1-Methylimidazoleacetic acid does not have a defined pharmacological target; it is an endogenous metabolite of histamine. Histamine is metabolized by histamine N-methyltransferase (HNMT) to form 1-methylhistamine, which is then further metabolized by monoamine oxidase B (MAO-B) to form 1-methylimidazoleacetic acid. As such, this compound is a downstream metabolite of histamine degradation and serves as a biomarker of histamine turnover rather than a direct modulator of receptor activity.

No specific in vitro activity as a drug is reported. As an endogenous metabolite, 1-methylimidazoleacetic acid is not known to exhibit pharmacological activity at receptors or enzymes. It is used as an analytical standard for quantification in biological samples and in metabolic studies. The compound is stable under standard laboratory conditions and is used to measure histamine turnover rates in clinical and research settings, particularly in patients with mast cell disorders.

No specific in vivo activity as a drug is reported. As a metabolite, 1-methylimidazoleacetic acid is excreted in urine and its concentration reflects systemic histamine metabolism. In clinical research, urinary levels of 1-methylimidazoleacetic acid are measured to assess histamine turnover in patients with mastocytosis and other conditions involving mast cell activation. No pharmacological efficacy studies (e.g., anti-inflammatory, antihistamine) have been conducted because this compound is not intended as a therapeutic agent.

Competitive enzyme inhibition or receptor binding assays are not performed with this compound as it is a metabolite rather than a target-modulating drug. Instead, analytical protocols for quantification are used: HPLC or LC-MS/MS with a C18 column, mobile phase of 0.1% formic acid in water/acetonitrile gradient, flow rate 0.3-0.5 mL/min, and detection by UV at 210-220 nm or mass spectrometry (MRM transition for 1-methylimidazoleacetic acid). Calibration curves are prepared using authentic standards. Biological samples (urine, plasma) are processed by protein precipitation or solid-phase extraction prior to analysis.

Cell-based assays are not typically performed with this metabolite, as it is not used as a pharmacological tool. For cytotoxicity or metabolic studies, cells (e.g., HepG2, mast cell lines) may be cultured with 1-methylimidazoleacetic acid at various concentrations (1-1000 uM) for 24-72 hours. Cellular responses (viability via MTT assay, histamine release via ELISA, gene expression by qPCR) are measured. No specific IC50 values for this compound have been reported. The compound may be used as an internal standard or positive control in assays quantifying histamine metabolites in cell supernatants.

Animal studies are not typically performed with 1-methylimidazoleacetic acid as it is not a drug candidate. In metabolic studies, animals (e.g., rats, mice) may be administered histamine or 1-methylimidazoleacetic acid itself (intraperitoneal or intravenous, 1-10 mg/kg), and urine or plasma collected over 4-24 hours. Concentrations of 1-methylimidazoleacetic acid are quantified by LC-MS/MS. No efficacy models have been described. Such studies are used to validate analytical methods for histamine metabolite quantification.

