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| 5mg |
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| Targets |
D3 Receptor
Cariprazine-d8 is a stable isotope-labeled internal standard that exhibits the same receptor binding profile as its non-labeled counterpart, Cariprazine. Cariprazine is a novel antipsychotic agent that acts as a partial agonist at dopamine D2 and D3 receptors and serotonin 5-HT1A receptors, with high affinity for D3 (Ki = 0.085 nM) and D2 (Ki = 0.49 nM) receptors, and moderate affinity for the 5-HT1A receptor (Ki = 2.6 nM). Cariprazine also exhibits partial agonism at D3 and D2 receptors and antagonism at 5-HT2B receptors. The deuterated version mimics these same molecular targets but is used for analytical quantification rather than pharmacological evaluation, serving as a tracer to study drug-receptor interactions via mass spectrometry. |
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| ln Vitro |
The in vitro biological activity of Cariprazine-d8 is presumed to be identical to its unlabeled parent compound. Cariprazine demonstrates potent partial agonist activity at human dopamine D2L and D3 receptors in in vitro functional assays, with EC₅0 values of approximately 0.5 nM and 0.3 nM, respectively. In [3H]spiperone binding assays using CHO cells expressing human recombinant receptors, Cariprazine displaces radioligand binding with high affinity, achieving 85-95% inhibition at 10 nM. The deuterated version is not typically used for efficacy assays but serves as an internal standard for LC-MS to accurately quantify drug concentrations in cell culture media or receptor binding assay buffers, ensuring precise exposure characterization.
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| ln Vivo |
The in vivo activity of Cariprazine-d8 is inferred from the well-characterized pharmacology of its unlabeled parent, Cariprazine. In animal models of schizophrenia, oral administration of Cariprazine (0.1-1 mg/kg) reduces conditioned avoidance response in rats with an ED₅0 of 0.2 mg/kg, demonstrating antipsychotic-like effects. In the phencyclidine (PCP)-induced hyperlocomotion mouse model, Cariprazine produces dose-dependent inhibition (ED₅0 = 0.38 mg/kg). Cariprazine also shows efficacy in the forced swim test for antidepressant activity. The compound exhibits preferential binding to D3 over D2 receptors in vivo, as demonstrated by ex vivo receptor occupancy studies in rat brain, with ED₅0 values of 0.07 mg/kg for D3 and 0.2 mg/kg for D2. Cariprazine-d8 is used as an internal standard for LC-MS quantification in these models.
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| Enzyme Assay |
A standard non-cell-based assay protocol for Cariprazine-d8 involves its use as an internal standard in an LC-MS/MS method for quantifying Cariprazine in human plasma. Prepare stock solutions of unlabeled Cariprazine and Cariprazine-d8 in methanol (1 mg/mL each). Prepare calibration standards in blank plasma (0.05-50 ng/mL). Add internal standard (10 ng/mL) to each standard. Perform liquid-liquid extraction using methyl tert-butyl ether (1 mL). Evaporate the organic layer under nitrogen and reconstitute in 150 uL mobile phase. Separate on a C18 column (2.1 × 50 mm, 1.7 um) using gradient elution with 0.1% formic acid in water and acetonitrile. Perform MS/MS detection in positive ion mode monitoring transitions: m/z 428 → 260 for Cariprazine and m/z 436 → 268 for Cariprazine-d8. Generate calibration curve by plotting peak area ratio vs. nominal concentration.
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| Cell Assay |
A standard in vitro cell-based protocol for the unlabeled Cariprazine uses CHO cells stably expressing human dopamine D3 receptors. Culture cells in Ham‘s F12 medium with 10% FBS, 100 U/mL penicillin, and 100 ug/mL streptomycin at 37degC with 5% CO2. Seed cells in 96-well plates at 2×10⁴ cells/well and grow for 24 hours. For cAMP inhibition assay, treat cells with increasing concentrations of Cariprazine (0.01 nM to 10 uM) for 10 minutes, then stimulate with forskolin (1 uM) and dopamine (0.3 uM) for 30 minutes at 37degC. Lyse cells and measure cAMP levels using HTRF (homogeneous time-resolved fluorescence) assay kit. Read fluorescence at 620 nm and 665 nm. Calculate EC₅0 values from dose-response curves. Use Cariprazine-d8 as an internal standard in LC-MS to accurately determine drug concentrations in the culture medium.
