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Pentetic acid
Pentetic acid
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Pentetic acid
Structure of DTPA
Structure of DTPA
Names
IUPAC name
N,N′-{[(Carboxymethyl)azanediyl]di(ethane-2,1-diyl)}bis[N-(carboxymethyl)glycine]
Systematic IUPAC name
2,2′,2′′,2′′′-{[(Carboxymethyl)azanediyl]bis(ethane-2,1-diylnitrilo)}tetraacetic acid
Other names
DTPA; H5dtpa; Diethylenetriaminepentaacetic acid; Penta(carboxymethyl)diethylenetriamine[1]
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.593 Edit this at Wikidata
KEGG
RTECS number
  • MB8205000
UNII
  • InChI=1S/C14H23N3O10/c18-10(19)5-15(1-3-16(6-11(20)21)7-12(22)23)2-4-17(8-13(24)25)9-14(26)27/h1-9H2,(H,18,19)(H,20,21)(H,22,23)(H,24,25)(H,26,27) checkY
    Key: QPCDCPDFJACHGM-UHFFFAOYSA-N checkY
  • C(CN(CC(=O)O)CC(=O)O)N(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Properties
C14H23N3O10
Molar mass 393.349 g·mol−1
Appearance White crystalline solid
Melting point 220 °C (428 °F; 493 K)
Boiling point decomposes at a higher temp.
<0.5 g/100 mL
Acidity (pKa) ~1.80 (20 °C) [2]
Hazards
Flash point Non-flammable
Related compounds
Related compounds
 EDTA, NTA
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Pentetic acid or diethylenetriaminepentaacetic acid (DTPA) is an aminopolycarboxylic acid consisting of a diethylenetriamine backbone with five carboxymethyl groups. The molecule can be viewed as an expanded version of EDTA and is used similarly. It is a white solid with limited solubility in water.

Coordination properties

[edit]

The conjugate base of DTPA has a high affinity for metal cations. Thus, the penta-anion DTPA5− is potentially an octadentate ligand assuming that each nitrogen centre and each –COO− group counts as a centre for coordination. The formation constants for its complexes are about 100 greater than those for EDTA.[3] As a chelating agent, DTPA wraps around a metal ion by forming up to eight bonds. Its complexes can also have an extra water molecule that coordinates the metal ion.[4] Transition metals, however, usually form less than eight coordination bonds. So, after forming a complex with a metal, DTPA still has the ability to bind to other reagents, as is shown by its derivative pendetide. For example, in its complex with copper(II), DTPA binds in a hexadentate manner utilizing the three amine centres and three of the five carboxylates.[5]

The distinction between H5DTPA, "DTPA", and DTPA5− is often not explicit.

Chelating applications

[edit]
Structure of the ytterbium complex of DTPA5-. Like related lanthanide complexes, the DTPA wraps around the metal ion as a octadentate ligand. Water is also bound to Yb3+, giving it a coordination number of nine.[6] Color code: red = O, blue = N, green = Yb

Like the more common EDTA, DTPA is predominantly used as chelating agent for complexing and sequestering metal ions.

DTPA has been considered for treatment of radioactive materials such as plutonium, americium, and other actinides.[4] In theory, these complexes are more apt to be eliminated in urine. It is normally administered as the calcium or zinc salt (Ca or Zn-DTPA), since these ions are readily displaced by more highly charged cations and mainly to avoid to depleting them in the organism. DTPA forms complexes with thorium(IV), uranium(IV), neptunium(IV), and cerium(III/IV).[7]

In August, 2004 the U.S. US Food and Drug Administration (USFDA) determined zinc-DTPA and calcium-DTPA to be safe and effective for treatment of those who have breathed in or otherwise been contaminated internally by plutonium, americium, or curium. The recommended treatment is for an initial dose of calcium-DTPA, as this salt of DTPA has been shown to be more effective in the first 24 hours after internal contamination by plutonium, americium, or curium. After that time has elapsed both calcium-DTPA and zinc-DTPA are similarly effective in reducing internal contamination with plutonium, americium or curium, and zinc-DTPA is less likely to deplete the body's normal levels of zinc and other metals essential to health. Each drug can be administered by nebulizer for those who have breathed in contamination, and by intravenous injection for those contaminated by other routes.[8]