Absorption, Distribution and Excretion
Objective: To investigate the expression of histidine decarboxylase (HDC) in normal and neoplastic gastric neuroendocrine cells and its relationship with major histamine metabolites. Methods: Conventional immunohistochemistry and dual immunofluorescence assays were used to detect the expression of vesicular monoamine transporter 2 (VMAT-2), HDC, and ghrelin in gastric neuroendocrine tumors (GNETs) using commercial antibodies. The study included gastric fundus (n=3) and gastric body (n=3) mucosal control tissues from 6 patients who underwent gastric adenocarcinoma surgery, and biopsy and/or gastric surgical specimens from 64 patients with primary GNETs, including metastatic specimens from 22 patients. In addition, the urinary excretion of the major histamine metabolite methylimidazolium acetate (U-MeImAA) was measured in 27 of the 64 GNET patients using high-performance liquid chromatography (HPLC). Results: In the gastric mucosa of the control tissues, co-localization studies identified some neuroendocrine cells that were immunoreactive only to VMAT-2, while others were immunoreactive only to HDC. The third cell population simultaneously expressed both antigens. Co-expression of HDC and ghrelin was not observed. Similar results were obtained in neuroendocrine cell proliferation foci associated with type A chronic atrophic gastritis and in tumors. The relative incidence of the three markers varied in tumors detected using conventional immunohistochemical methods. All of these GNETs showed immunoreactivity to VMAT-2 and HDC, and the immunohistochemical patterns and frequencies of their metastases were similar to those of the primary tumors. Increased urinary methylisoamino acid (U-MeImAA) excretion was detected in four patients, but only two patients presented with associated endocrine symptoms. Conclusion: Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC may be necessary for increased histamine production in GNET patients. Similar to metabolites of other amine neurotransmitters, brain histamine metabolites, such as distal methylhistamine (t-MH) and distal methylimidazolium acetate (t-MIAA), may exhibit concentration gradients in the cerebrospinal fluid. To test this hypothesis, we collected paired cisterns and lumbar cerebrospinal fluid samples from eight macaques (Macaca mulatta) and determined the levels of t-MH and t-MIAA using gas chromatography-mass spectrometry. In addition, we determined the level of p-MIAA, an endogenous isomer of t-MIAA and not a histamine metabolite. In all monkeys, the concentrations of t-MH (9.9 ± 1.4) and t-MIAA (40.8 ± 7.6) in the cisterns (pimol/mL, mean ± standard error) were higher than those in the lumbar cerebrospinal fluid (t-MH: 1.8 ± 0.3; t-MIAA: 6.8 ± 0.9; p-MIAA: 8.6 ± 0.6), while the concentration of p-MIAA (9.7 ± 1.2) showed no significant difference. The mean concentration gradients of t-MH (6.6±1.1) and t-MIAA (6.5±1.3) in the cisterns and lumbar cerebrospinal fluid showed no significant differences. These gradients were higher than those of most other neurotransmitter metabolites. There was no gradient in p-MIAA concentration. The concentrations of t-MH and t-MIAA were positively correlated in the cisterns, but not in the lumbar cerebrospinal fluid. The mean ratio of metabolite concentrations (t-MIAA/t-MH) in the cisterns (4.0 ± 0.4) and lumbar cerebrospinal fluid (4.4 ± 0.9) showed no significant difference. These steep gradients suggest that the levels of t-MH and t-MIAA in the lumbar cerebrospinal fluid may serve as effective probes for histamine metabolism in the brain. The concentrations of the major histamine metabolite, t-MIAA (disylmethylimidazolium acetate), in nine rat brain regions were determined using gas chromatography-mass spectrometry (GC-MS), which also determined its precursor amine, t-MH. The concentrations of t-MIAA varied by up to 15-fold in the cerebellum, medulla oblongata-pons, midbrain, caudate nucleus, hypothalamus, frontal cortex, hippocampus, and thalamus, with the highest concentration in the hypothalamus (2.21 nmol/g) and the lowest in the cerebellum (0.15 nmol/g). Except for the midbrain, the concentrations of t-MIAA and t-MH were significantly positively correlated in all brain regions, with relatively higher t-MIAA concentrations in the midbrain. Probenecid did not affect global t-MIAA levels. The monoamine oxidase inhibitor pargiline reduced t-MIAA levels in all brain regions.

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Metabolism / Metabolites
In the mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT) to produce distal methylhistamine (t-MH), which further generates distal methylimidazolium acetate (t-MIAA). We previously demonstrated that imidazolium acetate (IAA), a GABA agonist and a peripheral metabolite of histamine, is also present in the brain, and its concentration increases upon HMT inhibition. Furthermore, when [3H]histamine is injected intraventricularly into rats, some histamine is converted to IAA, and HMT inhibition accelerates this conversion. These results indicate that the brain has the capacity to oxidize histamine, but did not reveal whether this pathway functions under physiological conditions. To answer this question, we continuously infused rats with α-fluoromethylhistidine (α-FMHis), an irreversible inhibitor of the histamine synthase L-histidine decarboxylase, for over 4 weeks. Compared to the control group (untreated and saline-treated groups), the levels of histamine, t-MH, and t-MIAA were significantly reduced in all brain regions of the treated rats. Compared to the control group, the decrease in t-MIAA was greater in all brain regions than in t-MH, and t-MH was greater than that of histamine. Furthermore, the local decrease in histamine in the brain was positively correlated with its turnover rate. Conversely, the levels of IAA and promethylimidazolidineacetic acid (a t-MIAA isomer independent of histamine metabolism) remained unchanged. These results suggest that, unlike peripheral tissues, most of the IAA in the rat brain may not originate from histamine. Since histamine in the brain can be converted to IAA under specific conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow-turnover histamine pool in the brain and support the use of a chronic α-FMHis infusion model to study the brain's histaminergic system.

