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Purity: ≥98%
LY2795050 is a novel, potent and selective κ-opioid Receptor (KOR) antagonist with an IC50 of 0.72 nM. It has the potential to be used as a PET tracer to image KOR in vivo.
| Targets |
KOR ( Ki = 0.72 nM ); KOR ( Kb = 0.63 nM )
LY2795050 is a selective antagonist for the kappa opioid receptor (KOR) with a Ki of 0.72 nM and over 35-fold selectivity over mu and delta opioid receptor subtypes. [1] |
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| ln Vitro |
LY2795050 exhibits antagonist activity with a Kb value of 0.63 nM and high affinity for the KOR with a Ki value of 0.72 nM[1].
In radioligand competition binding assays, LY2795050 displayed high binding affinity for the cloned human kappa opioid receptor (KOR). [1] In functional GTPγS antagonist assays, LY2795050 behaved as a full antagonist at all three opioid receptor subtypes (kappa, mu, delta). [1] |
| ln Vivo |
LY2795050 (i.p., 0.032-0.1 mg/kg, 30 min) prevents dose-dependent grooming deficits caused by U50,488 in male and female mice[2]. Some behavioral effects of LY2795050 (i.p., 0.032-0.1 mg/kg, 0-150 min) exhibit sexual dimorphism[2].
In Sprague-Dawley rats, intravenous administration of LY2795050 (3 µg/kg) resulted in rapid brain uptake and washout. The ligand concentration was higher in the kappa-rich striatum compared to the cerebellum (a region with minimal opioid receptor expression) at all measured time points (10, 20, 40, 60 min), with a striatum-to-cerebellum ratio of >2 at early time points and 3.3 at 60 minutes post-injection. [1] In wild-type (WT) mice, intravenous administration of LY2795050 (3 µg/kg) led to higher ligand concentrations in the striatum (3.0 ± 0.6 ng/g) compared to the cerebellum (1.0 ± 0.6 ng/g) at 60 minutes post-dose. In KOR knockout (KO) mice, this difference was abolished (striatum: 0.6 ± 0.2 ng/g; cerebellum: 0.7 ± 0.2 ng/g), confirming that the binding is KOR-specific. [1] In rhesus monkeys, PET imaging with the radiolabeled tracer [¹¹C]LY2795050 showed a heterogeneous brain distribution consistent with known KOR density, with highest uptake in the globus pallidus and cingulate cortex. This specific binding was significantly reduced or abolished by pre-treatment with the non-selective opioid antagonist naloxone (1 mg/kg, iv) or the selective KOR antagonist LY2456302, demonstrating saturable and specific binding to opioid receptors, primarily KOR. [1] The specific binding of [¹¹C]LY2795050 in monkeys was reduced in a dose-dependent manner by LY2456302, with an estimated ID₅₀ (dose to inhibit 50% of binding) of 28.1 µg/kg for LY2456302. [1] |
| Animal Protocol |
C57BL/6J mice (gonadally intact, adult, male and female)
0.032-0.1 mg/kg i.p., 0.032-0.1mg/kg, 30 min For ex vivo tissue distribution studies in rodents, LY2795050 was dissolved in saline to a final concentration of 3 µg/mL. Sprague-Dawley rats (230-280 g) received an intravenous injection via the lateral tail vein at a dose of 3 µg/kg (1 mL/kg) and were sacrificed at 10, 20, 40, or 60 minutes post-dose. Wild-type and KOR knockout mice received the same dose and were sacrificed at 60 minutes post-dose. Striatum and cerebellum were dissected for LC/MS/MS analysis. [1] For PET imaging in rhesus monkeys, the radiotracer [¹¹C]LY2795050 was formulated in USP saline with absolute ethanol and sodium carbonate, passed through a sterile filter, and administered as an intravenous bolus via an infusion pump over 1 minute. Monkeys were anesthetized with isoflurane. For blocking studies, naloxone (1 mg/kg) or LY2456302 (e.g., 96 µg/kg) was administered intravenously prior to tracer injection. Arterial blood samples were collected to measure the metabolite-corrected plasma input function. PET data were acquired for 120 minutes post-injection. [1] |
| ADME/Pharmacokinetics |