Gadolinium (Gd3+)-DTPA compounds are MRI contrasting agents.[9]

DTPA under the form of iron(II) chelate (Fe-DTPA, 10 – 11 wt. %) is also used as aquarium plants fertilizer. The more soluble form of iron, Fe(II), is a micronutrient needed by aquatic plants. By binding to Fe2+ ions DTPA prevents their precipitation as Fe(OH)3, or Fe2O3 · n H2O poorly soluble oxy-hydroxides after their oxidation by dissolved oxygen. It increases the solubility of Fe2+ and Fe3+ ions in water, and therefore the bioavailability of iron for aquatic plants. It contributes so to maintain iron under a dissolved form (probably a mix of Fe(II) and Fe(III) DTPA complexes) in the water column. It is unclear to what extent does DTPA really contribute to protect dissolved Fe2+ against air oxidation and if the Fe(III)-DTPA complex cannot also be directly assimilated by aquatic plants simply because of its enhanced solubility. Under natural conditions, i.e., in the absence of complexing DTPA, Fe2+ is more easily assimilated by most organisms, because of its 100-fold higher solubility than that of Fe3+.

In pulp and paper mills DTPA is also used to remove dissolved ferrous and ferric ions (and other redox-active metal ions, such as Mn or Cu) that otherwise would accelerate the catalytic decomposition of hydrogen peroxide (H2O2 reduction by Fe2+ ions according to the Fenton reaction mechanism).[10] This helps preserving the oxidation capacity of the hydrogen peroxide stock which is used as oxidizing agent to bleach pulp in the chlorine-free process of paper making.[11] Several thousands tons of DTPA are produced annually for this purpose in order to limit the non-negligible losses of H2O2 by this mechanism.[3]

DTPA chelating properties are also useful in deactivating calcium and magnesium ions in hair products. DTPA is used in over 150 cosmetic products.[12]

Biochemistry

[edit]

DTPA is more effective than EDTA to deactivate redox-active metal ions such as Fe(II)/(III), Mn(II)/(IV) and Cu(I)/(II) perpetuating oxidative damages induced in cells by superoxide and hydrogen peroxide.[13][10] DTPA is also used in bioassays involving redox-active metal ions.

Environmental impact

[edit]

An unexpected negative environmental impact of chelating agents, as DTPA, is their toxicity for the activated sludges in the treatment of Kraft pulping effluents.[14] Most of the DTPA worldwide production (several thousands of tons)[3] is intended to avoid hydrogen peroxide decomposition by redox-active iron and manganese ions in the chlorine-free Kraft pulping processes (total chlorine free (TCF) and environmental chlorine free (ECF) processes). DTPA decreases the biological oxygen demand (BOD) of activated sludges and therefore their microbial activity.

[edit]

Compounds that are structurally related to DTPA are used in medicine, taking advantage of the high affinity of the triaminopentacarboxylate scaffold for metal ions.

