Inner-sphere Water Molecules Research Articles

Chelator-Assisted Precipitation-Based Separation of the Rare Earth Elements Neodymium and Dysprosium from Aqueous Solutions.

The rare earth elements (REEs) are critical resources for many clean energy technologies, but are difficult to obtain in their elementally pure forms because of their nearly identical chemical properties. Here, an analogue of macropa, G-macropa, was synthesized and employed for an aqueous precipitation-based separation of Nd3+ and Dy3+. G-macropa maintains the same thermodynamic preference for the large REEs as macropa, but shows smaller thermodynamic stability constants. Molecular dynamics studies demonstrate that the binding affinity differences of these chelators for Nd3+ and Dy3+ is a consequence of the presence or absence of an inner-sphere water molecule, which alters the donor strength of the macrocyclic ethers. Leveraging the small REE affinity of G-macropa, we demonstrate that within aqueous solutions of Nd3+, Dy3+, and G-macropa, the addition of HCO3 - selectively precipitates Dy2(CO3)3, leaving the Nd3+-G-macropa complex in solution. With this method, remarkably high separation factors of 841 and 741 are achieved for 50 : 50 and 75 : 25 mixtures. Further studies involving Nd3+:Dy3+ ratios of 95 : 5 in authentic magnet waste also afford an efficient separation as well. Lastly, G-macropa is recovered via crystallization with HCl and used for subsequent extractions, demonstrating its good recyclability.

Gadopiclenol: A q = 2 Gadolinium-Based MRI Contrast Agent Combining High Stability and Efficacy

Objectives Gadopiclenol is a q = 2 pyclen gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration, European Medicines Agency, and other European countries. The aim of this report is to demonstrate its stability in multiple stressed in vitro conditions and in vivo, in rat kidney, while maintaining its higher relaxivity compared with conventional GBCAs on the market. Materials and Methods Both gadopiclenol and its chemical precursor Pi828-Gd were characterized and compared with q = 1 gadolinium (Gd) complexes. The number of water molecules coordinated to the Gd (the hydration number, q) was determined by luminescence. 17O NMR (Nuclear Magnetic Resonance) measurements gave access to the water residence time τM. These parameters were used for the fitting of the nuclear magnetic relaxation dispersion profiles in water. Proton relaxivities of the complexes were determined in different media at 60 MHz (1.4 T), at different pH and temperature. The kinetic inertness was investigated in human serum, acidic media, under zinc competition in the presence of phosphate, and under ligand competition. The in vivo stability was evaluated in rat kidneys 12 months after repeated injections. Results The presence of 2 inner-sphere water molecules per Gd complex was confirmed for both pyclen derivatives. The high relaxivity of the complexes in water is maintained under physiological conditions, even under stressed conditions (ionic media, extreme pH, and temperature), which guarantees their efficiency in a large range of in vivo situations. Gd release from the q = 2 complexes was investigated in different potentially destabilizing conditions. Either no Gd release or a slower one than with “q = 1” stable macrocyclic GBCA (acidic conditions) was observed. Their kinetic inertness was demonstrated in physiological conditions, and the Gd release was below the lower limit of quantification of 0.1 μM after 12 days at 37°C in human serum. It was also demonstrated that gadopiclenol is stable in vivo in rat kidney 12 months after repeated injections. Conclusions Thanks to its optimized structural design, gadopiclenol is a highly stable and effective macrocyclic q = 2 GBCA.

Interaction of MRI Contrast Agent [Gd(DOTA)]- with Lipid Membranes: A Molecular Dynamics Study.

