DTPA Ligand Research Articles

RuIII Complexes of Edta and Dtpa Polyaminocarboxylate Analogues and Their Use as Nitric Oxide Scavengers

AbstractIn this study a series of RuIII complexes, chelated by analogues of ethylenediaminetetraacetic acid (edta) and diethylenetriaminepentaacetic acid (dtpa), were produced and tested for NO scavenging ability. Modifications to the edta and dtpa ligand frameworks were made in an effort to alter the reactivity, aqueous stability and pharmacokinetics of the resulting RuIII complexes. The X‐ray structure of the nitrosyl complex 38 confirms that the RuIII complex 27 reacts with NO to form a linear {Ru–NO}6 complex. The nitrosyl complex [C15H15N4O11Ru] crystallized in the P21/c space group with a = 12.731(3) Å, b = 10.894(2) Å, c = 14.241 (3) Å, β = 107.320(4)°, V = 1885.6(7) Å3, and Z = 4. Kinetic studies on the reactions of 14 (k = 2.38 × 106 M–1 s–1) and 27 (k = 2.30 × 105 M–1 s–1) with NO exemplify the difference in chemical properties obtained by ligand framework manipulation. Binding constants of 14 (KB = 5 × 106 M–1) and 27 (KB = 2 × 105 M–1) with NO were also measured, indicating the tight binding of NO by the RuIII complexes. The activity of the RuIII complexes to scavenge nitric oxide was evaluated using RAW264 murine macrophage cells. Ligand analogues of edta that have a pyridine donor as part of the N,N chelate such as 20 and 24 exhibit similar scavenging activity to the parent compound. Ligand analogues of dtpa that have R groups at the central amine in place of the carboxylic acid such as 31, 34, and 37 are also efficient NO scavengers. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Synthesis and preliminary evaluation of gadolinium complexes containing sulfonamide groups as potential MRI contrast agents

Four DTPA and DOTA derivative ligands containing sulfonamide groups and their gadolinium complexes were prepared and characterized. Relaxivity studies showed that these gadolinium complexes possessed higher relaxation effectiveness than those of the corresponding ionic gadolinium complex Gd-DTPA and Gd-DOTA, respectively. In vitro cytotoxicity assay demonstrated that these gadolinium complexes have low cytotoxicity to the human liver cells (L-02). Magnetic resonance imaging (MRI) and experimental data of biodistribution in mice indicated that these gadolinium complexes containing sulfonamide groups could be used as the potential MRI contrast agents for Hepatoma (H 22) and Ehrlich ascites carcinoma (EAC) in mice and specific organs such as the liver and could be mostly excreted by the kidneys.

A thermodynamic approach, using speciation studies, towards the evaluation and design of bone-seeking radiopharmaceuticals as illustrated for 117mSn(II)-PEI-MP

Blood plasma modeling has proved effective in the evaluation of clinical observations recorded for baboon and rat tests with 153Sm- ethylenediaminetetraphosphonic acid (EDTMP) as well as for 166Ho-EDTMP. In the search for a cure for metastatic bone cancer, 117mSn with its conversion electrons of discrete energies shows low bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalize on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalized with methylene phosphonate groups (PEI-MP) and labeled with 99mTc, has shown selective uptake into bone tumours. This paper relates the speciation of Sn(II)-PEI-MP and other known 117mSn(II) containing bone-seeking radiopharmaceuticals in blood plasma. Apparent formation constants for the complexation of SnII with PEI-MP, DTPA, HEDP and other important blood plasma ligands were measured potentiometrically or estimated by linear free energy relationships (LFER). These data were added to the ECCLES database in order to construct a blood plasma model for SnII. From this model it is predicted that SnII will remain bound to the polymer (PEI-MP) in blood plasma and therefore, have only slight reticuloendothelial uptake. Preliminary primate studies indeed proved that the complex between SnII and PEI-MP remains intact in blood plasma, which is consistent with the observation for PEI-MP labeled with 99mTc. From these data, it was also possible to explain in retrospect the lower bone uptake, the slow blood clearance and the liver uptake of the agents 117mSn(II) DTPA and 117mSn(II) HEDP agents as reported in the literature.

