5-HT1A receptor (partial agonist, Ki=0.12 nM); dopamine D2L receptor (partial agonist, Ki=0.3 nM); 5-HT2A antagonist (Ki=0.47 nM); alpha1B antagonist (Ki=0.17 nM); alpha2C antagonist (Ki=0.59 nM)

Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

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No specific in vitro assays for the deuterated form are provided. The non-deuterated parent Brexpiprazole is a partial agonist of human 5-HT1A and dopamine D2L receptors with Kis of 0.12 nM and 0.3 nM, respectively. It is also a 5-HT2A antagonist (Ki=0.47 nM) and shows antagonist activity at alpha1B (Ki=0.17 nM) and alpha2C (Ki=0.59 nM) receptors.

Cellular activity data for the deuterated form are not specifically reported. The non-deuterated Brexpiprazole shows partial agonist activity at 5-HT1A and dopamine D2L receptors in cell-based functional assays, modulating cAMP signaling. It demonstrates potentiation of neurite outgrowth and improvement of social recognition deficits in preclinical models.

Radioligand binding assays are performed using membrane preparations from CHO or HEK-293 cells expressing human receptors. [3H]-8-OH-DPAT for 5-HT1A, [3H]-spiperone for D2L, [3H]-ketanserin for 5-HT2A, and [3H]-prazosin for alpha1B are used. Test compound is incubated with membranes at varying concentrations. Bound radioligand is separated by filtration and counted by scintillation. Ki values are calculated from competition curves.

Cell-based functional assays for 5-HT1A partial agonism use CHO cells expressing human 5-HT1A receptors with a cAMP response element reporter. Cells are treated with serial dilutions of Brexpiprazole-d8 (or non-deuterated reference). Agonist activity is measured by quantifying intracellular cAMP accumulation via HTRF or ELISA after forskolin stimulation. D2L partial agonism is assessed by measuring inhibition of forskolin-stimulated cAMP.

In vivo animal studies with Brexpiprazole-d8 are not typically performed as it is primarily an analytical internal standard. Pharmacokinetic studies using the deuterated compound as a tracer involve oral or intravenous administration to rodents or dogs, followed by blood and brain tissue collection at multiple time points. LC-MS/MS analysis quantifies the labeled compound to determine absorption, distribution and brain penetration.

Absorption, Distribution and Excretion
Following a single dose, the time to peak concentration (Tmax) is 4 hours, and the absolute oral bioavailability is 95%. Steady-state concentrations of birepiperazole are reached within 10 to 12 days after administration. Both Cmax and AUC increase proportionally with single and multiple once-daily doses. A high-fat diet has no significant effect on the Cmax or AUC of birepiperazole. Following a single oral dose of radiolabeled birepiperazole, approximately 25% and 46% of the radioactive material are recovered in urine and feces, respectively. Less than 1% of the unchanged birepiperazole is excreted in urine, and approximately 14% of the oral dose is excreted unchanged in feces. The volume of distribution after intravenous administration of birepiperazole is 1.56 ± 0.42 L/kg, indicating extravascular distribution.
After once-daily administration, the apparent oral clearance of biriperazole is 19.8 (±11.4) mL/h/kg.
Metabolism/Metabolites
In vitro studies have shown that biriperazole is primarily metabolized by CYP3A4 and CYP2D6. After single and multiple administrations, biriperazole and its major metabolite DM-3411 are the major circulating components. At steady state, DM-3411 accounts for 23% to 48% of the plasma biriperazole exposure (AUC). DM-3411 is considered to be pharmacologically inactive.
Biological Half-Life
After once-daily or multiple administrations, the terminal elimination half-lives of biriperazole and its major metabolite DM-3411 are 91 hours and 86 hours, respectively.

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The deuterated form is designed as an analytical internal standard for LC-MS/MS quantification of Brexpiprazole in biological matrices. It exhibits identical chromatographic retention time as the non-deuterated compound but a distinct mass due to eight deuterium atoms. This allows precise and accurate quantification without isotopic interference for pharmacokinetic studies and therapeutic drug monitoring.

Hepatotoxicity
It has been reported that approximately 1% of patients taking bripiprazole long-term develop abnormal liver function, but the incidence is similar in the placebo or control groups. There are currently no reports of clinically significant acute liver injury caused by bripiprazole, and only a very small number of cases have been reported with the more commonly used aripiprazole. Therefore, liver injury caused by bripiprazole, even if it occurs, is certainly very rare. Probability score: E (unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on whether bripiprazole is excreted into breast milk. One case report indicates that bripiprazole may cause reduced lactation. A case report review found reports of bripiprazole causing lactation disorders and reduced milk production, but details are lacking. Until more data are available, alternative medications may be preferred. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
A woman with bipolar disorder was taking irinotecan 2 mg/day during late pregnancy. Her newborn was hospitalized in the neonatal intensive care unit (NICU) for 18 days with hypoxic-ischemic encephalopathy. During the baby's hospitalization, due to medication shortages, she reduced the irinotecan dose to 2 mg every two days. This mother had previously successfully breastfed two babies, pumping 10 times a day, producing 120 ml per day in the first week postpartum. After the baby was discharged, she restored the dose to 2 mg daily. At a follow-up outpatient visit, she could only express 30 ml per day. She then discontinued irinotecan and began a short course of metoclopramide. Ten days after discontinuing irinotecan, her milk production increased, allowing her to almost exclusively breastfeed her baby, whose weight gain was normal. Her serum prolactin levels also returned to normal. A review of adverse reaction cases reported in the U.S. Food and Drug Administration's Adverse Event Reporting System between 2015 and 2023 revealed 6 cases of "galactorrhea" and 10 cases of "nipple discharge" related to biriperazole. Other details were missing. Protein Binding: In vitro experiments showed that biriperazole binds to 99% of plasma proteins, primarily serum albumin and α1-acid glycoprotein.