Contrast agents are important imaging probes in clinical MRI, allowing the identification of anatomic changes that otherwise would not be possible. Intensive research on the development of new contrast agents is being made to image specific pathological markers or sense local biochemical changes. The most widely used MRI contrast agents are based on gadolinium(III) complexes. Due to their very high charge density, they have low permeability through tight biological barriers such as the blood-brain barrier, hampering their application in the diagnosis of neurological disorders. In this study, we explore the interaction between the widely used contrast agent [Gd(DOTA)]- (Dotarem) and POPC lipid bilayers by means of molecular dynamics simulations. This metal complex is a standard reference where several chemical modifications have been introduced to improve key properties such as bioavailability and targeting. The simulations unveil detailed insights into the agent's interaction with the lipid bilayer, offering perspectives beyond experimental methods. Various properties, including the impact on global and local bilayer properties, were analyzed. As expected, the results indicate a low partition coefficient (KP) and high permeation barrier for this reference compound. Nevertheless, favorable interactions are established with the membrane leading to moderately long residence times. While coordination of one inner-sphere water molecule is maintained for the membrane-associated chelate, the physical-chemical attributes of [Gd(DOTA)]- as a MRI contrast agent are affected. Namely, increases in the rotational correlation times and in the residence time of the inner-sphere water are observed, with the former expected to significantly increase the water proton relaxivity. This work establishes a reference framework for the use of simulations to guide the rational design of new contrast agents with improved relaxivity and bioavailability and for the development of liposome-based formulations for use as imaging probes or theranostic agents.

Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA. 1H NMRD profiles reveal that both chiral gadolinium complexes (Gd-X-PCTA-1 and Gd-X-PCTA-2) have a higher relaxivity than Gd-PCTA, while variable-temperature 17O NMR studies show that the two inner-sphere water molecules have distinct residence times τMa and τMb. Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA.

Experimental and Theoretical Investigation on the Extractive Mass Transfer of Eu3+ Ions Using Novel Amide Ligands in 1-Hexyl-3-methylimidazolium Bis(trifluoromethylsulfonyl)imide.

Novel amide ligands in the ionic liquid (1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) were utilized for the liquid-liquid biphasic mass transfer of Eu3+ ions from aqueous acidic waste solution. The cation exchange mechanism was found to be operative with the formation of [Eu(NO3)2L3]+ species (L = 4-chloro-N-(1-methyl-1H-pyrazol-3-yl)picolinamide). However, the presence of an inner-sphere water molecule was revealed by density functional theory (DFT) calculations. The viscosity-induced slower kinetics was evidenced during mass transfer, which was improved by increasing temperature. The process was exothermic in nature. The improvement in the kinetics of extractive mass transfer at higher temperatures is evinced by a reduction in the distribution ratio value. The spontaneity of the reaction was evidenced through the negative Gibbs free energy value, whereas the process enhances the entropy of the system, probably by releasing water molecules at least partially during complexation. The structures of bare ligands and complexes have been optimized by using DFT calculations. A high value of complexation energy, solvation energy, and associated enthalpy and free energy change reveal the efficacy in binding Eu with O and N donor atoms. In addition, natural population analysis, atoms-in-molecules analysis, and energy decomposition analysis have been employed to explore the nature of bonding existing in Eu-O and Eu-N bonds.

Kinetically Inert Macrocyclic Europium(III) Receptors for Phosphate.

The significant role that phosphate plays in environmental water pollution and biomedical conditions such as hyperphosphatemia highlights the need to develop robust receptors that can sequester the anion effectively and selectively from complex aqueous media. Toward that goal, four macrocyclic tris-bidentate 1,2-hydroxypyridonate (HOPO) europium(III) complexes containing either a cyclen, cyclam, TACN, or TACD ligand cap were synthesized and evaluated as phosphate receptors. The solubility of EuIII-TACD-HOPO in water was insufficient for luminescent studies. Whereas EuIII-cyclen-HOPO is eight coordinate with two inner-sphere water molecules, both EuIII-cyclam-HOPO and EuIII-TACN-HOPO are nine coordinate with three inner-sphere water molecules, suggesting that the two coordination states are very close in energy. As observed previously with linear analogues of tripodal HOPO complexes, there is no relationship between the number of inner-sphere water molecules and the affinity of the complex for phosphate. Whereas all three complexes do bind phosphate, EuIII-cyclen-HOPO has the highest affinity for phosphate with the anion displacing both of its inner-sphere water molecules. On the other hand, only one or two of the three inner-sphere water molecules of EuIII-TACN-HOPO and EuIII-cyclam-HOPO are displaced by phosphate, respectively. All three complexes are highly selective for phosphate over other anions, including arsenate. All three complexes are highly stable. EuIII-cyclen-HOPO and, to a lesser extent, EuIII-TACN-HOPO are more kinetically inert than the linear EuIII-Ser-HOPO. EuIII-cyclam-HOPO, on the other hand, is not. This study highlights the significant effect that minor changes in the ligand cap can have on both the ligand exchange rate and affinity for phosphate of tripodal 1,2-dihydroxypyridinonate complexes.