Synthesis and structural determination of binuclear nine-coordinate (NH 4) 4[Yb 2(dtpa) 2]·9H 2O

A single crystal X-ray analysis of the Yb III complex with diethylenetriaminepentaacetate acid (dtpa) has shown that the compound has a binuclear structure in contrast to the corresponding Yb III complex with other aminopolycarboxylic acids ligand that have a mononuclear structure. Five oxygen atoms and three nitrogen atoms from a ligand molecule construct a distorted square antiprism around Yb III ions. One of the square planes is capped by an oxygen atom from the adjacent dtpa ligand which result in the formation of a binuclear complex. The coordination polyhedron including this oxygen atom is described as a monocapped square antiprismatic structure.

In vivo comparison of macrocyclic and acyclic ligands for radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapeutic applications

The studies reported herein present the first in vitro and in vivo comparison of radioimmunoconjugates (RIC) radiolabeled with 177Lu using the acyclic CHX-A″-DTPA ligand and the macrocyclic ligands, C-DOTA and PA-DOTA. The in vivo studies include pharmacokinetics and biodistribution of the formed 177Lu-labeled immunoconjugates in a tumor bearing murine model with engineered monoclonal antibody HuCC49ΔCH2. The in vitro analysis indicated that the CHX-A″ RIC was superior with respect to immunoreactivity, radiolabeling with 177Lu, and specific activity. The in vivo pharmacokinetic data by itself indicated that the Lu(III)-PA-DOTA complex may not be as stable as Lu(III) complexes with CHX-A″ or C-DOTA. All three RICs demonstrated tumor targeting of human colon carcinoma xenografts in athymic mice. In these biodistribution studies, there appears to be no overall pattern or trend of one RIC over the other two. Based on these in vitro and in vivo studies, the CHX-A″ DTPA ligand should be considered a suitable bifunctional chelate for the radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapy applications.

The effect of gadolinium-based MRI contrast agents on the biodistribution of (67)Ga.

It has been reported that administration of the paramagnetic contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA, gadopentate) prior to 67Ga citrate could lead to poor quality scans, characterized by pronounced bone uptake and a loss of tumour avidity. Suggestions to account for this behaviour included in vivo dissociation or the presence of free DTPA in the formulation. The objective of this study was to assess this potential interference in 67Ga imaging using a mouse model. Commercial gadopentate and gadodiamide contrast agents at doses up to 5mmol*kg(-1) were injected into mature female Balb/c mice 4h before i.v. 67Ga citrate, then the biodistribution was determined at 24h. Gd-DTPA solutions containing excess Gd or DTPA were examined as well. The model was verified by identical studies using inactive Ga(III) or Fe(III) at 0.1mmol*kg(-1). The effects of Gd(III) or the DTPA ligand at this dose were also determined. Administration of Gd-DTPA was found to produce no marked changes in 67Ga biodistribution. Minor changes occurred after 0.1mmol*kg(-1) Gd(III) or the DTPA ligand, but could not account for the scan changes reported above. Inactive Ga(III) or Fe(III), as expected, caused a marked reduction of 67Ga uptake in all tissues except bone, leading to greatly increased total bone:total soft tissue ratios. It is concluded that Gd-DTPA or its constituents do not significantly alter the biodistribution of 67Ga citrate in mice. Extrapolating these findings to the human situation suggests that the previously reported scan changes may have been the result of other undetermined factors.

Water‐Exchange and Relaxometric Studies of Gd(III) Complexes with DTPA‐bis(amide) Ligands

