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Gadoteric acid
Gadoteric acid
Gadoteric acid
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Gadoteric acid
Clinical data
Trade namesArtirem, Dotarem, Clariscan, others[1]
Other namesDOTA-Gd, Gadoterate meglumine (USAN US)
AHFS/Drugs.comInternational Drug Names
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
  • gadolinium(3+) 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H25GdN4O8
Molar mass558.65 g·mol−1
3D model (JSmol)
  • [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1
  • 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
  • Key:GFSTXYOTEVLASN-UHFFFAOYSA-K
 ☒NcheckY (what is this?)  (verify)

Gadoteric acid, sold under the brand name Dotarem among others, is a macrocycle-structured gadolinium-based MRI contrast agent (GBCA). It consists of the organic acid DOTA as a chelating agent, and gadolinium (Gd3+), and is used in form of the meglumine salt (gadoterate meglumine).[4][5] The paramagnetic property of gadoteric acid reduces the T1 relaxation time (and to some extent the T2 and T2* relaxation times) in MRI, which is the source of its clinical utility. Because it has magnetic properties, gadoteric acid develops a magnetic moment when put under a magnetic field, which increases the signal intensity (brightness) of tissues during MRI imaging.[7]

Medical uses

[edit]

It is widely used in the United States for Breast MRI imaging for women who have or are suspected to have breast cancer. It is also used for imaging of blood vessels and inflamed or diseased tissue where the blood vessels become 'leaky'. It is often used when viewing intracranial lesions with abnormal vascularity or abnormalities in the blood–brain barrier. Gadoteric acid is used for MRI imaging of the brain, spine, and associated tissues for adult and pediatric (2 years of age or older) patients. The meglumine salt it takes the form of crosses the blood brain barrier of tissue with abnormal vasculature, highlighting the affected area with MRI. Gadoterate does cross the intact blood-brain barrier, so it might affect or enhance normal brain tissue in imaging.[7] Dotarem is administered through an intravenous bolus injection, either manually or through a power injection. Dotarem can stay in the body for years. [4][5]

Adverse effects

[edit]

It is retained in the brain at a measurable level after an injection at standard dose (0.1 mmol/kg).[8] In vitro studies found it neurotoxic, less so than linears agents.[9]

Drugs with gadolinium-based contrasting agents can cause nephrogenic systemic fibrosis (NSF, or gadolinium-induced fibrosis) for those with impaired elimination of the drug. Those most at risk for NSF include patients with chronic or severe kidney disease and acute kidney injury.[4][5][10]

The rate of side effects are uncommon (0.1 to 1.0%), including nausea, headache, injection site reactions, hypertension, hypotension, dizziness, feeling hot, and somnolence.[11]

Pharmacology

[edit]

A 2020 study found Clariscan was retained more in the cerebrum, cerebellum, kidney and liver of rats than those injected with Dotarem.[12]

History

[edit]

The drug, under the brand name Dotarem, was brought to market by Guerbet.[13] It was launched on French market in 1989 and was FDA-approved in United States in March 2013.[13] As of 2013, gadoteric acid was approved in around 70 countries.[14][15] Dotarem is the seventh FDA-approved GBCA for use in central nervous system MRI.[citation needed]

In 2019, GE Healthcare launched gadoteric acid medication (as gadoterate meglumine) under the brand name Clariscan.[5][16]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Gadoteric acid

View on Grokipedia
from Grokipedia
Gadoteric acid is a synthetic, macrocyclic gadolinium-based contrast agent (GBCA) utilized in magnetic resonance imaging (MRI) to enhance the visualization of lesions with disrupted blood-brain barriers or abnormal vascularity in the brain, spine, and associated tissues. It is chemically formulated as C16H25GdN4O8, featuring a stable, ionic structure derived from the tetraazacyclododecane ligand (DOTA) chelated with gadolinium(III) ion, which provides high thermodynamic stability to minimize free gadolinium release. Commonly administered intravenously as its meglumine salt, gadoterate meglumine, under the brand name Dotarem, it was approved by the U.S. Food and Drug Administration in 2013 for use in adults and pediatric patients aged 2 years and older, with approval expanded in 2017 to include patients younger than 2 years, including term neonates. As a paramagnetic agent, gadoteric acid shortens the longitudinal relaxation time (T1) of nearby protons, thereby increasing signal intensity primarily in T1-weighted MRI sequences to delineate pathological areas more clearly. It exhibits no significant protein binding or , with approximately 73-92% excreted unchanged via the s within 48 hours, and a plasma of approximately 1.5 hours in patients with normal renal function. Due to its macrocyclic design, gadoteric acid demonstrates lower retention in tissues compared to linear GBCAs, reducing the risk of in patients with severe renal impairment, though screening for function is recommended prior to administration. Clinical studies have confirmed its efficacy in enhancing MRI diagnostic accuracy for conditions such as tumors, , and vascular abnormalities, with a favorable profile characterized by a low incidence of adverse reactions, primarily mild and transient events like or injection-site reactions. The standard dosage is 0.1 mmol/kg body weight, delivered as a bolus injection, making it suitable for both routine and high-risk imaging protocols.