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pentetic acid

View on Grokipedia
from Grokipedia
Pentetic acid, systematically known as diethylenetriaminepentaacetic acid (DTPA), is a synthetic polyaminopolycarboxylic acid chelating agent with the molecular formula C14H23N3O10 and a molecular weight of 393.35 g/mol. Characterized by its white to off-white crystalline solid appearance, high solubility in , and of 219–220 °C (with decomposition at higher temperatures), it features a hexadentate that enables the formation of stable octahedral complexes with di- and trivalent metal cations, such as transition metals and actinides. This property makes pentetic acid a versatile compound widely applied in medical diagnostics and therapy, as well as in for metal sequestration and stabilization. In , pentetic acid and its salts play crucial roles in and imaging. The calcium trisodium salt (Ca-DTPA) and zinc trisodium salt (Zn-DTPA) are FDA-approved for treating internal contamination from radioactive transuranic elements like , , and , where they bind these metals to promote rapid urinary excretion and reduce radiation exposure. Administered intravenously, these agents are particularly effective in scenarios such as nuclear incidents, with Ca-DTPA preferred initially for its mobilization efficacy and Zn-DTPA for prolonged treatment to minimize depletion of essential metals like . Pentetic acid derivatives are also integral to diagnostic radiopharmaceuticals. , formed by complexing DTPA with the gamma-emitting isotope , is used for assessment and renal via intravenous administration, as well as for lung ventilation via . It is also used for of dynamics via . Historically, gadopentetate dimeglumine—a -DTPA complex approved by the FDA in 1988—served as a paramagnetic for (MRI), enhancing the visibility of intracranial tumors, lesions, and vascular abnormalities by shortening T1 relaxation times in tissues. However, its clinical use has diminished due to risks of in patients with impaired renal function and concerns over retention in the body. Beyond , pentetic acid finds applications in industry as a sequestrant for in detergents, , and production, where it prevents metal-catalyzed degradation, though its environmental persistence has prompted regulatory scrutiny in some contexts. Safety profiles indicate potential for eye irritation, , and organ damage with prolonged exposure, necessitating careful handling and medical supervision in therapeutic uses.

Structure and properties

Molecular structure

Pentetic acid, chemically known as diethylenetriaminepentaacetic acid (DTPA), possesses the molecular formula \ceC14H23N3O10\ce{C14H23N3O10} and the systematic IUPAC name 2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid. The molecular structure is built around a backbone, consisting of three tertiary atoms linked by two bridges (\ce−CH2−CH2−\ce{-CH2-CH2-}). This linear forms the central scaffold to which five pendant acetic acid groups (\ce−CH2COOH\ce{-CH2COOH}) are attached via the atoms: each of the two terminal nitrogens is substituted with two carboxymethyl groups, while the central carries a single carboxymethyl group. This arrangement results in an octadentate capable of forming eight coordinate bonds, with three donor atoms from the backbone and five donor oxygen atoms from the deprotonated groups. The is achiral, lacking any stereocenters, and exhibits a flexible conformation due to the rotatable single bonds in the and methylene linkages, enabling it to adopt various geometries. The can be depicted as: \ce(HO2CCH2)2N−CH2CH2−N(CH2CO2H)−CH2CH2−N(CH2CO2H)2\ce{(HO2CCH2)2N-CH2CH2-N(CH2CO2H)-CH2CH2-N(CH2CO2H)2} This representation highlights the symmetric placement of the pendant groups relative to the central nitrogen, facilitating efficient spatial arrangement around target ions.

Physical properties

Pentetic acid appears as a white to off-white crystalline solid in its anhydrous form. The molecular weight of pentetic acid is 393.35 g/mol. It has a melting point of 220 °C and decomposes above 235 °C. Pentetic acid exhibits limited solubility in water, approximately 5 g/L at 20 °C, and is sparingly soluble in , while remaining insoluble in non-polar solvents such as . The compound is hygroscopic, tending to absorb moisture from the air, and is often stored and supplied as a to maintain stability. Common salts, such as the pentasodium salt (Na₅DTPA), demonstrate markedly higher solubility, exceeding 1000 g/L at ambient temperatures, which facilitates its incorporation into aqueous formulations for medical and industrial uses. The calcium trisodium salt (CaNa₃DTPA), widely used in pharmaceutical preparations, is similarly highly soluble in water, enabling concentrations up to 200 g/L in injectable solutions.