AbstractThe water 1H and 17O NMR relaxation properties of aqueous solutions containing Gd(III) che lates of the DTPA‐BIPA, DTPA‐BAA, DTPA‐BDEA and DTPA‐BMA ligands were investigated, and the results were compared with those previously reported for the Gd(III) complex with DTPA ligand. The significant deviation from the monoexponential behavior at the estimation of temperature dependence of 1H longitudinal relaxation rate for Gd(III) complexes with DTPA‐BIPA, DTPA‐BAA and DTPA‐BDEA ligands is characteristic of the slow chemical ex change. The measurements of 17O NMR trans verse relaxation rates and EPR transverse electronic relaxation rates in the range 276–343 K, allowed the assessment of the water‐exchange lifetime between the coordination site and the bulk solvent. With this approach, we obtained the water‐exchange life time (τM) of 1515, 1429, 1538 and 2128 ns for [Gd(DTPA‐BIPA)(H2O)], [Gd(DTPA‐BAA)(H2O)], [Gd(DTPA‐BDEA)(H2O)] and [Gd(DTPA‐BMA)(H2O)], respectively. Compared with the τM value of 303 ns for [Gd(DTPA)(H2O)]2−, we are able to conclude that the water residence life time in creases when the two terminal carboxylate groups of DTPA were substituted by two amide groups.

Thermodynamic stability and kinetic inertness of MS-325, a new blood pool agent for magnetic resonance imaging.

Stability constants were measured for complexes formed between a modified DTPA ligand and the metal ions Gd(III), Eu(III), Fe(III), Ca(II), Cu(II), and Zn(II) at 25 degrees C in 0.1 M NaClO4. The gadolinium complex of this ligand is MS-325, a novel blood pool contrast agent for magnetic resonance imaging currently undergoing clinical trials. Stability constants were determined by 4 different methods: direct pH titration, pH titration with competition by EDTA, competition with DTPA using an HPLC-MS detection system, and competition with Eu(III) by monitoring equilibrium by luminescence spectroscopy. The 1:1 stability constants, log beta101, are the following: Gd, 22.06 (23.2 in 0.1 M Me4NCl); Eu, 22.21; Fe, 26.66; Ca, 10.45; Cu, 21.3; Zn, 17.82. The exchange kinetics of the Gd complex, MS-325, with the radioactive tracer (152,154)Eu were studied at 25 degrees C in 0.1 M NaClO4. The exchange reaction has acid-dependent and acid-independent terms. The rate expression is given by the following: R = k(a)[GdL][H]2 + kb[GdL][Gd][H] + kc[GdL][Gd]. The rate constants were determined to be the following: k(a) = 1.84 x 10(6) M(-2) x min(-1), kb = 2.87 x 10(3) M(-2) x min(-1), kc = 3.72 x 10(-3) M(-1) x min(-1). MS-325 is 2-3 times more stable than GdDTPA at pH 7.4 and is 10-100 times more kinetically inert.

Synthesis and crystal structure of a new bimetallic complex of diethylenetriamine pentaacetic acid: [YbAg2(dtpa)(H2O)]·3H2O

The reaction between Yb(III) nitrate, Ag(I) nitrate, and the diethylenetriamine pentaacetate (dtpa) ligand gives rise to a bimetallic complex. [YbAg2(dtpa)(H2O)]·3H2O is triclinic, space group P-1, with a = 8.768 (3), b = 9.862 (2), c = 13.055 (2) A, α = 75.40 (1), β = 83.00 (2) and γ = 87.46 (2)°. Each dtpa is coordinated to one ytterbium and six silver atoms. The resulting crystal structure can be described as 2D packing. In the layers, the ytterbium atoms are connected through [Ag(COO)]2 dimers. Strong hydrogen bonds, involving the noncoordinated water molecules, ensure crystal cohesion.

Physical parameters and biological stability of yttrium(III) diethylenetriaminepentaacetic acid derivative conjugates.

The solution equilibria, acid dissociation, and serum stability of a series of Y(III) complexes of DTPA ligands functionalized with p-nitrobenzyl, methyl, and trans-cyclohexyl substituents were studied. The thermodynamic stability of the complexes studied ranged from log K = 21.53 to 24.7. Acid dissociation rates were found to decrease as the substitution on the carbon backbone increased, and significant differences in dissociation rates were observed for the Y(III) complexes of a pair of diasteriomeric cyclohexyl-DTPA ligands. While one diastereomer was found to have the slowest acid dissociation rate of the entire DTPA series, it was remarkably labile in both serum stability and in vivo studies.

Electrophoretic method for the quantitative determination of a benzyl-DTPA ligand in DTPA monoclonal antibody conjugates.