In rhesus monkeys, after intravenous injection of [¹¹C]LY2795050, the parent compound was metabolized at a moderate rate, with approximately 40% of the parent tracer remaining in the plasma 30 minutes after injection. [1] The free fraction of [¹¹C]LY2795050 in plasma was approximately 1%. [1] In brain tissue, [¹¹C]LY2795050 exhibited rapid uptake kinetics, with local activity reaching peak within 20 minutes after injection. [1]
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| Toxicity/Toxicokinetics |
The study indicated that LY2795050, as a κ opioid receptor (KOR) antagonist, is expected to have a wider safety profile than KOR agonist tracers because opioid antagonists such as naloxone have a long history of safe clinical use. Specific toxicity data (e.g., LD₅₀, organ toxicity) for LY2795050 are not reported in this publication. [1]
In monkey PET studies, no adverse reactions were observed with administration of tracers (non-agonist LY2795050) up to 1 µg/kg and selective KOR antagonist LY2456302 up to 313 µg/kg, respectively. [1] |
| References |
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| Additional Infomation |
LY2795050 is a κ opioid receptor (KOR) antagonist that has been developed as a candidate PET radiotracer for imaging κ opioid receptors in the brain. [1] Its radiolabeled form, [¹¹C]LY2795050, is synthesized via a two-step radiosynthesis using iodophenyl precursor and [¹¹C]cyanide, with an average radiochemical yield of 12% and radiochemical and enantiomeric purity >99%. [1] [¹¹C]LY2795050 has been reported as the first selective KOR antagonist radiotracer successfully used for PET imaging and has since entered human studies. [1] Compared to the κ opioid receptor agonist tracer [¹¹C]GR103545, [¹¹C]LY2795050 exhibits faster brain uptake kinetics but lower specific binding signal (e.g., BPND in the cingulate cortex: 0.66 vs. 1.9). However, its antagonistic properties offer a significant safety advantage, allowing for larger doses to be injected without producing the psychoactive effects associated with κ opioid receptor agonists. [1]
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| Molecular Formula |
C23H22CLN3O2
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|---|---|
| Molecular Weight |
407.893
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| Exact Mass |
407.14
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| Elemental Analysis |
C, 67.73; H, 5.44; Cl, 8.69; N, 10.30; O, 7.84
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| CAS # |
1346133-08-1
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| Related CAS # |
1346133-08-1
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| PubChem CID |
56851583
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| Appearance |
White to off-white solid powder
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| LogP |
5.601
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
540
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(N)C1=CC=C(OC2=CC=C(CN3[C@H](C4=CC=CN=C4)CCC3)C=C2)C(Cl)=C1
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| InChi Key |
LOOCZNLSXJHWTG-NRFANRHFSA-N
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| InChi Code |
InChI=1S/C23H22ClN3O2/c24-20-13-17(23(25)28)7-10-22(20)29-19-8-5-16(6-9-19)15-27-12-2-4-21(27)18-3-1-11-26-14-18/h1,3,5-11,13-14,21H,2,4,12,15H2,(H2,25,28)/t21-/m0/s1
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| Chemical Name |
3-chloro-4-[4-[[(2S)-2-pyridin-3-ylpyrrolidin-1-yl]methyl]phenoxy]benzamide
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| Synonyms |
LY2795050; LY 2795050; LY-2795050; (S)-LY2795050
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~50 mg/mL (~122.6 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4516 mL | 12.2582 mL | 24.5164 mL | |
| 5 mM | 0.4903 mL | 2.4516 mL | 4.9033 mL | |
| 10 mM | 0.2452 mL | 1.2258 mL | 2.4516 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05547542 | Recruiting | Drug: CVL-354 Drug: [11C]-LY2795050 |
Opioid Use Disorder | Cerevel Therapeutics, LLC | March 1, 2023 | Phase 1 |
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