A seven-coordinate Mn(II) complex with a pyridine-based 15-membered macrocyclic ligand containing one acetate pendant arm: structure, stability and relaxation properties.

A new 15-membered pyridine-based macrocyclic ligand containing one acetate pendant arm (N-carboxymethyl-3,12,18-triaza-6,9-dioxabicyclo[12.3.1]octadeca-1(18),14,16-triene, L1) was synthesized and its Mn(II) complex MnL1 was investigated in the context of MRI contrast agent development. The X-ray molecular structure of MnL1 confirmed a coordination number of seven with an axially compressed pentagonal bipyramidal geometry and one coordination site available for an inner-sphere water molecule. The protonation constants of L1 and the stability constants of Mn(II), Zn(II), Cu(II) and Ca(II) complexes were determined by potentiometry, and revealed higher thermodynamic stabilities in comparison with complexes of 15-pyN3O2, the parent macrocycle without an acetate pendant arm. The MnL1 complex is fully formed at physiological pH 7.4, but it shows fast dissociation kinetics, as followed by relaxometry in the presence of an excess of Zn(II). The short dissociation half-life estimated for physiological pH (ca. 3 minutes) is related to fast spontaneous dissociation of the non-protonated complex. At lower pH values, the proton-assisted dissociation pathway becomes important, while the Zn(II) concentration has no effect on the dissociation rate. 17O NMR and 1H NMRD data indicated the presence of one inner-sphere water molecule with a rather slow exchange (k298ex = 4.5 × 106 s-1) and provided information about other microscopic parameters governing relaxation. The relaxivity (r1 = 2.45 mM-1 s-1 at 20 MHz, 25 °C) corresponds to typical values for monohydrated Mn(II) chelates. Overall, the acetate pendant arm in L1 has a beneficial effect with respect to 15-pyN3O2 in increasing the thermodynamic stability and kinetic inertness of its Mn(II) complex, but leads to a reduced number of inner-sphere water molecules and thus lower relaxivity.

Computational insight into a mechanistic overview of water exchange kinetics and thermodynamic stabilities of bis and tris-aquated complexes of lanthanides.

A thorough investigation of Ln3+ complexes with more than one inner-sphere water molecule is crucial for designing high relaxivity contrast agents (CAs) used in magnetic resonance imaging (MRI). This study accomplished a comparative stability analysis of two hexadentate (H3cbda and H3dpaa) and two heptadentate (H4peada and H3tpaa) ligands with Ln3+ ions. The higher stability of the hexadentate H3cbda and heptadentate H4peada ligands has been confirmed by the binding affinity and Gibbs free energy analysis in aqueous solution. In addition, energy decomposition analysis (EDA) reveals the higher binding affinity of the peada4- ligand than the cbda3- ligand towards Ln3+ ions due to the higher charge density of the peada4- ligand. Moreover, a mechanistic overview of water exchange kinetics has been carried out based on the strength of the metal-water bond. The strength of the metal-water bond follows the trend Gd-O47 (w) > Gd-O39 (w) > Gd-O36 (w) in the case of the tris-aquated [Gd(cbda)(H2O)3] and Gd-O43 (w) > Gd-O40 (w) for the bis-aquated [Gd(peada)(H2O)2]- complex, which was confirmed by bond length, electron density (ρ), and electron localization function (ELF) at the corresponding bond critical points. Our analysis also predicts that the activation energy barrier decreases with the decrease in bond strength; hence k ex increases. The 17O and 1H hyperfine coupling constant values of all the coordinated water molecules were different, calculated by using the second-order Douglas-Kroll-Hess (DKH2) approach. Furthermore, the ionic nature of the bonding in the metal-ligand (M-L) bond was confirmed by the Quantum Theory of Atoms-In-Molecules (QTAIM) and ELF along with energy decomposition analysis (EDA). We hope that the results can be used as a basis for the design of highly efficient Gd(iii)-based high relaxivity MRI contrast agents for medical applications.

55/52Mn2+ Complexes with a Bispidine-Phosphonate Ligand: High Kinetic Inertness for Imaging Applications.

