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

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

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[Carbonyl-11C](S)-3-chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide

[11C]LY2795050
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: May 23, 2013.

Chemical name:[Carbonyl-11C](S)-3-chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamideimage 161005129 in the ncbi pubchem database
Abbreviated name:[11C]LY2795050
Synonym:
Agent category:Compound
Target:Kappa (κ) opioid receptors (KOR)
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 that mediate opioid effects have been identified with molecular cloning: delta, δ (enkephalin-preferring); kappa, κ (dynorphin-preferring); and mu, µ (ß-endorphin–preferring) (1). Each type of opioid receptor consists of subtypes of receptors as suggested by pharmacological studies (2, 3). These receptors have high specificity in both the central and peripheral nervous systems, and their presence is ubiquitous. The opioid receptors (G-protein–coupled; decrease adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, cardiovascular, and mental and endocrine function (2-5). Although µ opioid receptors are the major receptor to mediate the analgesic effects of opioids, κ opioid receptors (KOR) and δ opioid 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, the κ antagonist prevents neurodegeneration.

In humans, the κ1 and κ2 KORs 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 KORs 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 KOR 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, respectively). GR89696 is centrally penetrating, with a log P value of 3.14, and it has potent antinociceptive, sedative, and diuretic effects. The Ki values for GR89696 κ1- and κ2-receptor binding are in the low nanomolar or subnanomolar range. GR89696 is an agonist for the κ2 opioid receptor and an antagonist for the κ1 receptor in the guinea pig hippocampus (13). [11C]GR103545 was studied as a positron emission tomography (PET) agent for use with the noninvasive study of κ opioid receptors in the brain. However, there is a need for KOR antagonist radioligands because they tend to bind to both high- and low-affinity receptors (14). Hence, antagonists bind to a higher number of receptors than the agonists (15). (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (LY2795050) was determined to be a selective KOR antagonist. Zheng et al. (16) prepared and evaluated [carbonyl-11C]LY2795050 ([11C]LY2795050) for use with in vivo PET imaging of KOR distribution in monkey brain tissue.

Synthesis

[PubMed]

Zheng et al. (16) reported a two-step synthesis of [11C]LY2795050 by reaction of the corresponding iodophenyl precursor ((S)-3-(1-(-4-(2-chloro-4-iodophenoxy)benzyl(pyrrolidin-2-yl)pyridine))) with H[11C]CN in the presence of K2CO3 and Pd2dba3 in dimethylformamide for 5 min at 80°C, followed by hydrolysis with addition of NaOH and H2O2 to yield [11C]LY2795050. [11C]LY2795050 was purified with high-performance liquid chromatography (HPLC), with >99% radiochemical and enantiomeric purity. The average yield was 12% at end of synthesis, with a total synthesis time of 45 min. The average specific activity (n = 16) was 23.68 GBq/μmol (640 mCi/μmol) at end of synthesis.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Zheng et al. (16) performed in vitro competition binding assays with cloned human opioid receptors. LY2795050 exhibited Ki values of 0.72, 25.8, and 153 nM for the κ, µ, and δ opioid receptors, respectively. LY2795050 exhibited only antagonistic activity in all three opioid receptor functional assays.

Animal Studies

Rodents

[PubMed]

Ex vivo biodistribution studies in normal rats (n = 4) injected with 3 μg/kg unlabeled LY2795050 were performed by Zheng et al. (16). LY2795050 brain tissue concentrations were determined with mass spectrometry-HPLC at 10, 20, 40, and 60 min after intravenous injection. There was a rapid accumulation in the striatum and cerebellum, followed by a fast washout. The concentrations in the striatum were 4.0, 2.0, 0.8, and 0.5 ng/g at 10, 20, 40, and 60 min, respectively. The striatum/cerebellum ratios were 2 and 2.5 at 10 min and 60 min, respectively. Zheng et al. (16) performed ex vivo distribution studies in the striatum and cerebellum of wild-type (WT) and KOR-knockout (κ-KO) mice. LY2795050 concentrations were 3.0 ± 0.6 ng/g (n = 9) and 0.6 ± 0.2 ng/g (n = 8) in the striatum of WT and κ-KO mice (P < 0.05), respectively. On the other hand, the ligand concentrations were similar in the cerebellum of WT (1.0 ± 0.6 ng/g ) and κ-KO (0.7 ± 0.2 ng/g ) mice. No blocking studies were performed.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Zheng et al. (16) studied three rhesus monkeys with [11C]LY2795050 PET imaging under baseline conditions and after pretreatment with naloxone (1 mg/kg), an opioid receptor competitive antagonist, or co-injection of the selective KOR antagonist LY2456302 (0.01–0.3 mg/kg). There was a heterogeneous distribution of radioactivity in the brain, with the highest levels in the basal ganglia and cingulate cortex and the lowest level in the cerebellum. Regional brain accumulation peaked within 20 min. Regional total distribution volume (VT) values and binding potential (BPND) were derived using the arterial input function and a two-tissue-compartment model (2TCM). High levels of [11C]LY2795050 radioactivity were found in the globus pallidus (VT = 5.2 ± 1.4 ml/g), putamen (VT = 4.2 ± 0.5 ml/g), substantia nigra (VT = 3.8 ± 1.4 ml/g), and cingulate cortex (VT = 3.7 ± 1.4 ml/g). Intermediate levels were found in the insula (VT = 3.4 ± 1.0 ml/g), caudate (VT = 3.0 ± 1.4 ml/g), frontal cortex (VT = 3.0 ± 1.1 ml/g), and temporal cortex (VT = 2.8 ± 0.9 ml/g). Low levels were found in the cerebellum (VT = 2.4 ± 0.6 ml/g). Pretreatment with naloxone revealed that the specific binding values for [11C]LY2795050 were reduced in all regions to the level of the cerebellum. BPND values of these brain regions determined with the 2TCM were similar to those determined with the simplified reference tissue model. There was a dose-dependent inhibition of radioactivity in the brain with LY2456302, with 50% inhibition of the [11C]LY2795050 binding dose of 0.028 mg/kg.

Human Studies

[PubMed]

No publication is currently available.

References

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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]
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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]
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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]
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Reubi J.C., Schar J.C., Waser B., Wenger S., Heppeler A., Schmitt J.S., Macke H.R. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82. [PubMed: 10774879]
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Ginj M., Zhang H., Waser B., Cescato R., Wild D., Wang X., Erchegyi J., Rivier J., Macke H.R., Reubi J.C. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103(44):16436–41. [PMC free article: PMC1618814] [PubMed: 17056720]
16.
Zheng M.Q., Nabulsi N., Kim S.J., Tomasi G., Lin S.F., Mitch C., Quimby S., Barth V., Rash K., Masters J., Navarro A., Seest E., Morris E.D., Carson R.E., Huang Y. Synthesis and Evaluation of 11C-LY2795050 as a kappa-Opioid Receptor Antagonist Radiotracer for PET Imaging. J Nucl Med. 2013;54(3):455–63. [PMC free article: PMC3775344] [PubMed: 23353688]

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