Chemical reactivity

Pentetic acid, systematically known as diethylenetriaminepentaacetic acid (DTPA), functions as a polyprotic acid due to its five carboxylic acid groups attached to a diethylenetriamine backbone. These groups enable stepwise deprotonation, with reported pKa values of approximately 1.8, 2.6, 4.4, 8.8, and 10.4 at 25°C, reflecting the increasing difficulty in removing successive protons from the carboxylates. The first three pKa values are particularly low, indicating strong acidity for the initial deprotonations, while the higher values correspond to the loss of protons from less acidic sites, including potential involvement of the amine nitrogens in later steps. This acid-base behavior allows DTPA to exist in multiple protonation states, influencing its solubility and reactivity in different chemical environments. The state of DTPA is highly -dependent, with the fully protonated H₅DTPA⁰ form dominating at low (below approximately 1), where all five carboxylic groups are neutral. As rises, occurs progressively: at mildly acidic to neutral (around 4–7), the tri-anionic H₂DTPA³⁻ species predominates, with three carboxylates deprotonated; in alkaline conditions ( > 10), the penta-anionic DTPA⁵⁻ form prevails, maximizing negative charge and coordination potential. These shifts in affect the molecule's electrostatic properties and hydrogen-bonding capabilities, contributing to its versatility as a chelating agent precursor, though the free ligand's reactivity remains centered on acid-base equilibria rather than direct metal binding in this context. DTPA demonstrates good hydrolytic stability under neutral aqueous conditions, resisting decomposition at physiological and , which supports its use in buffered solutions without significant degradation. However, exposure to strong acids or bases at elevated temperatures (above 200°C) leads to or of the amide-like linkages, breaking down the backbone. This stability profile contrasts with its behavior in extreme media, where or extremes can weaken intramolecular interactions. In terms of properties, DTPA is inherently inert and does not undergo direct oxidation or reduction under typical conditions, lacking -active functional groups. Instead, it indirectly influences processes by chelating and stabilizing metal ions, preventing their participation in oxidative reactions; for instance, it deactivates trace levels of -active metals like iron or that could catalyze unwanted oxidations in formulations. The free ligand's compatibility with various media is high, though it readily reacts with divalent and trivalent metal ions to form chelates, a behavior that underscores its role as a multidentate without altering its intrinsic non-redox nature.

Coordination chemistry

Ligand behavior

Pentetic acid, or diethylenetriaminepentaacetic acid (DTPA), serves as a multidentate capable of coordinating metal ions through its three secondary atoms and five oxygen atoms, offering eight potential donor sites that support hexadentate to octadentate binding modes. This donor set, with the nitrogens providing borderline basicity and the oxygens acting as hard donors, facilitates the formation of stable chelate rings via the ligand's diethylenetriamine backbone and pendant arms. In , DTPA typically envelops the central metal in a cage-like structure, most commonly employing an N₃O₅ for larger ions such as trivalent lanthanides and actinides, though variations like N₃O₃ occur with smaller metals. The ligand's inherent flexibility, stemming from its linear yet branched architecture, enables adaptation to diverse metal radii and geometries, including distorted tricapped trigonal prismatic or square antiprismatic arrangements that accommodate octahedral-like preferences in certain complexes. DTPA demonstrates selectivity toward hard Lewis acids, such as Ca²⁺, Fe³⁺, and trivalent actinides, owing to its oxygen-rich donor profile that aligns with hard-soft acid-base principles for effective binding of high-charge-density cations. Coordination is readily confirmed spectroscopically: analysis shows shifts in asymmetric and symmetric stretches (typically from ~1600 cm⁻¹ and ~1400 cm⁻¹ in the free to altered positions upon metal binding), reflecting and engagement of oxygen donors. spectra further evidence through perturbations and broadened or split signals due to restricted ligand rotation and paramagnetic effects in metal-bound forms.

