Polyaminopolycarboxylic Ligands Research Articles

Dissolution of Tc(IV) in the presence of polyamino polycarboxylate ligands

Dissolution of Tc(IV) in the presence of polyamino polycarboxylate ligands

Lanthanide complexes with polyaminopolycarboxylates as prospective NMR/MRI diagnostic probes: peculiarities of molecular structure, dynamics and paramagnetic properties.

The paramagnetic lanthanide complexes with polyaminopolycarboxylate (PAPC) ligands attract considerable attention from the standpoint of potential applications thereof as relaxation agents used in medical magnetic resonance imaging (MRI) and in luminescent materials, as well as owing to promising use thereof as paramagnetic labels for studying the properties of biopolymers since they exhibit thermodynamic stability, good solubility in aqueous media and moderate toxicity. For the last decades, the NMR methods have been used to determine the physical and chemical properties of paramagnetic Ln compounds. The studies concerning paramagnetic NMR lanthanide-induced shifts (LISs) in dissolved Ln complexes, as well as the analysis of band shape as a function of temperature make it possible to obtain valuable information on the structure, intra- and intermolecular dynamics and paramagnetic properties thereof. This review is devoted solely to the following features: firstly, the processes of intramolecular dynamics of lanthanide complexes with polyamino-polycarboxylate ligands such as DOTA, EDTA and DTPA and their derivatives studied by NMR; secondly, the LISs of lanthanide complexes with EDTA, DOTA, DTPA and some of their derivatives depending on temperature and pH. Moreover, in this review, for the first time, the dependence of the activation energy of molecular dynamics in complexes with polydentate ligands on the atomic number of the lanthanide cation is analyzed and a monotonic change in energy is detected, which is due to the effect of lanthanide contraction. It should be noted that this phenomenon is quite general and may also appear in the future in many other series of lanthanide complexes with both other multidentate ligands and with bidentate and monodentate ligands. In the future, it is possible to predict the dependence of the properties of certain lanthanide complexes on the ionic radius of the lanthanide cation based on the approaches presented in the review. In this review, we have also presented the dynamic NMR as the main research method widely used to analyze the processes of molecular dynamics, and the structural studies based on the NMR relaxation spectroscopy and LIS analysis.

Computational prediction of interaction and pharmacokinetics profile study for polyamino-polycarboxylic ligands on binding with human serum albumin

Human serum albumin (HSA) is one of the most abundant plasma proteins available in blood and responsible for transport of fatty acids, drugs and metabolites at its binding sites which are very important for the assessment of pharmacokinetics profile of the polyamino-polycarboxylic ligands.

Evaluation of Vanadium(IV) as a Non-radioactive Surrogate for Technetium(IV) by Comparison of Stability Constants for Polyamino Polycarboxylate Ligand Complexation

The stability constants for the Tc(IV) and V(IV) complexation with the polyamino polycarboxylate ligands IDA, NTA, HEDTA and DTPA were determined using liquid–liquid extraction techniques. These stability constants were then used to evaluate the validity of using V(IV) as a chemical analogue for Tc(IV). Results suggest that Tc(IV), as TcOOH+, will form β 1−11 complexes with the selected ligands, while V(IV), as VO2+, will form β 101 complexes. The values for these determined stability constants are (in log10 unit) 10.9 ± 0.1, 11.4 ± 0.1, 14.9 ± 0.1, and 20.1 ± 0.1 for Tc(IV) in 0.5 mol·L−1 NaCl at 25 °C, for IDA, NTA, HEDTA and DTPA, respectively, they are 9.3 ± 0.1, 11.6 ± 0.2, 15.8 ± 0.1, and 20.8 ± 0.1 for V(IV) in 0.5 mol·L−1 NaCl at 25 °C, for the same suite of ligands. The incorporation of a hydroxide into the metal ligand complexes formed by Tc(IV) is proposed as the largest factor differentiating the apparent stability constants of Tc(IV) and V(IV). This work shows that V(IV) is a poor analog for Tc(IV); however, despite the differences in complexation mechanism between V(IV) and Tc(IV), V(IV) still appears to have some use for predicting Tc(IV) complexation behavior.