Chemical properties

Structure

Gadoteric acid, also known as gadoterate, has the C₁₆H₂₅GdN₄O₈ and consists of a gadolinium(III) (Gd³⁺) chelated by the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (). The ligand features a rigid 12-membered macrocyclic ring composed of four atoms, each connected to pendant arms that coordinate to the Gd³⁺ , forming a stable cage-like structure that encapsulates the metal and minimizes dissociation. This macrocyclic architecture provides gadoteric acid with exceptional thermodynamic stability, characterized by a stability constant of log Ktherm = 25.6 (at 25°C, 0.1 M ), and high kinetic inertness, rendering it highly resistant to dechelation even under physiological conditions. As a result, gadoteric acid is classified as a macrocyclic gadolinium-based (GBCA), offering superior resistance to Gd³⁺ release compared to linear chelates, which exhibit lower stability constants (typically log Ktherm ≈ 17–22) and greater propensity for dissociation. The presence of four groups in the ligand imparts an anionic charge to the complex, contributing to its ionic nature and enhancing water solubility for clinical applications.

Physical and chemical properties

Gadoteric acid, with a molecular formula of C16H25GdN4O8, has a of 558.65 g/mol. In its clinical formulation as gadoterate meglumine (e.g., Dotarem), it appears as a clear, colorless to pale yellow at a concentration of 0.5 mol/L (approximately 0.38 g/mL of the salt). The compound exhibits high water solubility, enabling the preparation of stable 0.5 M solutions, and these formulations maintain a range of 6.5–8.0. Gadoteric acid shows thermal stability up to 100°C, as evidenced by its use in synthesis processes involving heating at this without , and it resists dissociation in biological fluids due to its macrocyclic structure, with a Gd³⁺ release estimated at approximately 43 years at physiological (7.4) and 37°C. Its spectroscopic properties include induction of paramagnetic shifts and broadening in 1H NMR spectra owing to the Gd³⁺ ion, along with a T1 relaxivity (r1) of 3.4–3.8 mM−1s−1 in human plasma at 1.5 T and 37°C.

Clinical use

Indications

Gadoteric acid is primarily indicated for use as an intravenous contrast agent in magnetic resonance imaging (MRI) to detect and characterize lesions in the central nervous system (CNS), including brain tumors, multiple sclerosis plaques, and metastases associated with blood-brain barrier disruption. It enhances visualization of areas with abnormal vascularity or BBB permeability in the brain, spine, and associated tissues, aiding in the diagnosis and assessment of intracranial abnormalities. Clinical trials have demonstrated improved lesion detection, with contrast-enhanced images showing enhanced border delineation, internal morphology, and overall visualization in 56% to 94% of adult patients compared to non-contrast MRI (p < 0.05). In the United States, indications are limited to CNS applications. In other regions, such as the , gadoteric acid is approved for additional uses including whole-body MRI for (e.g., , liver, lesions like or hepatic hemangiomas) and vascular imaging such as (MRA) of supra-aortic vessels. These applications leverage its paramagnetic properties to provide better contrast in tissues with disrupted vascular integrity, though detailed mechanisms are outlined elsewhere. Gadoteric acid is approved for pediatric use in CNS imaging starting from term neonates (≥37 weeks ), with established and in patients from birth to 17 years based on studies involving over 180 children. In adults with renal impairment, it is recommended only if estimated (eGFR) exceeds 30 mL/min/1.73 m², due to risks in severe cases. Pediatric trials similarly reported enhanced visualization in 50% to 88% of cases under 2 years, supporting its role in young patients with suspected CNS . As of March 2025, FDA labeling includes warnings for risks of (ARDS) and associated with gadolinium-based contrast agents; see profile for details.