Bispidine (3,7-diazabicyclo[3.3.1]nonane) provides a rigid and preorganized scaffold that is particularly interesting for the stable and inert complexation of metal ions, especially for their application in medical imaging. In this study, we present the synthesis of two bispidine ligands with N-methanephosphonate (H4L1) and N-methanecarboxylate (H3L2) substituents as well as the physico-chemical properties of the corresponding Mn2+ and Zn2+ complexes. The two complexes [Mn(L1)]2- and [Mn(L2)]- have relatively moderate thermodynamic stability constants according to potentiometric titration data. However, they both display an exceptional kinetic inertness, as assessed by transmetallation experiments in the presence of 50 equiv excess of Zn2+, showing only ∼40 and 20% of dissociation for [Mn(L1)]2- and [Mn(L2)]-, respectively, after 150 days at pH 6 and 37 °C. Proton relaxivities amount to r1 = 4.31 mM-1 s-1 ([Mn(L1)]2-) and 3.64 mM-1 s-1 ([Mn(L2)]-) at 20 MHz, 25 °C, and are remarkable for Mn2+ complexes with one inner-sphere water molecule (q = 1); they are comparable to that of the commercial contrast agent [Gd(DOTA)(H2O)]-. The presence of one inner-sphere water molecule and an associative water exchange mechanism was confirmed by temperature-dependent transverse 17O relaxation rate measurements, which yielded kex298 = 0.12 × 107 and 5.5 × 107 s-1 for the water exchange rate of the phosphonate and the carboxylate complex, respectively. In addition, radiolabeling experiments with 52Mn were also performed with H2(L1)2- showing excellent radiolabeling properties and quantitative complexation at pH 7 in 15 min at room temperature as well as excellent stability of the complex in various biological media over 24 h.

Towards bright dysprosium emitters: Single and combined effects of environmental symmetry, deuteration, and gadolinium dilution

With the aim of creating new light emitting systems, two new dysprosium complexes of formula [DyQcy3(H2O)] (1-Dy) and [H3O][DyQcy4] (2-Dy) (where HQcy = 1-phenyl-3-methyl-4-cyclohexylcarbonyl-pyrazol-5-one) have been synthesized and characterized by spectroscopy. The reaction conditions to address the synthesis toward these tris-(diketonate)dysprosium or tetrakis(diketonate)dysprosium complexes have been optimized. The Qcy ligand provides effective sensitization of the luminescence of Dy3+ ion. 1-Dy and 2-Dy have been investigated by single crystal X-ray diffraction analysis, both species being packed via a system of hydrogen bonds. The dependence of quantum yield and lifetime of the excited state of Dy3+ ions have been examined by implementing two common approaches: replacing protons with deuterium in the coordinated H2O or in cation H3O+ and diluting Dy3+ cations with Gd3+ ions, to suppress vibrational and concentration quenching, respectively. It has been found that deuteration turns out to be very effective on both quantum yield and lifetime, but only in the case of replacement of the inner-sphere water molecules. The strategy of gadolinium dilution leads in all cases to an increase in lifetime. In addition, the possibility of a subtle tuning of the luminescence color has been discovered due to the change in the gadolinium content and deuteration, and a white light luminescent (CIE 0.31, 0.34) composition has been obtained.

Sequestration of Am3+ and Eu3+ into ionic liquid containing Aza-macrocycle based multiple-diglycolamide ligands: Extraction, complexation, luminescence and DFT studies

Extraction of Am3+ and Eu3+ was carried out into a room temperature ionic liquid, C8mim⋅Tf2N, using two multiple-diglycolamide extractants with three or four diglycolamide arms tethered to either a triaza- or tetraazamacrocyclic ligand termed as TAM-3-DGA and TAM-4-DGA, respectively. The metal ion extraction was highly efficient as only 5 × 10-4 M solutions of TAM-3-DGA resulted in D values of 680 and 845 for Am3+ and Eu3+, respectively, at pH 2.0, while the respective values with a five times lower concentration of TAM-4-DGA were 142 and 296, which is probably the best reported thus far. Though Eu3+ ion was preferentially extracted over Am3+, the selectivity was not as good as reported in molecular diluent-based extraction systems. The extracted species contained two units of the extractant and did not contain any nitrate ion suggesting a cation-exchange mechanism. Studies on the temperature effect on metal ion extraction were carried out to determine the thermodynamic parameters. Luminescence studies of the extracts were also performed which suggested strong complex formation with no inner-sphere water molecules. To understand the ligand coordination to Eu3+ and Am3+ and other bonding parameters, DFT studies were carried out.

