardiovascular, mental and endocrine function (2-5). Although µ opioid receptors are the major receptor to mediate the analgesic effects of opioids, δ and κ receptors are also important in antinociception. Opioids have been found to protect cells from ischemia injury in the heart and brain via the δ receptors. On the other hand, κ antagonist prevents neurodegeneration.

In humans, the κ opioid receptors (κ1 and κ2 ) are the most abundant brain opioid receptors and are widely distributed in deeper layers of the neocortex (particularly temporal, parietal, and frontal cortices), striatum, and thalamus, with lower levels in the amygdala, hippocampus, occipital cortex, and cerebellum (6, 7). The κ opioid receptors have been implicated in several clinical brain disorders, including substance abuse (8), epilepsy (9), Tourette’s syndrome (10), and Alzheimer’s disease (11).

(±)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a novel, highly potent, and selective κ opioid receptors agonist (12). The (–)-isomer, (–)-4-methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine, also known as GR103545, is the more potent optical isomer of GR89696 (IC50, 0.018 nM versus 6.0 nM). GR89696 is centrally penetrating, with a log P value of 3.14, and has potent antinociceptive, sedative, and diuretic effects. Ki values for GR89696 κ1- and κ2-receptor binding are in the low nanomolar or subnanomolar range. GR89,696 is an agonist for κ2 opioid receptors and an antagonist at κ1 receptors in the guinea pig hippocampus (13). [11C]GR103545 is being developed as a PET agent for the non-invasive study of the κ receptors in the brain.

Synthesis

[PubMed]

Ravert et al. (14) reported synthesis of [11C]GR89696 by N-acetylation of the corresponding normethylcarbamoyl precursor ((±)-1-[(3,4-dichlorophenyl)acetyl]-4-(phenylmethyl)-2-[(1-pyrrolidinyl)methyl]piperidine) with [11C]methyl chloroformate in the presence of triethylamine in ethylene chloride. An average radiochemical yield was 20% with a total synthesis time of 29 min. An average specific activity was 75.5 GBq/μmol (2794 mCi/μmol at end of synthesis) with a radiochemical purity of >99%. Later, the same procedure was used to prepared the (+)- and (-)- [11C]enantiomer using the (+)- or (-)- normethylcarbamoyl precursor with the average yields of 14% and specific activities of 69.3 MBq/nmol (2.6 mCi/nmol at end of synthesis) (15). Chemical purity was >95% and radiochemical purity was >98%.

Nabulsi et al. (16) reported a two-step, one-pot procedure of [11C]GR103545 in an automated synthesis. In the first step, the normethylcarbamoyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide in the presence and of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [11C]methyl trifluoromethanesulfonate to provide [11C]GR103545 with >94% radiochemical purity and a specific activity of 322 ± 81 MBq/nmol (8.7 ± 2.2 mCi/nmol) at the end of synthesis (n = 15). The radiochemical yield was 8.2 ± 2.5% with the total synthesis time of ~43 min.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Naylor et al. (17) reported in vitro functional assays using rabbit vas deferens (κ-specific tissue, IC50 = 0.041 nM), rat vas deferens (µ -specific tissue, IC50 > 10,000 nM), and hamster vas deferens (δ -specific tissue IC50 > 10,000 nM). As reported by Butelman et al. (18), GR89696 displaced [3H]bremazocine binding (representing both κ1- and κ2-receptors) with a Ki of 1.15 ± 0.47 nM in the rhesus monkey cortical membranes. Ki values for the κ1- and κ2-receptors were 0.5 and 6.3 nM, respectively. GR89696 also displaced binding of [3H]DAMGO ([D-Ala (2),N-Me-Phe (4),Gly-ol(5)]-enkephalin, µ-sites) and [3H]DPDPE ([D-Pen2,5]-enkephalin, δ-sites) with Ki values of 0.65 ± 0.15 and 30.61 ± 11.8 nM, respectively. GR89696 was a potent, high-efficacy agonist on cloned κ-receptors expressed in CHO cells, as measured by its ability to stimulate [35S]GTPγS binding (ED50, 0.097 ± 0.005 nM), whereas GR89696 was approximately 100-fold less potent at µ-receptors in C6 glioma cells (ED50, 9.5 ± 2.4 nM).