Complex formation and stability

Pentetic acid (DTPA) forms highly stable 1:1 complexes with a variety of metal ions, primarily through its octadentate coordination, resulting in overall stability constants (log β) that reflect the strength of . These constants increase with the metal ion's , demonstrating greater affinity for higher-charged species. For instance, the log β value for the Ca(II)-DTPA complex is 10.7 at 20°C and μ = 0.1 M KCl, while for Fe(III)-DTPA it reaches 28.6 under similar conditions, and for Gd(III)-DTPA it is approximately 21.8. For Pu(IV)-DTPA, the stability is notably high, with log β ≈ 31.8, underscoring DTPA's utility in .
Metal IonChargelog β (DTPA complex)Conditions
Ca²⁺+210.720°C, μ=0.1 M KCl
Fe³⁺+328.620°C, μ=0.1 M KCl
Gd³⁺+321.825°C, μ=0.1 M
Pu⁴⁺+4≈31.825°C, I=1.0 M NaClO₄
Stepwise formation constants for DTPA complexes illustrate the chelate effect, where initial binding to carboxylate groups is followed by stronger amine coordination, with each successive log K_i decreasing but cumulatively yielding high overall stability; for example, in Fe(III)-DTPA formation, the constants reflect progressive deprotonation and wrapping around the metal center. Thermodynamic parameters for DTPA complexation with trivalent ions such as Eu(III), Am(III), and Cm(III) reveal an -driven process, characterized by positive changes (endothermic contributions) and large positive gains due to desolvation and conformational flexibility during multidentate binding. For the Eu(III)-DTPA complex, ΔH = +15.4 kJ/mol and ΔS = +431 J/K/mol at 25°C and high (I = 6.60 M NaClO₄), resulting in a favorable ΔG = -113.1 kJ/mol. Similar trends hold for actinides like Am(III), with ΔH ≈ +6.8 kJ/mol and ΔS ≈ +404 J/K/mol, emphasizing the role of release in stabilizing the complexes. DTPA displays pronounced selectivity for trivalent ions (e.g., Gd³⁺, In³⁺) over divalent ones (e.g., Ca²⁺, Zn²⁺), as indicated by log β values that are 10-15 orders of magnitude higher for +3 ions, driven by enhanced electrostatic interactions and better geometric fit within the cavity. This preference aligns with the Irving-Williams series for first-row transition metals, where complex stability follows the order Mn(II) < Fe(II) < Co(II) < Ni(II) < Cu(II) > Zn(II), applicable to DTPA chelates due to similar ligand field effects. Kinetically, DTPA complexation proceeds rapidly at , with formation rate constants often exceeding 10³ M⁻¹ s⁻¹ for trivalent metals under neutral conditions, enabling quick in practical applications. Dissociation, however, is slow, conferring kinetic inertness; for Gd(III)-DTPA, the acid-catalyzed dissociation rate in 0.1 M HCl is significantly lower than for related ligands like DTPA-BMA, with half-lives on the order of hours to days depending on . Complex formation with DTPA is highly pH-dependent, achieving optimal efficiency between pH 4 and 7, where the ligand exists predominantly as partially protonated species (e.g., H₃L²⁻ or H₂L³⁻) that facilitate deprotonation during binding without excessive proton competition. Below pH 4, protonation of donor sites impedes coordination, reducing effective stability, while above pH 7, potential hydroxide formation with the metal can compete, though the complexes remain stable in mildly basic media.

Applications

Medical and pharmaceutical uses

Pentetic acid, commonly referred to as DTPA, plays a central role in for internal contamination with transuranic elements such as , , and . The calcium trisodium salt (CaNa₃DTPA) is the preferred initial agent, administered intravenously to exchange its calcium ions for the toxic metals, forming stable, water-soluble complexes that are primarily excreted via the kidneys, thereby accelerating urinary elimination and reducing systemic retention. Following the first dose, the trisodium salt (ZnNa₃DTPA) is often used for subsequent maintenance therapy to minimize depletion of essential metals such as while continuing decorporation. In radiopharmaceutical applications, DTPA is widely utilized in diagnostic . Technetium-99m-labeled DTPA (⁹⁹ᵐTc-DTPA) is injected intravenously for renal , where it serves as a marker for (GFR) and overall kidney perfusion, enabling the evaluation of renal function in conditions like obstructive uropathy or transplant assessment. Similarly, gadopentetate dimeglumine (Gd-DTPA) functions as an extracellular in (MRI), temporarily altering proton relaxation times to enhance the visibility of vascular structures, tumors, and inflammatory lesions; it received FDA approval in 1988 based on pivotal clinical trials demonstrating improved diagnostic accuracy. Emerging research highlights DTPA's potential in targeted for cancer, particularly through conjugates like ¹⁷⁷Lu-DTPA-linked antibodies that deliver beta-emitting radiation to tumor cells overexpressing specific antigens, such as in neuroendocrine models. Preclinical studies from 2022 showed potent antitumor effects with minimal off-target toxicity, suggesting viability for clinical translation in refractory malignancies. Dosage and administration of DTPA for typically involve intravenous infusion of 1 gram daily, diluted in 100-250 mL of dextrose or saline over 30-60 minutes, with treatment duration guided by results and contamination severity. Close monitoring of serum calcium, electrolytes, and renal function is essential, as DTPA's strong affinity for divalent cations can induce , potentially leading to cardiac arrhythmias if unmanaged. Efficacy data from animal models indicate that prompt DTPA administration can achieve greater than 90% reduction in body burden for and in and larger mammals, with prophylactic dosing yielding the highest decorporation rates through enhanced urinary and fecal . Human case studies, including accidental exposures in nuclear workers, corroborate these findings, reporting significant metal clearance and improved outcomes when is initiated within hours of .