Comparison of phosphonate, hydroxypropyl and carboxylate pendants in Fe(III) macrocyclic complexes as MRI contrast agents

Fe(III) macrocyclic complexes containing a macrocycle and three pendant groups including phosphonate (NOTP =1,4,7-triazacyclononane-1,4,7-triyl-tris(methylenephosphonic acid), carboxylate (NOTA = 1,4,7 - triazacyclononane - N,N′,N″ – triacetate) or hydroxypropyl (NOHP =(2S,2’S,2”S)-1,1′,1″-(1,4,7-triazonane-1,4,7-triyl)tris(propan-2-ol)) were studied in order to compare the effect of these donor groups on solution chemistry and water proton relaxivity. All three complexes, Fe(NOTP), Fe(NOHP) and Fe(NOTA), display a large degree of kinetic inertness to dissociation in the presence of phosphate and carbonate, under acidic conditions of 100 mM HCl or 1 M HCl or to trans-metalation with Zn(II). The r1 proton relaxivity of the complexes at 1.4 T, 33 °C is compared over the pH range of 1 to 10. At pH 7.4, 33 °C, 1.4 T, Fe(NOHP) has the largest relaxivity (1.5 mM−1 s−1), Fe(NOTP) is second at 1.0 mM−1 s−1, whereas Fe(NOTA) is the lowest at 0.61 mM−1 s−1. Fe(NOTP), Fe(NOHP) and Fe(NOTA) all show an increase in relaxivity at very acidic pH values (< 3) that is consistent with an acid-catalyzed process. Variable temperature 17O NMR studies at near neutral pH are consistent with the absence of an inner-sphere water molecule for Fe(NOTP) and Fe(NOHP), supporting second-sphere or outer-sphere water contributions to proton relaxation. Fe(NOTP) shows contrast enhancement in T1 weighted MRI studies in mice and clears through a renal pathway.

Structural changes in acetylurea complexes with rare-earth (Gd–Er) bromides: Coexistence of different coordination polyhedra in Dy and Ho compounds

Crystal structures of acetylurea (AcUr) complexes with middle rare-earth bromides, [Ln(AcUr)2(H2O)5]Br3·H2O (Ln = Gd, Tb), [Ln(AcUr)2(H2O)4.5][Ln(AcUr)2(H2O)4]Br6·2H2O (Ln = Dy, Ho) and [Er(AcUr)2(H2O)4]Br3, were studied by X-ray diffraction. Complex cations contain two bidentate AcUr molecules and five (Gd and Tb) or four (Er) inner-sphere water molecules; coordination numbers 9 or 8, respectively. Compounds of Dy and Ho contain two types of complex cations with coordination numbers 9 and 8.

SYNTHESIS AND SPECTRAL CHARACTERISTICS OF HETEROMETALLIC COMPLEXES OF Pr(III) WITH Zn(II), CO(II) BASED ON ETHYLENEDIAMINETETRAACETIC AND ETHYLENEDIAMINEDISUCCINIC ACIDS