Dosage and administration

Gadoteric acid, formulated as a 0.5 M solution (e.g., in Dotarem), is administered intravenously as a bolus injection at a standard dose of 0.1 mmol/kg body weight, equivalent to 0.2 mL/kg, for contrast-enhanced of the or body regions. This dose corresponds to a maximum volume of 20 mL per injection in adults, typically for patients up to 100 kg body weight, and is delivered manually or via power injector at a rate of approximately 2 mL/second. In pediatric patients from term neonates to 17 years, the recommended dose is 0.1 mmol/kg body weight (0.2 mL/kg), with volume scaled to body weight (e.g., maximum 10 mL for up to 50 kg), and an infusion rate of 1–2 mL/second to minimize discomfort. The solution requires no dilution prior to administration and is compatible with power injectors, facilitating dynamic imaging sequences; following injection, a ensures complete delivery. A single dose is standard for each examination. , repeat administration is not specified in FDA labeling. Per non-US guidelines, repeat doses totaling up to 0.2 mmol/kg may be used within 24 hours for specialized protocols, provided clinical justification exists and renal function is monitored. For patients at risk of renal impairment, post-administration hydration is recommended to support elimination and reduce potential complications.

Pharmacology

Mechanism of action

Gadoteric acid, a gadolinium-based , functions through the of the Gd³⁺ ion, which possesses seven unpaired electrons, creating a local that influences nearby protons in biological tissues. This paramagnetic effect shortens the T1 relaxation time of these protons, thereby increasing the signal intensity on T1-weighted (MRI) sequences, which enhances the visibility of tissues and lesions. The agent's relaxivity, quantified as r1, typically ranges from 3.5 to 4.3 mM⁻¹ s⁻¹ and varies with strength, while it exhibits no significant T2 shortening at clinical doses, minimizing unwanted signal loss. Following intravenous administration, gadoteric acid distributes primarily in the , approximating the volume of extracellular water without significant protein binding or cellular uptake. The intact chelate diffuses passively and accumulates in regions of abnormal or blood-brain barrier disruption, such as tumors, abscesses, or infarcts, where it leaks into the to provide contrast enhancement. The macrocyclic structure of gadoteric acid confers high thermodynamic stability (log K_therm = 25.6) and kinetic stability, preventing the release of toxic free Gd³⁺ ions under physiological conditions and ensuring the agent remains intact throughout its distribution. This stability is crucial for safe contrast enhancement, as free gadolinium would otherwise pose significant toxicity risks due to its reactivity with biological molecules.

Pharmacokinetics

Gadoteric acid is administered intravenously and rapidly distributes into the space following injection. The volume of distribution at is approximately 200 mL/kg, reflecting its confinement to the extracellular compartment with no significant protein binding. The plasma elimination in healthy adults is about 1.5 hours, consistent with its extracellular distribution and renal elimination profile. Gadoteric acid undergoes no and is excreted unchanged primarily via glomerular filtration in the kidneys. Renal clearance is approximately 1.3 mL/min/kg, comparable to total clearance, indicating negligible non-renal elimination pathways. In healthy adults, about 95% of the administered dose is eliminated in the within 24 hours, with less than 1% via hepatobiliary excretion. In patients with renal impairment, the of gadoteric acid are significantly altered. The elimination prolongs to around 5 hours in moderate impairment (eGFR 30–59 mL/min/1.73 m²) and approximately 14 hours in severe impairment (eGFR <30 mL/min/1.73 m²), due to reduced clearance. It is effectively removed by , with nearly complete elimination after multiple sessions. Long-term tissue retention of gadoteric acid is minimal compared to linear gadolinium-based contrast agents, owing to its macrocyclic structure and high stability. Trace amounts of have been detected in and after repeated exposures, but levels are substantially lower and decrease over time without significant clinical implications in most cases.

Safety profile

Common adverse effects

Gadoteric acid, administered as gadoterate , is generally well-tolerated, with most adverse effects being mild, transient, and self-limiting. In clinical trials involving over 2,800 patients, approximately 4% reported at least one adverse reaction, though the majority were minor. The most frequently observed common adverse effects, occurring at rates of 0.1–1%, include (0.6%), (0.4%), injection site (0.4%), injection site coldness (0.2%), and burning sensation (0.2%). Other notable effects in this range encompass (altered taste; uncommon, ≥1/1,000 to <1/100), , , , asthenia (), and injection site reactions such as warmth or . These symptoms are typically dose-related and resolve without intervention. Mild reactions, manifesting as , pruritus, or urticaria, occur in less than 0.5% of cases and are usually transient, resolving spontaneously. Post-marketing data from over 142 million administrations (as of 2025) indicate a very low overall adverse reaction rate of approximately 0.008%, with common mild effects including (0.0013%) and urticaria (0.0014%). In post-marketing studies involving 220,353 patients, the rate was 0.25%, predominantly mild effects.