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As an analytical standard, Brexpiprazole-d8-1 is not intended for therapeutic use and thus toxicology studies are not performed on the labeled compound. The non-deuterated Brexpiprazole has an established clinical safety profile as an approved antipsychotic for schizophrenia and as an adjunctive treatment for major depressive disorder.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.

[2]. Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors. Eur Neuropsychopharmacol. 2015 Apr;25(4):505-11.

[3]. Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin-dopamine activity modulator. Eur Neuropsychopharmacol. 2015 Mar;25(3):356-64.

Brexpiprazole is an N-arylpiperazine compound. It is an atypical antipsychotic and a novel partial agonist of D2 dopamine and serotonin 1A receptors, known as a serotonin-dopamine activity modulator (SDAM). It has high affinity for serotonin, dopamine, and alpha-adrenergic receptors. Although structurally similar to aripiprazole, Brexpiprazole has different binding affinities for dopamine and serotonin receptors. Compared to aripiprazole, Brexpiprazole is less likely to cause partially agonist-mediated adverse reactions (such as extrapyramidal symptoms) due to its lower intrinsic activity against D2 receptors. Furthermore, it exhibits stronger antagonistic activity against 5-HT1A and 5-HT2A receptors. Brexpiprazole was first approved by the FDA on July 10, 2015. Currently, Brexpiprazole is approved for the treatment of depression, schizophrenia, and dementia-related agitation in Alzheimer's disease. It is also being investigated for the treatment of other mental illnesses, such as post-traumatic stress disorder. Brexpiprazole is an atypical antipsychotic. Brexpiprazole is an atypical antipsychotic used to treat schizophrenia and major depressive disorder. The incidence of elevated serum transaminases during Brexpiprazole treatment is low, but it has not been found to be associated with clinically significant cases of acute liver injury.

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Drug Indications
Brexpiprazole is indicated as adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults. It is also indicated for the treatment of schizophrenia in patients aged 13 years and older. Brexpiprazole is also indicated for the treatment of dementia-related agitation in Alzheimer's disease; however, it is not indicated for on-demand (“prn”) treatment of this condition. Treatment of Schizophrenia.
Treatment of Schizophrenia

Mechanism of Action

Although the exact mechanism of action of iriperazole in mental illness is not fully elucidated, its efficacy may be attributed to its partial agonistic activity against 5-HT1A and dopamine D2 receptors, as well as its antagonistic activity against 5-HT2A receptors. Iriperazole has sub-nanomolar affinity for these receptors. These therapeutic targets are associated with mental illnesses such as schizophrenia and depression. The partial D2 receptor agonist effect allows the drug to stimulate D2 receptors at low dopamine levels and attenuate their activation at high dopamine levels. Partial agonistic activity against 5-HT1A receptors may be associated with improvements in memory function and cognitive abilities. Antagonistic activity against α-adrenergic receptors is also associated with schizophrenia and depression.
Pharmacodynamics

Iriperazole is an atypical antipsychotic drug used to improve symptoms of mental illnesses, such as cognitive deficits and affective symptoms.
Brexpiprazole has affinity for a variety of monoaminergic receptors (denoted by Ki), including serotonin 5-HT1A (0.12 nM), 5-HT2A (0.47 nM), 5-HT2B (1.9 nM), 5-HT7 (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and norepinephrine α1A (3.8 nM), α1B (0.17 nM), α1D (2.6 nM), and α2C (0.59 nM) receptors. Brexpiprazole exhibits partial agonist activity against 5-HT1A, D2, and D3 receptors, and antagonist activity against 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C receptors. Brexpiprazole also has affinity for histamine H1 receptors (19 nM) and muscarinic M1 receptors (67% inhibition at 10 µM).

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Brexpiprazole-d8-1 is a stable isotope-labeled internal standard used exclusively for research and bioanalytical applications. The parent drug Brexpiprazole was first approved by the FDA in 2015 and is marketed under the brand name Rexulti. The deuterated version facilitates accurate quantitation in pharmacokinetic studies, therapeutic drug monitoring, and metabolic profiling of Brexpiprazole.

C25H27N3O2S

441.615078210831

433.182

1427049-19-1

Brexpiprazole;913611-97-9

11978813

Off-white to light yellow solid powder

4.7

1

5

7

31

636

0

S1C=CC2=C1C=CC=C2N1C([2H])([2H])C([2H])([2H])N(CCCCOC2=CC=C3C=CC(NC3=C2)=O)C([2H])([2H])C1([2H])[2H]

ZKIAIYBUSXZPLP-UHFFFAOYSA-N

InChI=1S/C25H27N3O2S/c29-25-9-7-19-6-8-20(18-22(19)26-25)30-16-2-1-11-27-12-14-28(15-13-27)23-4-3-5-24-21(23)10-17-31-24/h3-10,17-18H,1-2,11-16H2,(H,26,29)

7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)