Oxovanadium(iv) cations in heterometallic and heteroligand complex formation

The formation of heterometallic oxovanadium(iv) diethylenetriaminepentaacetates with titanium(iii), chromium(iii), cobalt(ii), nickel(ii), and manganese(ii) cations in aqueous solutions was studied by spectrophotometry and pH-metry. The stabilizing influence of heterometallic chelation on an unstable oxidation state of Ti iii and the labilizing effect of oxovanadium(iv) cations on the coordination of Cr iii cations by the carboxylate ligand anions in the heterometallic complex were shown. The optimum conditions for the formation of the heterometallic dtpa complexes were selected and their thermodynamic stability was estimated. The states of the oxovanadium(iv) cations in the monoand heteroligand systems involving polyamine, polyaminopolycarboxylate, and alkylpolyphosphonate ligands were studied. Specific features of ligand coordination and formation of the mixed-ligand chelates were investigated. A variety of molecular compositions of complex oxovanadium(iv) oxyethylenediphosphonate particles formed in ranges of pH 2.2—3.0, 4.5—5.5, and 6.3—6.4 was found. The preferability of formation of polynuclear oxovanadium(iv) oxyethylidenediphosphonates, viz., binuclear particles with oxovanadium(iv) cation to ligand molar ratios of 2 : 1 and 2 : 5 and trinuclear particles with a molar ratio of components of 3 : 2, was shown.

A comparative thermodynamic study of the formation of scandium complexes with DTPA and DOTA

The complexation of scandium(iii) by various polyaminopolycarboxylic ligands (DTPA and DOTA) was studied by capillary electrophoresis with ICP-MS detection in 0.1 mol L−1NaCl ionic strength solutions at 25 °C.

Stability of 47Sc-complexes with acyclic polyamino-polycarboxylate ligands.

The aim of this study was to evaluate acyclic ligands which can be applied for labeling proteins such as monoclonal antibodies and their fragments with scandium radionuclides. Recently, scandium isotopes (47Sc, 44Sc) are more available and their properties are convenient for radiotherapy or PET imaging. They can be used together as “matched pair” in theranostic approach. Because proteins denaturize at temperature above 42 °C, ligands which efficiently form complexes at room temperature, are necessary for labelling such biomolecules. For complexation of scandium radionuclides open chain ligands DTPA, HBED, BAPTA, EGTA, TTHA and deferoxamine have been chosen. We found that the ligands studied (except HBED) form strong complexes within 10 min and that the radiolabelling yield varies between 96 and 99 %. The complexes were stable in isotonic NaCl, but stability of 46Sc-TTHA, 46Sc-BAPTA and 46Sc-HBED in PBS buffer was low, due to formation by Sc3+stronger complexes with phosphates than with the studied ligands. From the radiolabelling studies with n.c.a. 47Sc we can conclude that the most stable complexes are formed by the 8-dentate DTPA and EGTA ligands.

Pyridine‐Based Lanthanide Complexes Combining MRI and NIR Luminescence Activities

A series of novel triazole derivative pyridine-based polyamino-polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd(3+) and near-infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln(3+) complexes, as assessed by pH potentiometric measurements, are in the range log K(LnL)=17-19, with a high selectivity for lanthanides over Ca(2+), Cu(2+), and Zn(2+). The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd(3+) chelates. The water exchange of the Gd(3+) complexes (k(ex)(298)=7.7-9.3×10(6) s(-1)) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV(≠)=7.2-8.8 cm(3) mol(-1)). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet-state energies associated with good quantum yields for both Nd(3+) and Yb(3+) complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd(3+) and the luminescent lanthanide complexes, respectively.

Stevens rearrangement as a tool for the structural modification of polyaminopolycarboxylic ligands

Polyaminopolycarboxylic acids are a well known class of ligands employed for metal ion complexation. Despite the large commercial availability, reports of their use as substrates for direct structural modifications are rare. Herein we report a simple and efficient protocol for the preparation of substituted polyaminopolycarboxylic ligands relying on a one-pot N-alkylation-Stevens rearrangement cascade.