Animal Studies

Rodents

[PubMed]

Ex vivo biodistribution studies in CD-1 mice injected with 7-15 MBq (0.2-0.4 mCi, 3 μg/kg) were performed by Ravert et al. (14) showing high accumulation of radioactivity in the brain (5.4% injected dose (ID) at 5 min post injection). The cerebellum radioactivity was washed out most rapidly with a half-life of 16 min. Brain region to cerebellum ratios increased over time with ratios at 90 min of 7.8, 5.6, and 4.5 for the hypothalamus, olfactory tubercle, and striatum, respectively. The accumulation of [11C]GR89696 correlated with known κ opioid receptor densities and was inhibited by κ1 opioid agonist (U69593) and GR89696 but not by 5HT-2 antagonist (ketanserin) and D2 antagonist (spiperone).

[11C]GR103545 (the (-)-enantiomer of [11C]GR89696), demonstrated high affinity in mouse brain with hypothalamus/cerebellum and olfactory tubercle/cerebellum ratios of 11.4 and 8.7 at 90 minutes (15), respectively. (+)-[11C]GR89696 showed low affinity and region-to-cerebellum ratios of 1 for all brain regions. The accumulation of [11C]GR103545 in the olfactory tubercle, hypothalamus, striatum and pre-frontal cortex was inhibited by pretreatment with GR103545 with 50% at 0.01 mg/kg and 85-96% at 0.1 mg/kg, whereas GR89696 was less potent with <10% inhibition at 0.01 mg/kg and 40-62% at 0.2mg/kg. Pretreatment with naltrindole (δ) and cyprodime (µ) showed no effect on the binding of [11C]GR103545 in these brain areas. [11C]GR103545 exhibited a selective and saturable binding for the κ opioid receptor.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Talbot et al. (19) studied three adult male baboons with [11C]GR103545 and [11C]GR89696 PET imaging under baseline conditions and after pretreatment with an opioid receptor competitive antagonist, naloxone (1 mg/kg). Regional total distribution volume [VT] values and specific-to-nonspecific equilibrium partition coefficients (V3”) were derived using the arterial input function and a 2-tissue-compartment model. High levels of [11C]GR103545 radioactivity were found in cingulate cortex (VT = 10.91 ± 6.1 ml/g), striatum (VT = 10.5 ± 5.9 ml/g), frontal cortex (VT = 8.5 ± 3.7 ml/g), temporal cortex (VT = 8.1 ± 4.3 ml/g), and parietal cortex (VT = 7.5 ± 3.8 ml/g). Intermediate levels were found in thalamus (VT = 6.9 ± 3.6 ml/g) and medial temporal lobe (VT = 7.0 ± 3.8 ml/g), and low levels in brain stem (VT = 5.1 ± 2.9 ml/g) and occipital cortex (VT = 4.9 ± 2.5 ml/g). Lowest levels were found in the cerebellum (VT = 3.7 ± 1.6 ml/g). Pretreatment with naloxone revealed that the specific binding of [11C]GR103545 in all regions were reduced to low levels (V3” = 0.1-0.4), whereas little effect was found in the cerebellum. V3” values of [11C]GR103545 in all regions (cerebellum as a reference) were higher than [11C]GR89696, whereas (+)-[11C]GR89696 V3” values were negligible. The fraction of unchanged [11C]GR103545 in plasma samples determined by HPLC was 27% at 60 min after injection.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R21 DA66505-01, K012 MH01603-01