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As an endogenous metabolite, 1-methylimidazoleacetic acid undergoes renal excretion. Its plasma half-life is likely short (minutes to hours) due to rapid urinary clearance. Powder should be stored at -20degC for up to 3 years and in solution at -80degC for up to 1 year. For in vivo studies, the compound can be dissolved in saline or PBS. Specific ADME parameters (bioavailability, volume of distribution, clearance) are not applicable as this is not a drug but a metabolite.

Toxicity Summary
Identification and Uses: Methylimidazolium acetate is a urinary metabolite of histamine and also the final product of histamine metabolism. Human Studies: No relevant data available. Animal Studies: No relevant data available.

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Density: 1.3+/-0.1 g/cm3. Boiling point: 384.4+/-17.0 degC. Flash point: 186.3+/-20.9 degC. LogP: -0.92. Hydrogen bond donor count: 1, acceptor count: 3. Rotatable bond count: 2. The compound may be irritating to skin, eyes, and respiratory tract. Standard laboratory precautions apply: use gloves, lab coat, and goggles; avoid inhalation and ingestion. No specific acute or chronic toxicity studies have been published.

[1]. Determination of 1-methylhistamine and 1-methylimidazoleacetic acid in human urine as a tool for the diagnosis of mastocytosis. J Chromatogr B Biomed Sci Appl. 1999 Jan 8;721(1):135-40.

1-Methylimidazoleacetic acid is a monocarboxylic acid, a structure in which one methyl hydrogen atom in the acetic acid molecule is replaced by a 1-methyl-1H-imidazol-4-yl group. It is a metabolite and a GABA agonist. It belongs to the imidazole class of compounds and is also a monocarboxylic acid. Functionally, it is related to acetic acid. It is the conjugate acid of 1-methyl-4-imidazolium acetate. 2-(1-methyl-1H-imidazol-4-yl)acetic acid has been reported in humans, grapes, and other organisms with relevant data. It is a urinary metabolite of histamine and a final product of histamine metabolism; the RN given here refers to the parent compound.

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1-Methylimidazoleacetic acid (1-Methylimidazole-4-acetic acid) is an endogenous metabolite of histamine used primarily as a urinary biomarker. It belongs to the class of imidazoleacetic acid derivatives. It is used in the study of mastocytosis, a rare disorder characterized by abnormal mast cell accumulation and activation, where histamine metabolites serve as markers of disease activity. The compound is also relevant to histamine-related research, including allergic and inflammatory conditions. No clinical trial data or regulatory approvals exist.

C6H8N2O2

140.14

140.059

2625-49-2

35454-39-8 (hydrochloride)

75810

Solid Powder

1.3±0.1 g/cm3

384.4±17.0 °C at 760 mmHg

186.3±20.9 °C

0.0±0.9 mmHg at 25°C

1.574

-0.92

1

3

2

10

138

0

CN1C=C(CC(=O)O)N=C1

ZHCKPJGJQOPTLB-UHFFFAOYSA-N

InChI=1S/C6H8N2O2/c1-8-3-5(7-4-8)2-6(9)10/h3-4H,2H2,1H3,(H,9,10)

2-(1-methylimidazol-4-yl)acetic acid

1-Methylimidazole-4-acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). Please store this product in a sealed and protected environment, avoid exposure to moisture.

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.)