Solid Phase Synthesis of Oxytocin Analogues Conjugated to Polyamino Polycarboxylic Ligands

An easy solid phase synthesis of oxytocin analogues conjugated to polyaminopolycarboxylic ligand, such as diethylenetriaminepentaacetic acid (DTPA) and tetraazacyclododecanetetraacetic acid (DOTA) is reported. These new products can be labeled with suitable radiometals (e.g. 90Y, 111In, 177Lu), giving rise to radiopharmaceuticals with potential application in imaging and/or therapy of tumors over-expressing oxytocin receptors. Keywords: Oxytocin, solid phase peptide synthesis, targeting, DOTA, DTPA, radiolabeled peptides

Sensitized luminescence properties of dinuclear lanthanide macrocyclic complexes bearing a benzophenone antenna

Dinuclear lanthanide (Ln=Tb 3+ or Eu 3+) complexes (Ln 2 L2) of two octadentate macrocyclic polyaminopolycarboxylic ligands connected through a benzophenone (BP) moiety ( L2) have been synthesized. Sensitized luminescence properties of Ln 2 L2 in water have been studied in comparison to those of BP-conjugated mononuclear Ln complexes (Ln L1). The luminescence intensity of Tb 2 L2 is lower than that of Tb L1 because of lower triplet quantum yield of the BP moiety. In contrast, Eu 2 L2 shows higher intensity than Eu L1. For both Eu complexes, energy level of triplet excited-state BP ( 3BP*) is only 3 kJ mol −1 higher than that of 5D 2 excited-state of Eu 3+. The 5D 2 state formed by a triplet-energy transfer (TET) from 3BP* is therefore deactivated by a back energy transfer (BET) to the ground-state BP, resulting in low luminescence intensity of Eu L1. In contrast, within Eu 2 L2, TET from 3BP* to 5D 0 state of two Eu 3+ ions is accelerated, thus leading to higher luminescence intensity. Another notable feature of Eu 2 L2 is the luminescence quantum yield independent of its concentration. In contrast, for Eu L1 system, an intermolecular BET occurs from 5D 2 state of Eu 3+ to the ground-state BP conjugated to another Eu L1 complex, resulting in a yield decrease with the concentration increase.

Sequestering ability of polyaminopolycarboxylic ligands towards dioxouranium(VI) cation

In the present paper, some results of an investigation (at t = 25 °C by potentiometry, ISE-H + glass electrode) on the sequestering ability of five different polyaminopolycarboxylic ligands [Nitrilotriacetate (NTA), ethylenediamine- N,N,N′ ,N′-tetraacetate (EDTA), ethylene glycol-bis(2-aminoethylether)- N,N,N′ ,N′-tetraacetate (EGTA), diethylenetriamine- N,N,N′ ,N″ ,N″-pentaacetate (DTPA), triethylenetetraamine- N,N,N′ ,N″ ,N′′′ ,N′′′-hexaacetate (TTHA)] towards dioxouranium(VI) cation in sodium chloride aqueous solutions, at I = 0.7 mol L −1 are reported. Calculations performed on potentiometric data gave evidence of the formation of the following species (log β in parenthesis): UO 2(NTA)H 0 (12.27); UO 2(NTA) − (8.21); UO 2(NTA)OH 2− (2.39); UO 2(EDTA)H − (15.19); UO 2(EDTA) 2− (9.81); UO 2(EDTA)OH 3− (3.58); UO 2(EGTA)H − (17.35); UO 2(EGTA) 2− (11.60); UO 2(EGTA)OH 3− (2.77); UO 2(DTPA)H 2 − (22.14); UO 2(DTPA)H 2− (17.86); UO 2(DTPA) 3− (11.79); UO 2(DTPA)OH 4− (3.09); UO 2(TTHA)H 3 − (28.41); UO 2(TTHA)H 2 2− (24.73); UO 2(TTHA)H 3− (19.14); UO 2(TTHA) 4− (12.12). In presence of complexones, the formation of scarcely soluble species occurs at higher pH values than in simple UO 2 2+ aqueous solutions. The stability of dioxouranium(VI)–polyaminopolycarboxylate species follows the trend: TTHA > DTPA > EGTA > EDTA > NTA, it is dependent on the ligand structure and this dependence was modeled. Polyaminopolycarboxylate ligands are good sequestering agents towards UO 2 2+, indicating the possibility of being employed in the UO 2 2+ polluted sites remediation, and in the chelating therapy in medicine. A literature data critical evaluation was made, evidencing the high discrepancies occurring between different authors in both the stability constant values and the proposed speciation models.

Conjugates of gadolinium complexes to bile acids as hepatocyte-directed contrast agents for magnetic resonance imaging.