Serious risks and contraindications

Gadoteric acid, a macrocyclic -based (GBCA), carries a very low risk of (NSF), a rare fibrosing disorder primarily associated with free gadolinium ions (Gd³⁺) released in patients with severe renal impairment. The incidence of NSF with macrocyclic agents like gadoteric acid is less than 0.07% in patients with stage 4 or 5 (eGFR <30 mL/min/1.73 m²), and no unconfounded cases have been reported with gadoteric acid alone. A 2025 review of over 170 million doses confirmed no cases of NSF associated with gadoteric acid. This risk is linked to impaired renal clearance, which allows dissociation of the stable gadoteric acid complex and subsequent Gd³⁺ toxicity in tissues. Gadolinium retention following gadoteric acid administration has been detected in the , , and via MRI and tissue analysis, persisting for years post-exposure in some cases. However, no confirmed clinical symptoms or have been associated with this retention in humans. Macrocyclic GBCAs like gadoteric acid exhibit lower retention rates compared to linear agents; for instance, a 2020 rat study demonstrated reduced levels in the after repeated dosing of macrocyclic formulations versus linear ones. serves as the primary retention site, with skin showing higher elimination rates. Acute reactions to gadoteric acid, including anaphylactoid events such as and , occur at a frequency of 0.001–0.01%. These reactions can be severe, though fatal cases are exceedingly rare with macrocyclic agents. A 2025 review reported the incidence of hypersensitivity reactions as less than 0.00035%. Contraindications include a history of clinically significant to gadoteric acid or other GBCAs. There are no available data on gadoterate use in women to inform drug-associated for major birth defects and . In animal reproduction studies, no adverse developmental effects were observed in rats and rabbits at doses about 16 and 10 times, respectively, the recommended human dose. Use during only if the potential benefit justifies the potential to the and imaging cannot be delayed, as can cross the . Use is not recommended in patients with known or chronic severe renal impairment (eGFR <30 mL/min/1.73 m²) unless the diagnostic benefit outweighs the ; screen renal function prior to administration in all patients. Caution is advised in patients with decompensated due to potential renal impairment and NSF .

History

Development

Gadoteric acid originated from research on chelates conducted by the Guerbet Group in during the and . The foundational ligand, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, was first synthesized in 1976 by Hermann Stetter and Wolfram Frank through the reaction of cyclen with . The Gd-DOTA complex, known as gadoteric acid, was developed by Guerbet in the mid- to exploit the macrocyclic structure of DOTA for superior stability with ions. Preclinical studies in the 1980s evaluated the complex's properties in animal models, including rats and rabbits, confirming its high thermodynamic and kinetic stability, which prevented dissociation of free Gd³⁺ even at elevated doses. These investigations demonstrated effective enhancement of MRI contrast in tissues while showing no of nephrogenic systemic fibrosis-like lesions or significant , underscoring the macrocyclic design's role in minimizing gadolinium-related risks. A key innovation was the macrocyclic architecture of Gd-DOTA, which provided greater resistance to transmetallation and dechelation compared to linear chelates, thereby reducing the potential for free Gd³⁺ . This approach was patented by Guerbet in 1986 for the salt of the Gd-DOTA complex, highlighting its diagnostic potential in imaging applications. Phase I–III clinical trials in the late encompassed over 50 studies involving approximately 3,500 subjects, primarily assessing , efficacy, and safety across various MRI indications. These trials, conducted in Europe, enrolled around 4,200 patients between 1988 and 1989 in , , and , and revealed a low rate of about 0.8%, with superior tolerability over agents used in comparable imaging procedures. Following successful outcomes, gadoteric acid received its initial marketing approval in France in 1989 and was commercialized as Dotarem.