A simple electrophoretic IEF procedure was developed for the quantitation of bifunctional DTPA ligand molecules in DTPA-protein conjugates. From a calibration plot of pI versus substitution ratios of reference conjugates, the concentrations of DTPA conjugated to protein were determined. Molar ratios of DTPA to protein agreed satisfactorily with the ratios obtained by a spectrophotometric technique using a colored yttrium(III) complex of arsenazo III. The IEF method was successfully applied on preparations of benzyl-DTPA to mAbs MOPC-21, SC-20 (aCEA), and human serum albumin.

Study of FT-Raman Spectroscopy on the Effects of Lanthanide Ions and Their Complexes on the Fluidity of Dipalmitoylphosphatidylethanolamine Bilayer

The effects of lanthanide ions and their complexes of citrate and DTPA ligands on the fluidity of dipalmitoylphosphatidylethanolamine (DPPE) bilayers have been studied by FT-Raman spectroscopy. the results show that lanthanide ions of lower concentrationn decrease the fluidity of acyl chains of DPPE bilayers and change the conformation of C C-C backbone from gauche to the trans lanthanide ions of higher concentration, however, increase the fluidity of acyl chains and increase the gauche population of C-C-C backbone. Lanthanide complex of citrate have no effect on the fluidity of acyl chains of DPPE bilayers in the region of experimental concentration, but La-DTPA complex increase slightly the fluidity of acyl chains. the results also indicated that lanthanide ion of lower concentration changed the lattice packing of hydrocarbon chains from hexagonal form to orthorhombic form, but it is still in hexagonal or distorted hexagonal lattice cell in the gel state in the presence of metal ions and lanthanide complexes of higher concentration

Crystal, molecular, electronic and vibrational structures of di-μ-thiocyanato-bis-[di-(3-aminopropyl)amine]-dicopper(II) diperchlorate

The crystal and molecular structures of the dimeric [Cu(dpta)(NCS)(ClO 4)] 2. (dpta=di(3-aminopropyl)amine) have been reinvestigated by X-ray diffraction. The crystals are orthorhombic, space group Pbca with a = 13.938(3), b = 12.424(3), c = 15.864(2) A ̊ , V = 2747(1) A ̊ 3 and Z = 4 . The structure was refined to R = 0.050 ( R w = 0.049) from 1742 observed unique reflections. Each Cu atom is coordinated to the 3 N atoms of a dtpa ligand and to the N atom of an NCS − group in an almost square planar arrangement. The Cu atom makes further axial contacts with the S atom of another [Cu(dpta)(NCS)] + unit and with one O atom of a ClO 4 − group thus forming a centrosymmetric dimeric unit [(dpta)Cu SCN NCSCu(dpta)] 2+. Such units are held together by the ClO 4 − ions which provide CuO contacts and H bonds to neighbouring dpta H atoms. The ultimate arrangement around Cu may be described as a strongly elongated octahedron. The bond lengths (in Å) are: CuN(primary amine) =1.999(6) and 2.012(6), CuN(secondary amine) = 2.052(5), CuN(NCS) = 2.000(6), CuS = 2.795(2), CuO = 2.93(1). Considering the plane of the two bridging NCS groups as equatorial, the dpta ligand is in a meridional position with chair-chair conformation in full agreement with molecular mechanics calculations. Chair-skew boat conformers, however, are predicted to lie close in energy. The IR and Raman spectra of the compound were assigned by normal coordinate analysis and MNDO calculations. The bands 855 (R), 890 (IR) and 980 (IR + R) cm −1 are typical for mer-coordinated dpta and can be used as a diagnostic tool to detect the ligand coordination mode.

Synthesis and metal complex selectivity of macrocyclic DTPA and EDTA bis(amide) ligands

Several macrocyclic bis(amide) derivatives of DTPA and EDTA were prepared. Protonation constants as well as Gd 3+ and Zn 2+ complex stability constants of these ligands were determined by potentiometric titrations. The stability constants of the Gd 3+ complexes increase with increasing ring size of the DTPA bis(amidc) macrocycle series, reflecting the enhanced participation of the amide carbonyl oxygens in metal ion coordination.