A series of structurally different Gd(III) conjugates incorporating a bile acid moiety have been prepared. Polyaminopolycarboxylic ligands such as diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) have been selected as chelating subunit for the Gd(III) ion. Cholic acid, cholylglycine, and cholyltaurine have been incorporated as the bile acid moieties. In first generation conjugates the Gd(III) complex is linked to the carboxyl group of cholic acid. Second generation conjugates feature the attachment of the Gd(III) complex to the 3 position of the steroidic backbone of the bile acid. Finally, in third generation conjugates the Gd(III) complex is attached to the epsilon nitrogen atom of cholyllysine. The conjugates are eliminated through the biliary route to a various extent (7.5 to 77% in rats) according to their structural features. Among the most promising terms, a second generation conjugate in which the Gd(III) complex is linked to cholic acid through the 3alpha hydroxy group seems to enter hepatocytes using the Na(+)/taurocholate transporter. Noticeably, some of the second generation conjugates are characterized by very high tolerabilities (LD(50) up to 9.5 mmol/kg) after intravenous administration in mice.

Gadolinium complexes containing polyamino polycarboxylate ligands for Magnetic Resonance Imaging (MRI) contrast agents

Gadolinium complexes containing polyamino polycarboxylate ligands for Magnetic Resonance Imaging (MRI) contrast agents

Ligand preorganization in metal ion complexation: molecular mechanics/dynamics, kinetics, and laser-excited luminescence studies of trivalent lanthanide complex formation with macrocyclic ligands TETA and DOTA.

The molecular mechanics and dynamics calculations, kinetics, and laser-excited luminescence studies were carried out for trivalent lanthanide (Ln(3+)) complexes of macrocyclic polyaminopolycarboxylate ligands TETA and DOTA (where TETA is 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid and DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to further understand the observed thermodynamic, kinetic, and structural properties and to examine how ligand preorganization affects metal ion complexation. Excitation spectroscopy (emission monitored at 614.0 nm) of the (7)F(0) --> (5)D(0) transition of Eu(3+) was used to study the aqueous properties of the Eu(3+)-TETA system. A stopped-flow spectrophotometric method was used to study the formation kinetics of the aqueous Ce(3+)-TETA/DOTA systems in the pH range 6.1-6.7. Molecular mechanics calculation results are consistent with the proposed mechanism of Ln(DOTA)(-) formation, i.e., formation of a carboxylate O-bonded precursor, followed by metal ion moving into the preformed macrocyclic cavity. For Ln(TETA)(-) formation, at least two carboxylate O-bonded intermediates have been predicted and Ln(3+) ion assisted reorganization of the TETA ligand is present. The calculated bond distances and overall structures of Ln(DOTA)(-) and Ln(TETA)(-) were in agreement with the single-crystal and solution NMR structural data. The origin of the difference in thermodynamic stability of Ln(DOTA)(-) and Ln(TETA)(-) complexes and the corresponding formation intermediates is mainly due to the differences in water-occupancy energy (i.e., whether there is an apical coordinated water molecule), the ligand strain energy, and the cation-ligand interaction energy. Kinetic studies revealed that the formation rates of the Ce(TETA)(-) complex are smaller at lower pH and temperature but become greater at higher pH and temperature, as compared to those of the Ce(DOTA)(-) complex. This is attributed to the lanthanide ion and both mono- and di-hydroxide ion assisted TETA conformational reorganization and higher kinetic activation parameters. The presence of a di-hydroxide ion assisted intermediate rearrangement pathway could make the Ce(TETA)(-) complex formation rate faster at higher pH, and the higher activation barrier makes Ce(TETA)(-) complex formation rate slower at lower pH, as compared to those of the Ce(DOTA)(-) complex.

Dimeric W3SO3 cluster complexes: synthesis, characterization, and potential applications as X-ray contrast agents.

Our continued research on the use of heavy metal cluster complexes as a new class of X-ray contrast agents in medical diagnostic imaging is described. A series of 2:3 cluster-ligand complexes, [(W(IV)3SO3)2L3]4- (L = linear polyaminopolycarboxylate ligands), were isolated from the reaction of aqua ion [W(IV)3SO3(H2O)9]4- (prepared in large quantities through an improved literature process) with respective ligands in refluxing DMF. The salts of [(W(IV)3SO3)2L3]4- complex anions were fully characterized using routine techniques such as elemental analysis, MS, HPLC, UV-vis, IR, and NMR. The solid structures of two complex anions, [(W(IV)3SO3)2(PDTA)3]4- and [(W(IV)3SO3)2(HO-PDTA)3]4-, were determined by X-ray crystallography. They are the first examples wherein two W(IV)3SO3 clusters are complexed and linked by three ligands that contain two terminal iminodiacetate (bis-IDA) groups. Complexation of the unstable aqua ion [W(IV)3SO3(H2O)9]4- with ligands has imparted desired biological compatibility to the tungsten metal cluster. These complexes are stable and highly soluble in H2O. The potential utility of such tungsten cluster complexes as X-ray contrast agents was evaluated in both in vitro and in vivo animal studies. In addition, the syntheses of several new linear polyaminopolycarboxylate ligands used in this study are reported.

