Contrast agent; Gadoteric acid is an extracellular, non-specific, macrocyclic gadolinium-based contrast agent used in magnetic resonance imaging (MRI). It distributes in the extracellular space and enhances signal intensity by shortening the T1 relaxation time of nearby water protons. [1, 2]

Gadoteric acid offers early improved absorbability, stronger mouthwash, and better and more visible repairability in DCE-MRI of cellular liver cancer (particularly hypervascular lesions) [1].

---

Regarding in vitro activity, the primary function of gadoteric acid is to alter proton relaxation, characterized by its relaxivity. In aqueous solutions at 20 MHz and 37°C, it has a T1 relaxivity (r1) of approximately 3.4 mM⁻¹·s⁻¹ and a T2 relaxivity (r2) of approximately 4.27 mM⁻¹·s⁻¹ . Its ability to enhance MRI contrast is directly linked to this relaxivity. For instance, in dynamic contrast-enhanced MRI (DCE-MRI) of hepatocellular carcinoma, gadoteric acid has been shown to provide significantly stronger "wash-in" and "wash-out" effects compared to hepatocyte-specific agents, leading to better contrast and conspicuity of hypervascular lesions . In comparative animal studies, macrocyclic GBCAs like gadoteric acid exhibit consistent enhancement kinetics across different body regions (brain, liver, kidney), although agents with higher relaxivity like gadobutrol produce greater absolute signal enhancement (SE) .

In patients with liver cirrhosis and hepatocellular carcinoma (HCC), gadoteric acid-enhanced MRI showed significantly stronger wash-in (median 0.9 vs. 0.4 for gadoxetic acid, P < 0.001) and stronger wash-out (median 19.8 vs. 9.3 for gadoxetic acid, P = 0.006) of HCC lesions. Contrast-to-noise ratio (CNR) during the late arterial phase was significantly higher with gadoteric acid (median 72.7 vs. 49.4 for gadoxetic acid, P = 0.005). Arterial phase hyperenhancement (APHE) was observed in 91.3% of nodules on gadoteric acid-enhanced MRI vs. 73.9% on gadoxetic acid-enhanced MRI (P = 0.133). Non-peripheral washout on the portal venous phase was observed in 82.6% of nodules with gadoteric acid vs. 73.9% with gadoxetic acid (P = 0.479). [1]
In a large post-marketing surveillance study of 84,621 patients, gadoteric acid was administered intravenously at a dose of 0.1 mmol/kg body weight (average volume 16.4 mL, range 0.6-38 mL). The average volume injected per kg body weight was 0.22 ± 0.07 mL/kg. Manual injection was used in 74.5% of cases, and automated injection in 25.5%. Image quality was rated as good or excellent in 97.1% of examinations. Diagnostic image quality was achieved in 99.7% of all MRI examinations. [2]

---

The routine use of dynamic-contrast-enhanced MRI (DCE-MRI) of the liver using hepatocyte-specific contrast agent (HSCA) as the standard of care for the study of focal liver lesions is not widely accepted and opponents invoke the risk of a loss in near 100% specificity of extracellular contrast agents (ECA) and the need for prospective head-to-head comparative studies evaluating the diagnostic performance of both contrast agents. The Purpose of this prospective intraindividual study was to conduct a quantitative and qualitative head-to-head comparison of DCE-MRI using HSCA and ECA in patients with liver cirrhosis and HCC. Twenty-three patients with liver cirrhosis and proven HCC underwent two 3 T-MR examinations, one with ECA (Gadoteric acid) and the other with HSCA (gadoxetic acid). Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), wash-in, wash-out, image quality, artifacts, lesion conspicuity, and major imaging features of LI-RADS v2018 were evaluated. Wash-in and wash-out were significantly stronger with ECA compared to HSCA (P < 0.001 and 0.006, respectively). During the late arterial phase (LAP), CNR was significantly lower with ECA (P = 0.005), while SNR did not differ significantly (P = 0.39). In qualitative analysis, ECA produced a better overall image quality during the portal venous phase (PVP) and delayed phase (DP) compared to HSCA (P = 0.041 and 0.008), showed less artifacts in the LAP and PVP (P = 0.003 and 0.034) and a higher lesion conspicuity in the LAP and PVP (P = 0.004 and 0.037). There was no significant difference in overall image quality during the LAP (P = 1), in artifacts and lesion conspicuity during the DP (P = 0.078 and 0.073) or in the frequency of the three major LI-RADS v2018 imaging features. In conclusion, ECA provides superior contrast of HCC-especially hypervascular HCC lesions-in DCE-MR in terms of better perceptibility of early enhancement and a stronger washout.[1]

Protein/enzyme activity experiments for Gadoteric acid focus on measuring its ability to alter proton relaxation rates, a property known as relaxivity. These experiments are typically conducted in aqueous solutions or biological fluids (like plasma or serum) using specialized nuclear magnetic resonance (NMR) relaxometers. The procedure involves dissolving the contrast agent at specific concentrations and measuring the relaxation times (T1 and T2) of water protons. The relaxivity values (r1 and r2, expressed in mM⁻¹·s⁻¹) are then calculated from the slope of the relaxation rate (1/T1 or 1/T2) plotted against the gadolinium concentration. Unlike gadobenate dimeglumine, Gadoteric acid does not bind to serum proteins, so its relaxivity in plasma is similar to that measured in water .