References

1.
Minami M., Satoh M. Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res. 1995;23(2):121–45. [PubMed: 8532211]
2.
Satoh M., Minami M. Molecular pharmacology of the opioid receptors. Pharmacol Ther. 1995;68(3):343–64. [PubMed: 8788562]
3.
Waldhoer M., Bartlett S.E., Whistler J.L. Opioid receptors. Annu Rev Biochem. 2004;73:953–90. [PubMed: 15189164]
4.
Molina P.E. Opioids and opiates: analgesia with cardiovascular, haemodynamic and immune implications in critical illness. J Intern Med. 2006;259(2):138–54. [PubMed: 16420543]
5.
Barry U., Zuo Z. Opioids: old drugs for potential new applications. Curr Pharm Des. 2005;11(10):1343–50. [PubMed: 15853689]
6.
Hiller J.M., Fan L.Q. Laminar distribution of the multiple opioid receptors in the human cerebral cortex. Neurochem Res. 1996;21(11):1333–45. [PubMed: 8947923]
7.
Peckys D., Landwehrmeyer G.B. Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study. Neuroscience. 1999;88(4):1093–135. [PubMed: 10336124]
8.
Mello N.K., Negus S.S. Interactions between kappa opioid agonists and cocaine. Preclinical studies. Ann N Y Acad Sci. 2000;909:104–32. [PubMed: 10911926]
9.
de Lanerolle N.C., Williamson A., Meredith C., Kim J.H., Tabuteau H., Spencer D.D., Brines M.L. Dynorphin and the kappa 1 ligand [3H]U69,593 binding in the human epileptogenic hippocampus. Epilepsy Res. 1997;28(3):189–205. [PubMed: 9332884]
10.
Chappell P.B., Leckman J.F., Scahill L.D., Hardin M.T., Anderson G., Cohen D.J. Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette's syndrome: a pilot study. Psychiatry Res. 1993;47(3):267–80. [PubMed: 8396784]
11.
Mathieu-Kia A.M., Fan L.Q., Kreek M.J., Simon E.J., Hiller J.M. Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer's disease patients. Brain Res. 2001;893(1-2):121–34. [PubMed: 11223000]
12.
Birch P.J., Rogers H., Hayes A.G., Hayward N.J., Tyers M.B., Scopes D.I., Naylor A., Judd D.B. Neuroprotective actions of GR89696, a highly potent and selective kappa-opioid receptor agonist. Br J Pharmacol. 1991;103(3):1819–23. [PMC free article: PMC1907793] [PubMed: 1657267]
13.
Caudle R.M., Mannes A.J., Iadarola M.J. GR89,696 is a kappa-2 opioid receptor agonist and a kappa-1 opioid receptor antagonist in the guinea pig hippocampus. J Pharmacol Exp Ther. 1997;283(3):1342–9. [PubMed: 9400009]
14.
Ravert H.T., Mathews W.B., Musachio J.L., Scheffel U., Finley P., Dannals R.F. [11C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1- piperazinecarboxylate ([11C]GR89696): synthesis and in vivo binding to kappa opiate receptors. Nucl Med Biol. 1999;26(7):737–41. [PubMed: 10628552]
15.
Ravert H.T., Scheffel U., Mathews W.B., Musachio J.L., Dannals R.F. [(11)C]-GR89696, a potent kappa opiate receptor radioligand; in vivo binding of the R and S enantiomers. Nucl Med Biol. 2002;29(1):47–53. [PubMed: 11786275]
16.
Nabulsi N.B., Zheng M.Q., Ropchan J., Labaree D., Ding Y.S., Blumberg L., Huang Y. [11C]GR103545: novel one-pot radiosynthesis with high specific activity. Nucl Med Biol. 2011;38(2):215–21. [PubMed: 21315277]
17.
Naylor A., Judd D.B., Lloyd J.E., Scopes D.I., Hayes A.G., Birch P.J. A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines. J Med Chem. 1993;36(15):2075–83. [PubMed: 8393489]
18.
Butelman E.R., Ko M.C., Traynor J.R., Vivian J.A., Kreek M.J., Woods J.H. GR89,696: a potent kappa-opioid agonist with subtype selectivity in rhesus monkeys. J Pharmacol Exp Ther. 2001;298(3):1049–59. [PubMed: 11504802]
19.
Talbot P.S., Narendran R., Butelman E.R., Huang Y., Ngo K., Slifstein M., Martinez D., Laruelle M., Hwang D.R. 11C-GR103545, a radiotracer for imaging kappa-opioid receptors in vivo with PET: synthesis and evaluation in baboons. J Nucl Med. 2005;46(3):484–94. [PubMed: 15750163]

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (94K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:


Related information

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...