Thermodynamic and structural aspects of manganese(II) complexes with polyaminopolycarboxylic ligands based upon 1,4,7,10-tetraazacyclododecane (cyclen). Crystal structure of dimeric [MnL]2·2CH3OH containing the new ligand 1,4,7,10-tetraazacyclododecane-1,4-diacetate

The formation of manganese(II) complexes with polyaminopolycarboxylic ligands based upon 1,4,7,10-tetraazacyclododecane (cyclen) has been studied in aqueous solution by means of potentiometric and microcalorimetric techniques affording log K, ΔH° and TΔS° values for the complexation reactions. The ML complexes present high stability constants, due to both favourable enthalpic and entropic contributions; with the unique exception of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), the entropic term is prevalent. The new ligand 1,4-DO2A (1,4,7,10-tetraazacyclododecane-1,4-diacetic acid) forms a more stable complex than the 1,7-DO2A isomer. The thermodynamic results are discussed in terms of ligand characteristics: number and type of donor atoms, overall charge, substituent location. The crystal structure of [MnL]2·2CH3OH (H2L = 1,4-DO2A), obtained by single crystal X-ray analysis, displays a centrosymmetric dimeric [Mn2L2] unit in which each manganese atom is seven-coordinated by four nitrogen atoms of a cyclen macrocycle, one oxygen atom of each of the acetate groups linked to this macrocyclic unit, and one oxygen atom pertaining to an acetate group of the other cyclen molecule in the same dimeric unit and bridging the two metal centers. The resulting binuclear complex contains a doubly bridged bimetallic core with Mn ⋯ Mn distance of 3.537(1) A.

ChemInform Abstract: Thermodynamic and Structural Properties of Gd(III) Complexes with Polyamino-polycarboxylic Ligands: Basic Compounds for the Development of MRI Contrast Agents

Abstract The main purpose of this review is to collect equilibrium data in aqueous solution and structural properties in the solid state for significant examples of Gd(III) complexes with both acyclic and macrocyclic polyamino-polycarboxylic ligands. The intent is to determine the ligand characteristics which contribute to the complexes’ stability. Several aspects connected with the use of similar Gd(III) complexes as contrast agents in nuclear magnetic resonance imaging are also considered.

Luminescence study on hydration states of lanthanide(III)–polyaminopolycarboxylate complexes in aqueous solution

The hydration states of lanthanide (Ln)(III) complexes (Ln=Sm, Eu, Tb and Dy) with a series of polyaminopolycarboxylate ligands were evaluated in detail on the basis of the linear correlation between the luminescence decay constants kobs and the inner-sphere hydration number NH2O in D2O–H2O solutions. The kobs of Ln(III) complexes in D2O showed that these ligands were not effective in causing non-radiative de-excitation of the excited states for these ions. The NH2O of Sm(III) in a certain polyaminopolycarboxylate complex was apparently larger than those of Eu(III), Tb(III) and Dy(III) in the complexes. These results suggest that the empirical formulae proposed in this study are valid for the calibration of kobs vs. NH2O and that the total coordination number, i.e. the sum of the number of ligand donor groups and the NH2O of Sm(III) is possibly unity larger than those of Eu(III), Tb(III) and Dy(III) in the complexes.

Luminescence study on determination of the inner-sphere hydration number of Am(III) and Nd(III)

A correlation between the luminescence decay constant k obs (the reciprocal of the excited state lifetime) and the inner-sphere hydration number N H 2O of Am(III) and Nd(III) in aqueous solution was investigated to establish a method for determining the N H 2O from measurements of the luminescence lifetime. The calibration relations were proposed on the basis of the linear correlation of the k obs vs. volume percentage of H 2O in D 2O–H 2O solutions and the N H 2O in H 2O, i.e. nine for Am(III) and Nd(III). The k obs of Am(III) and Nd(III) complexed with a series of polyaminopolycarboxylate ligands in H 2O and D 2O were measured to validate the calibration relations, and the N H 2O and coordination numbers of these ions in the complexes were evaluated and compared with the other luminescent ions systematically.