Cellular studies have demonstrated that Gadoteric acid (Gd-DOTA) exhibits low cytotoxicity and distinct cellular uptake patterns. In renal tubular cell models (LLC-PK1), Gd-DOTA induced less necrosis and apoptosis compared to linear GBCAs like gadopentetate dimeglumine at angiographic concentrations (125 mmol/L) . In cancer cell lines, such as K562 leukemia cells, Gd-DOTA showed concentration-dependent decreases in cell viability, suggesting potential direct effects on malignant cells . Importantly, human whole blood studies have confirmed that white blood cells (WBCs) take up Gd-DOTA both ex vivo and in vivo. In patients undergoing contrast-enhanced MRI, isolated WBCs showed substantial gadolinium uptake (21–444 attogram/WBC, ~0.2–5.5 µM intracellular concentration), whereas no uptake was detected in erythrocytes . Furthermore, Gd-DOTA demonstrated antioxidant properties in the FRAP (Ferric Reducing Ability of Plasma) assay but did not alter red blood cell morphology, hemolysis, or reactive oxygen species (ROS) levels .

Several animal models have been used to study Gadoteric acid. To investigate its effects on the submandibular gland, researchers used a repeated-dose model in Sprague Dawley rats. The animals were divided into groups, including a control group, a saline group, and a Gadoteric acid group, which received daily intraperitoneal injections of 0.1 mmol/kg for eight days. On the 9th day, the rats were sedated, and their submandibular glands were removed for histopathological and immunohistochemical analysis to assess tissue damage and apoptosis . Another common procedure is used for pharmacokinetic and biodistribution studies. In this model, mice receive a single intratracheal instillation of a Gadoteric acid solution. The distribution and clearance of the contrast agent are then monitored non-invasively over time using dynamic T1-weighted magnetic resonance imaging (MRI). Pharmacokinetic parameters are calculated by measuring the signal enhancement in specific tissues, such as the lungs and kidneys .

Absorption, Distribution and Excretion
The kinetics of total gadolinium appeared to be linear within the studied dose range (0.1 to 0.3 mmol/kg). In healthy volunteers, after administration of 0.1 mmol/kg gadoteric meglumine, the Cmax, Tmax, AUC0-t, and AUC0-∞ values for female subjects were 799.03 (192.63) µmol/L, 5.00 (0.10-10.00) min, 953.51 (76.22) µmolh/L, and 970.72 (73.34) µmolh/L, respectively, while the corresponding values for male subjects were 836.85 (451.02) µmol/L, 5.00 (0.11-10.00) min, 1038.74 (240.46) µmolh/L, and 1061.16 (239.24) µmolh/L, respectively. Following administration of 0.1 mmol/kg gadoteric acid meglumine, total gadolinium was primarily excreted in the urine, with 72.9 ± 17.0% in female subjects and 85.4 ± 9.7% (mean ± standard deviation) in male subjects excreted within 48 hours. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2% in female subjects and 92.0 ± 12.0% in male subjects recovering in the urine within 48 hours. The steady-state volume of distribution of total gadolinium in healthy subjects was 179 ± 26 mL/kg in female subjects and 211 ± 35 mL/kg in male subjects, roughly equivalent to the extracellular volume of distribution. The distribution of gadoteric acid in blood cells remains unclear. In healthy subjects, renal clearance and total clearance of total gadolinium were comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg for women, and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg for men), indicating that the drug is primarily cleared by the kidneys. Metabolites/Metabolites: It is currently unclear whether gadoteric acid is metabolized. Biological Half-Life: Following intravenous administration of 0.1 mmol/kg gadoteric acid, the mean elimination half-life was approximately 1.4 ± 0.2 hours for women and 2.0 ± 0.7 hours for men. [L49911]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Calcium gadolinate is one of the most stable gadolinium contrast agents and is theoretically one of the safest drugs for use during lactation. Guidelines from multiple professional organizations indicate that breastfeeding mothers do not need to interrupt breastfeeding after receiving gadolinium-containing contrast agents. However, since there is currently no published experience on the use of calcium gadolinate during lactation, other contrast agents may be preferred, especially when breastfeeding newborns or premature infants. ◉ Effects on Breastfed Infants
No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

---

Protein Binding
In vitro experiments show that calcium gadolinate does not bind to proteins.