Industrial and environmental applications

Pentetic acid, also known as diethylenetriaminepentaacetic acid (DTPA), serves as a versatile chelating agent in various industrial applications due to its ability to form stable complexes with metal ions, particularly divalent and trivalent metals such as calcium, magnesium, iron, and . In the and industry, DTPA is incorporated as an additive in formulations for and products, where it sequesters Ca²⁺ and Mg²⁺ ions to prevent scale formation and enhance by removing metal impurities that could otherwise reduce . This role positions DTPA as an eco-friendly alternative to phosphates in water-softening compositions, helping to maintain the stability of dyes and perfumes by preventing their interaction with trace metals. In processes, DTPA is employed to sequester iron and ions in cooling systems, thereby inhibiting and scale deposition on metal surfaces. Its strong chelating properties outperform those of EDTA for these metals, ensuring system longevity in industrial settings like power plants and facilities by preventing precipitate formation that could damage equipment. Within the nuclear industry, DTPA facilitates the of radioactive surfaces and the extraction of actinides, such as and , from waste streams through selective complexation that exploits the softer Lewis acid character of these elements. For environmental remediation, DTPA enhances the removal of from contaminated via soil washing and chelation-assisted phytoextraction techniques. In soil washing applications, DTPA-functionalized nanoparticles achieve over 70% removal of metals like , , and from leachates, even in complex matrices containing multiple contaminants, by forming stable complexes that facilitate extraction without significantly altering properties. In phytoextraction, low doses of DTPA (e.g., 10-20 mmol kg⁻¹ ) applied to polluted sites increase metal uptake in such as , enabling multiple harvests to accumulate contaminants like lead and in shoots while minimizing leaching risks through barriers. These methods leverage DTPA's coordination with divalent metals to mobilize for plant-based or washing-mediated cleanup.

Biological and environmental aspects

Biochemical mechanisms

Pentetic acid, also known as diethylenetriaminepentaacetic acid (DTPA), exhibits limited absorption in biological systems, with poor oral (approximately 5% in rats) due to its hydrophilic nature and low gastrointestinal permeability. When administered intravenously as calcium or trisodium salts (Ca-DTPA or Zn-DTPA), it rapidly distributes into the , achieving a of approximately 17 liters, and shows negligible binding to plasma proteins. This distribution pattern reflects its role as a systemic chelator rather than a cellularly retained agent, with rapid clearance primarily through the kidneys via glomerular filtration. In terms of metal decorporation, DTPA functions by forming highly stable, octadentate complexes with toxic metals such as , , and , effectively displacing them from endogenous ligands like or citrate. These water-soluble complexes are then excreted unchanged through the , enhancing the elimination of transuranic elements that would otherwise persist in tissues with long biological half-lives. The process relies on DTPA's high affinity for these metals (log K values exceeding 20 for many actinides), which outcompetes physiological binding sites and facilitates rapid decorporation, particularly when administered soon after exposure. DTPA does not participate in direct enzymatic catalysis within biological systems; however, at excess doses, it can indirectly inhibit metalloproteins by sequestering essential cofactors such as Zn²⁺, leading to cellular zinc depletion and disruption of zinc-dependent enzymes like matrix metalloproteinases or carbonic anhydrases. This inhibitory effect arises from DTPA's strong chelating capacity (formation constant for Zn-DTPA ~18.8), which reduces free zinc availability in the cytosol, though such impacts are typically observed only at supraphysiological concentrations and are reversible upon cessation. Regarding cellular uptake, DTPA exhibits minimal intracellular accumulation due to its charged, polar structure, primarily remaining in the without significant transmembrane transport, aligning with its classification as a Class III compound (high solubility, low permeability). The of DTPA are characterized by biphasic elimination, with an initial rapid alpha phase (half-life of 1.4-14.5 minutes) reflecting distribution and glomerular filtration, followed by a slower beta phase (half-life of 20-30 minutes overall in plasma after intravenous administration). Unbound DTPA is excreted predominantly unchanged in the (over 95% within 24 hours), while metal-DTPA complexes follow the same renal pathway without metabolic alteration, ensuring efficient clearance and minimal tissue retention.