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| Animal Protocol |
A typical in vivo animal protocol for Cariprazine-d8 involves a pharmacokinetic (PK) study in male Sprague-Dawley rats. Use rats weighing 200-250 g (n = 5-6 per group). Administer a single oral dose of unlabeled Cariprazine hydrochloride (0.3 mg/kg) suspended in 0.5% methylcellulose. Collect blood samples via tail vein at various time points (0, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72 h) into heparinized tubes. Centrifuge at 3,000 rpm for 10 minutes to obtain plasma. For brain PK studies, euthanize rats at designated time points and collect whole brain tissues, homogenize in PBS (1:3 w/v). Spike plasma and brain homogenate samples (50 uL) with Cariprazine-d8 (10 ng/mL). Perform liquid-liquid extraction with ethyl acetate, evaporate to dryness, and reconstitute in mobile phase. Analyze by LC-MS/MS. Calculate PK parameters including Cmax, Tmax, AUC(0-t), t½, and bioavailability using WinNonlin.
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| ADME/Pharmacokinetics |
Cariprazine-d8 is an internal standard, so its PK is identical to its unlabeled parent. Cariprazine is orally bioavailable with Tmax of 3-6 hours in humans. The volume of distribution is large (>25 L/kg), indicating extensive tissue distribution. Plasma protein binding is high (96-99%), primarily to albumin and alpha1-acid glycoprotein. Cariprazine is extensively metabolized in the liver, primarily by CYP3A4 and to a lesser extent by CYP2D6, to two major active metabolites: desmethylcariprazine and didesmethylcariprazine. The elimination half-life of Cariprazine is long (approximately 2-4 days), while its active metabolites have even longer half-lives (up to 1-3 weeks). Excretion occurs primarily via feces (60-70%) and urine (20-30%). The deuterated standard allows for precise quantification of the parent drug and its active metabolites in PK studies by mass spectrometry.
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| Toxicity/Toxicokinetics |
Cariprazine-d8 is a research-grade internal standard, not a therapeutic agent. Its toxicity profile is inferred from its unlabeled parent, Cariprazine, which is generally well-tolerated at therapeutic doses (1.5-6 mg/day). Common adverse effects include akathisia, extrapyramidal symptoms, insomnia, nausea, and dizziness. Cariprazine has a black box warning for increased mortality in elderly patients with dementia-related psychosis. In animal toxicology studies, oral LD₅0 values exceed 500 mg/kg in rats and mice. Chronic administration in dogs (2-10 mg/kg/day) produced dose-dependent neurological effects including tremors and ataxia. No genotoxicity was observed in Ames test or chromosomal aberration assays. For laboratory handling, standard safety precautions (gloves, lab coat) should be used. Store as powder at -20degC, protected from light and moisture.
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| References | |
| Additional Infomation |
Cariprazine-d8 (RGH-188 d8) is the stable isotope-labeled (deuterated) version of Cariprazine, a novel second-generation antipsychotic drug developed by Gedeon Richter and Actavis (now AbbVie). Cariprazine was approved by the FDA in 2015 for the treatment of schizophrenia and bipolar mania, with additional approvals for bipolar depression (2019) and as an adjunctive treatment for major depressive disorder (2022). Its mechanism of action as a dopamine D3/D2 receptor partial agonist distinguishes it from other antipsychotics, with preferential binding to D3 receptors. Cariprazine-d8 serves as a critical internal standard for LC-MS/MS bioanalysis in preclinical and clinical research. It is intended for research use only and not for human therapeutic or diagnostic applications.
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| Molecular Formula |
C21H32CL2N4O
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| Molecular Weight |
427.410983085632
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| Exact Mass |
434.245
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| CAS # |
1308278-50-3
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| Related CAS # |
Cariprazine;839712-12-8;Cariprazine-d6;1308278-67-2
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| PubChem CID |
76286959
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| Appearance |
White to off-white solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
491
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(=CC=CC=1N1C([H])([H])C([H])([H])N(CC[C@H]2CC[C@H](NC(=O)N(C)C)CC2)C([H])([H])C1([H])[H])Cl
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| InChi Key |
KPWSJANDNDDRMB-DHNBGMNGSA-N
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| InChi Code |
InChI=1S/C21H32Cl2N4O/c1-25(2)21(28)24-17-8-6-16(7-9-17)10-11-26-12-14-27(15-13-26)19-5-3-4-18(22)20(19)23/h3-5,16-17H,6-15H2,1-2H3,(H,24,28)/i12D2,13D2,14D2,15D2
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| Chemical Name |
1,1-dimethyl-3-[4-[2-[2,2,3,3,5,5,6,6-octadeuterio-4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]urea
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3397 mL | 11.6984 mL | 23.3967 mL | |
| 5 mM | 0.4679 mL | 2.3397 mL | 4.6793 mL | |
| 10 mM | 0.2340 mL | 1.1698 mL | 2.3397 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.
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