---

In a post-marketing surveillance study of 84,621 patients, gadoteric acid was well tolerated. Adverse events occurred in 285 patients (0.34%). The most common adverse events were nausea (144 patients, 0.17%), vomiting (43 patients, 0.05%), urticaria (25 patients, 0.03%), and dizziness (20 patients, 0.02%). Serious adverse events were reported in 8 patients (0.009%), including anaphylactic shock, ventricular fibrillation, heart arrest, and circulatory failure. All patients recovered. [2]
Patients with a history of allergies had a significantly higher risk of adverse events (0.62%, P < 0.001) compared to the general population. Patients with a previous allergic reaction to contrast medium also had a higher risk (1.23%, P < 0.001). There was no elevated incidence of adverse events in patients with renal failure or liver dysfunction. [2]
In the comparative study with gadoxetic acid, gadoteric acid produced fewer artifacts during the late arterial phase (P = 0.003) and portal venous phase (P = 0.034) and had higher lesion conspicuity during the late arterial phase (P = 0.004) and portal venous phase (P = 0.037). [1]

[1]. MR imaging of hepatocellular carcinoma: prospective intraindividual head-to-head comparison of the contrast agents gadoxetic acid and gadoteric acid. Sci Rep. 2022 Nov 3;12(1):18583.

[2]. Tolerability and diagnostic value of gadoteric acid in the general population and in patients with risk factors: results in more than 84,000 patients. Eur J Radiol. 2012 May;81(5):885-90.

Gadoteric acid (usually used as a salt, gadoterate meglumine) is a macrocyclic ionic gadolinium-based contrast agent (GBCA). It consists of the organic acid DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and gadolinium (Gd³⁺), with DOTA used for its chelating properties. Gadoteric acid meglumine exhibits extremely high thermodynamic, apparent, and kinetic stability, partly due to its macrocyclic structure, resulting in improved safety due to reduced gadolinium dechelation tendency. On March 20, 2013, the U.S. Food and Drug Administration (FDA) approved gadoterate under the brand name DOTAREM for use in adults and children aged 2 years and older for magnetic resonance imaging (MRI) of the brain (intracranial), spine, and related tissues to detect and visualize areas of blood-brain barrier (BBB) disruption and/or vascular abnormalities.

---

Drug Indications
Gadotate is indicated for use in the detection and visualization of areas of blood-brain barrier (BBB) disruption and/or vascular abnormalities in the brain (intracranial), spine, and related tissues of adult and pediatric patients (including full-term newborns) using magnetic resonance imaging (MRI).
FDA Label

---

Mechanism of Action
Gadotate is a paramagnetic molecule that generates a magnetic moment when placed in a magnetic field. This magnetic moment enhances the relaxation rate of protons in nearby water, thereby increasing the signal intensity (brightness) of the tissue. In MRI, the imaging of normal and diseased tissues depends on variations in radiofrequency signal intensity, which are caused by differences in proton density, spin-lattice relaxation time (T1), or spin-spin relaxation time (T2). When placed in a magnetic field, calcium gadotate shortens the T1 and T2 relaxation times of the target tissue. At recommended doses, this effect is most pronounced in T1-weighted sequences.

---

Gadoteric acid (gadoterate meglumine, Gd-DOTA, Dotarem) is a macrocyclic, ionic, extracellular gadolinium-based contrast agent approved for MRI of the central nervous system, abdomen, and for MR angiography. [2]
In a prospective intraindividual study comparing gadoteric acid and the hepatocyte-specific contrast agent gadoxetic acid for HCC diagnosis, gadoteric acid provided superior contrast of HCC lesions, particularly hypervascular lesions, with better perceptibility of early enhancement and stronger washout. However, it lacks the hepatobiliary phase information provided by hepatocyte-specific agents. [1]

C16H25GDN4O8

558.65

559.091

72573-82-1

158536

White to off-white solid

701.6ºC at 760 mmHg

378.1ºC

1

12

5

29

510

0

C1CN(CCN(CCN(CCN1CC(=O)O)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-].[Gd+3]

GFSTXYOTEVLASN-UHFFFAOYSA-K

InChI=1S/C16H28N4O8.Gd/c21-13(22)9-17-1-2-18(10-14(23)24)5-6-20(12-16(27)28)8-7-19(4-3-17)11-15(25)26;/h1-12H2,(H,21,22)(H,23,24)(H,25,26)(H,27,28);/q;+3/p-3

2-[4,7-bis(carboxylatomethyl)-10-(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+)

Gadoteric acid; 72573-82-1; DOTA-Gd; Artirem; Artirem (TN);

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)

H2O : ~100 mg/mL (~179.01 mM; with ultrasonication (<60°C))

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 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).

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)]
*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)

---

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
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

---

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.

---

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