Fate, toxicity, and ecological impact

Pentetic acid (DTPA) demonstrates moderate in the environment, with biodegradability varying by conditions. Under aerobic conditions, DTPA undergoes slow biological degradation, outperforming EDTA in relative rates but remaining resistant overall, particularly when complexed with metals like Fe³⁺. In contrast, it shows high resistance to anaerobic , limiting breakdown in oxygen-poor environments such as sediments or landfills. occurs in surface waters upon exposure to UV light, though rates are enhanced in the presence of ferric ions, contributing to partial mineralization. DTPA also adsorbs strongly to sediments and soils due to its ionic nature, reducing its mobility and potential for leaching into . Toxicity profiles for DTPA indicate low acute risk to mammals at typical exposure levels. Oral LD50 values exceed 2 g/kg in rats (4.55 g/kg). Overdose or prolonged exposure can lead to , primarily through of essential ions like Ca²⁺, resulting in , renal dysfunction, and symptoms such as , , and muscle cramps. DTPA is not classified as carcinogenic by the International Agency for Research on Cancer (IARC), with no evidence of or tumor promotion in available studies. Ecological impacts of DTPA center on its role as a chelating agent and direct effects on aquatic life. It exhibits moderate toxicity to aquatic invertebrates, with an LC50 of approximately 343 mg/L for carinata over 24 hours, indicating potential harm at elevated concentrations in freshwater systems. By mobilizing from sediments through complexation, DTPA increases their , facilitating uptake by organisms and risking in food webs, particularly in contaminated ecosystems. Regulatory frameworks address DTPA's environmental persistence and potential risks. Under EU REACH (as of 2025), aminocarboxylic acids like DTPA face scrutiny for possible persistent, bioaccumulative, and toxic (PBT) classification, with restrictions proposed for concentrations exceeding 0.1% in detergents to mitigate release into waterways. In the United States, the Environmental Protection Agency (EPA) monitors DTPA in effluents, particularly from industrial and medical sources, to assess chelator impacts on treatment processes and receiving waters. Mitigation strategies for DTPA contamination emphasize . Microbial consortia, including aerobic bacteria capable of utilizing DTPA as a carbon source, have shown promise in degrading the compound, though efficiency depends on environmental factors like and metal presence. Combined biological-photochemical approaches further accelerate breakdown, offering viable options for remediating soil and water impacted by DTPA release.