Regulatory approvals

Gadoteric acid, marketed as Dotarem (gadoterate ), received its initial regulatory approval in in 1989 from the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) for use as a in (MRI). By 2013, the agent had gained approval in approximately 70 countries worldwide, reflecting broad international recognition of its safety and efficacy profile. In the United States, the (FDA) approved Dotarem in March 2013 for intravenous use in adults and pediatric patients aged 2 years and older, designating it as a macrocyclic gadolinium-based (GBCA) with the lowest associated risk of (NSF). This approval was extended in 2019 to include full pediatric use from birth (term neonates ≥37 weeks gestational age) to 17 years, based on updated safety data confirming no increased risks in younger patients. The entry of generics followed patent expiry, with GE Healthcare receiving FDA approval for Clariscan (gadoterate meglumine) in November 2019 as a macrocyclic GBCA equivalent to Dotarem for MRI enhancement in adults and pediatric patients aged 2 years and older. In 2017, the (EMA) reviewed gadolinium-containing contrast agents and confirmed the favorable risk-benefit profile of macrocyclic agents like Dotarem for their approved indications, including pediatric use. Post-approval label updates addressed emerging safety concerns. In December 2017, the FDA issued a class-wide warning for all GBCAs, including Dotarem, regarding gadolinium retention in the and other tissues, though no clinical adverse effects were identified at that time. Subsequent studies in 2020 reaffirmed the agent's favorable safety profile, supporting unrestricted use in patients with mild renal impairment ( ≥30 mL/min/1.73 m²) without dosage adjustments, as macrocyclic stability minimizes dissociation risks. As of 2025, over 170 million doses of gadoterate meglumine have been administered globally, with recent reviews reaffirming its safety across all age groups.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/204781s015lbl.pdf
  2. https://go.drugbank.com/drugs/DB09132
  3. https://www.biospace.com/fda-approves-guerbet-s-dotarem-gadoterate-meglumine-for-pediatric-patients-younger-than-two-years
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Gadoteric-Acid
  5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204781s001lbl.pdf
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC8746842/
  7. https://pdf.hres.ca/dpd_pm/00044974.PDF
  8. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204781Orig1s000PharmR.pdf
  9. https://patents.google.com/patent/CA3181564A1/en
  10. https://www.sciencedirect.com/science/article/abs/pii/S0168127322000010
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC7963719/
  12. https://www.tandfonline.com/doi/full/10.2147/RMI.S46798
  13. https://radiopaedia.org/articles/gadoterate-meglumine?lang=us
  14. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/204781Orig1s017ltr.pdf
  15. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/204781s016lbl.pdf
  16. https://www.guerbet.com/media/td3nxfqa/04-pdot-pi-digital-july2024_36-approved.pdf
  17. https://adus-radiologie.ch/files/ESUR_Guidelines_10.0.pdf
  18. https://www.spandidos-publications.com/10.3892/ijmm.2016.2744
  19. https://ec.europa.eu/health/documents/community-register/2005/200503299136/anx_9136_en.pdf
  20. https://www.sciencedirect.com/topics/medicine-and-dentistry/gadoteric-acid
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC4559982/
  22. https://insightsimaging.springeropen.com/articles/10.1186/s13244-019-0824-5
  23. https://www.guerbet.com/media/yobfx4cu/spc-dotarem-pfs_dec-2020.pdf
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC12490340/
  25. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2757311
  26. https://link.springer.com/article/10.1007/s00330-023-10281-3
  27. https://journals.lww.com/investigativeradiology/fulltext/2025/11000/safety_of_gadoterate_meglumine__a_review_of.2.aspx
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC6269889/
  29. https://patents.google.com/patent/FR2596992A1/en
  30. https://www.openaccessjournals.com/articles/safety-and-clinical-usefulness-of-gadoteric-acid-including-postmarketing-surveillance-9387.html
  31. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204781Orig1s000ClinPharmR.pdf
  32. https://www.prnewswire.com/news-releases/fda-approves-dotarem-gadoterate-meglumine-first-macrocyclic-and-ionic-gadolinium-based-contrast-agent-in-usa-199354771.html
  33. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204781s012lbl.pdf
  34. https://www.gehealthcare.com/about/newsroom/press-releases/ge-healthcare-announces-us-fda-approval-macrocyclic-mri-contrast-agent-clariscan%25E2%2584%25A2
  35. https://www.ema.europa.eu/en/medicines/human/referrals/gadolinium-containing-contrast-agents
  36. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body
  37. https://ajronline.org/doi/pdf/10.2214/AJR.23.30036
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