Spectrophotometric method for the determination of a bifunctional DTPA ligand in DTPA-monoclonal antibody conjugates.

A simple spectrophotometric method was developed to quantitate micromolar concentrations of a bifunctional DTPA ligand in DTPA monoclonal antibody (mAb) conjugates. Titration of a brightly colored 1:2 yttrium (III) complex of arsenazo III with the ligand 1B4M-DTPA obeyed Beer's law over the concentration range 0-2.0 microM 1B4M-DTPA at 652 nm. From a calibration plot of absorbance versus 1B4M molarity, concentrations of 1B4M-DTPA conjugated to mAb were determined. Mole ratios of 1B4M-DTPA to mAb agreed satisfactorily with the ratios obtained by a radioanalytical technique using carbon-14-labeled 1B4M-DTPA and a binding assay using 111In. The spectrophotometric method was applied successfully to the preparation of 1B4M-DTPA mAb anti-TAC, a mAb conjugate used in clinical trials of 90Y radioimmunotherapy.

Aminopolycarboxylates of rare earths—V: Kinetics of exchange between Ce(III) and Tb(III) ethylenediaminetetraacetate complexes and the diethylenetriaminepentaacetate ligand

The kinetics of the ligand-exchange reactions between Ceedta and dtpa and between Tbedta and dtpa were studied spectrophotometrically at 25° in the pH range 4.4–6.5. In the Tbedta-dtpa system, the exchange takes place by H +-catalyzed dissociation of the complexes and also by collision of the complexes and the dtpa ligand (dtpa 5−, Hdtpa 4− and H 2dtpa 3−). In the Ceedta-dtpa system, attack by the dtpa ligands is very effective, and thus the reaction occurs predominantly via an associative mechanism. The reaction rate increase accompanying elevation of the pH can be interpreted by the higher efficiency of collision with dtpa species containgng less protons. In the reaction of Ceedta, formation of a very rapidly produced intermediate was detected, in which, besides the edta, one of the imda groups of the dtpa is also coordinated. The rate-determining step of the reactions is the further transformation of this mixed ligand complex intermediate, the dissociation of edta from the complex.

Effect of Redox Potential on the Stability of Zinc and Copper Chelates in Flooded Soils

AbstractStability of Zn and Cu chelates of EDTA and DTPA was studied under controlled redox potential‐pH soil conditions. The metal chelates ZnEDTA, ZnDTPA, CuEDTA, and CuDTPA were reacted with soil suspensions incubated at six different redox potentials (−200, −100, 0, +100, +300, and +500 mV) and at pH 7 for reaction periods varying from 2 to 192 hours.The redox potential has a very significant effect on the stability of all four metal chelates studied. The percentage of added Zn/Cu that remained in soil solution decreased with decreasing redox potential from +500 to −200 mV. Even though Zn and Cu chelates were stable at higher redox potentials, their stability decreased with time, apparently due to physical adsorption and microbial decomposition of metal‐chelate complex. At lower redox potentials, Zn and Cu chelates were found to be highly unstable. This instability was found to be mainly due to chemical fixation of added Zn and Cu, not due to physical/microbial decomposition of metal‐chelate complex. Iron, Mn, Ca, and Mg were found to be forming metal‐chelate complexes with EDTA and DTPA ligand molecules once Zn and Cu were removed from their metal‐chelate complexes.

β-decay effects of 144CeDTPA compound in frozen solution

The present study concerns bond rupture in 144CeDTPA compound as a result of β-decay in frozen solution. The dependences of percentage bond rupture on the concentrations of hydrogen ion, CeDTPA complex ion and free cerium ion were studied. The reaction mechanism of bond rupture is discussed: it is assumed that the geminate fragments ( 144Pr ion and DTPA ligand ion) and the daughter chelate compound stay in excited states in frozen solution and that the fates of these excited species are affected by successive reactions in a stage of liquefaction. The hypothesis is advanced that the electronic excitation by emission of a β-particle accompanying emission of a conversion electron or a shake off electron and the multiple ionization by the Auger effect play important roles for the bond rupture.