Synthesis and analogs

Production methods

Pentetic acid, also known as diethylenetriaminepentaacetic acid (DTPA), is primarily synthesized through a Strecker-like reaction involving (DETA), , and , followed by acid to convert the resulting nitriles to carboxylic acids. This method, first reported in by A. E. and colleagues, proceeds in aqueous or alcoholic media under controlled temperature (typically 50–80°C) to form the pentanitrile intermediate, which is then hydrolyzed using hydrochloric or at elevated temperatures (100–150°C) for several hours, yielding DTPA with purities exceeding 95% after neutralization and isolation. Overall yields for this route range from 80% to 90%, though it involves handling toxic , necessitating stringent safety protocols in industrial settings. An alternative synthesis employs direct alkylation of DETA with under basic conditions, often using or carbonate to neutralize the generated HCl and maintain around 10–11.5. The reaction is conducted in , with added gradually to DETA at low temperatures (-20 to 30°C) to control exothermicity, followed by heating to 30–60°C for 2–5 hours; the penta-sodium salt of DTPA is isolated by after adjustment and cooling, achieving yields of 95–99% with high purity. This method avoids but generates chloride byproducts and requires careful temperature management to minimize side reactions like over-alkylation. A more recent variant uses hydroxyacetonitrile (glycolonitrile) instead of and , reacting DETA stepwise with hydroxyacetonitrile at 5–10 and temperatures of 10–100°C, followed by hydrolysis and purification via decolorization, concentration, acidification ( 1–5), and . This approach yields 88–95% DTPA with purity over 99.5%, offering milder conditions, reduced toxicity, and lower byproduct formation compared to traditional routes, making it suitable for scaled production. On an industrial scale, DTPA production typically employs batch processes in aqueous media using reactors to handle the corrosive acidic steps, with capacities ranging from hundreds to thousands of tons annually to meet demand in applications. Purification involves ion-exchange to remove impurities like unreacted amines or partial alkylates, followed by from or and drying, ensuring pharmaceutical-grade quality. Historical development traces to mid-20th-century patents optimizing these routes for chelator , with ongoing refinements focused on and . Raw material costs for DTPA synthesis are approximately $5–10 per kg, dominated by DETA and alkylating agents, while the multi-step acidification contributes to energy-intensive operations, influencing overall production economics. Pentetic acid (DTPA) shares structural similarities with other aminopolycarboxylic acids used as chelating agents, but differs in denticity and coordination geometry, influencing their metal-binding affinities. Ethylenediaminetetraacetic acid (EDTA), a hexadentate analog featuring four carboxylate groups and two tertiary amines in a linear ethylenediamine backbone, forms hexadentate complexes with metals but exhibits lower thermodynamic stability for trivalent ions compared to DTPA. For example, the overall stability constant (log β) for the Fe³⁺-EDTA complex is 25.1 at 25°C and ionic strength 0.1 M, whereas for Fe³⁺-DTPA it is 27.8 under similar conditions, reflecting DTPA's greater number of donor groups (five carboxylates and three nitrogens) that enable stronger chelation of hard Lewis acids like trivalent metals. In contrast, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid () is a rigid macrocyclic chelator with four donors in a 12-membered ring and four pendant arms, providing thermodynamic stability comparable to DTPA (e.g., log β ≈ 25 for Lu³⁺- versus 22.5 for Lu³⁺-DTPA) but superior kinetic inertness due to the preorganized cavity, which resists dissociation . This property makes preferable for labeling radiometals in (PET) imaging agents, where long-term stability is critical to minimize transchelation. N-Hydroxyethylethylenediaminetriacetic acid (HEDTA), with three groups, one tertiary , and a hydroxyethyl on the secondary amine, offers only pentadentate coordination, resulting in weaker binding to actinides compared to DTPA's structure. This reduced donor set limits HEDTA's effectiveness for sequestering transuranic elements like or , as evidenced by lower extraction efficiencies in lanthanide-actinide separation processes, though it provides faster complexation kinetics for certain applications. Phosphonate-based functional analogs, such as diethylenetriamine-N,N,N',N'',N''-pentakis(methylenephosphonic acid) (DTPMP), replace DTPA's groups with s to alter selectivity toward alkaline earth and transition metals, enhancing affinity for Ca²⁺ and Mg²⁺ (log K ≈ 20 for Ca²⁺-DTPMP) over due to the stronger binding of phosphonate oxygens to smaller s. These variants are employed in scenarios requiring pH-independent or specific ion discrimination, such as scale inhibition in . DTPA evolved from EDTA in the mid-20th century as an enhanced chelator for nuclear applications, incorporating an additional nitrogen bridge to boost and stability for actinides and lanthanides in decorporation therapies and .

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Diethylenetriaminepentaacetic-acid
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