New heterometallic f-d-complexes of Pr (III), Co(II), Zn(II) with aminopolycarboxylic acids (ethylenediaminetetraacetic, ethylenediaminedisuccinic acids) have been synthesized and spectroscopically characterized. It was found that complexes with a molar ratio of Pr:M3d: EDTA=1:2:2 are formed for ethylenediaminetetraacetic compounds, and that in the case of complexes based on EDDS, heteronuclear compounds of the equimolar composition Pr: M3d: EDDS = 1: 1: 1 are formed. It is shown that it is expedient to carry out the synthesis of heterometallic complexes on the basis of mono­nuclear polycarboxylates of 3d metals, which act as a «building block» for the preparation of a heterobinuclear compound by the exo coordination of additional metal ions. The complexes are characterized by the method of electron absorption spectroscopy. It is shown that independent of 3d-metal, for both heterometallic systems based on EDDS, a hypsochromic shift of the absorption maxima relative to νmax is observed for the homonuclear praseodymium complex. For ethylenediaminetetraacetate systems, the absorption maxima undergo both low- and high-frequency shift, which indicates the different nature of the ligand field effect, which is caused primarily by differences in the structure of the corresponding heteronuclearaminopolycarboxylates due to the presence of a chiral carbon atom in the EDDS molecule. For the supersensitive transitions Pr(III)) 3H4 →3P2 and 3H4 → 1D2 , the covalence parameters of the Ln-O bond have been calculated: osci­llator power (P), nepheloxetic parameter (β), covalence parameter (b1/2), Sinha parameter (δ). Analysis of the spectroscopic parameters indicates a decrease in the covalence of the lanthanide-ligand bond in the transition from mono- to heteronuclear complex, and a decrease in the local symmetry of the lanthanide ion occurs in the order Ln (III) aqua ion &lt;hete­rometallic complex &lt;monometallic complex. Heteronuclear complexes are several orders of magnitude more stable than mononuclear ones due to the formation of additional bonds or metallacycles with donor ligand atoms. It is noted that the stability of complexes with EDDS is lower than that of the corresponding complexes with EDTA due to the different size and number of chelated metallacycles. The obtained heteronuclear complexes belong to folded complexes, in which the ligand-complexone realizes the maximum denticity to the lanthanide ion, and the coordination sphere of the 3d-cation is formed by carboxyl groups EDTA / EDDS and inner-sphere water molecules. In this case, the ions of 3d-metals are in a distorted octahedral environment, and the coordination number of Pr(III) is 8.

Magnetic CoFe2O4/Graphene oxide nanocomposite for highly efficient separation of f-block elements

A magnetic nanocomposite, CoFe2O4/Graphene oxide (CoFe2O4/GO) was fabricated for highly efficient separation of f-block elements. The growth of CoFe2O4 nanoparticles on the GO nanosheets was confirmed by the X-ray diffraction pattern. The sorbent was found to be superparamagnetic with a large magnetization saturation (38 emu g‒1). This magnetic nanocomposite was found to have high sorption capacity for f-block elements following their ionic potential. The sorption kinetics followed the pseudo-second-order model, whereas the sorption data fitted well in the Freundlich isotherm due to the surface heterogeneity. The thermodynamic analysis revealed the process to be entropically driven and spontaneous. The complex with trivalent f-cation was found to be asymmetric with no inner-sphere water molecules. The spectroscopic analysis confirmed the strong complexation of Sm(III) with oxygen-containing functionalities of CoFe2O4/GO. The excellent radiolytic stability and regeneration ability of CoFe2O4/GO showed that the sorbent could be successfully applied for nuclear waste remediation.

Crystal Structures of Acetylurea Complexes with Rare-Earth Bromides: Surprising Structural Changes

Crystal structures of complexes of acetylurea (AcUr) with middle rare-earth bromides, [Ln(AcUr) 2 (H 2 O) 5 ]Br 3 . H 2 O (Ln = Gd, Tb), [Ln(AcUr) 2 (H 2 O) 4.5 ][Ln(AcUr) 2 (H 2 O) 4 ]Br 6 . 2H 2 O (Ln = Dy, Ho) and [Er(AcUr) 2 (H 2 O) 4 ]Br 3 , were studied by X-ray diffraction. Complex cations contain two bidentate AcUr molecules and five (Gd and Tb) or four (Er) inner-sphere water molecules; coordination numbers 9 or 8, respectively. Compounds of Dy and Ho contain two types of complex cations with coordination numbers 9 and 8.

A Frequency-Selective pH-Responsive paraCEST Agent.

Paramagnetic chemical exchange saturation transfer (paraCEST) agents are well-suited for imaging tissue pH because the basis of CEST, chemical exchange, is inherently sensitive to pH. Several previous pH-sensitive paraCEST agents were based on an exchanging Ln3+ -bound water molecule as the CEST antenna but this design often added additional line-broadening to the bulk water signal due to T2 exchange. We report herein a pH-sensitive paraCEST agent that lacks an inner-sphere water molecule but contains one Ln-bound -OH group for CEST activation. The Yb3+ complex, Yb(1), displayed a single, highly shifted CEST peak originating from the exchangeable Yb-OH proton, the frequency of which changed over the biologically relevant pH range. CEST images of phantoms ranging in pH from 6 to 8 demonstrate the potential of this agent for imaging pH. Initial rodent imaging studies showed that Gd(1) remains in the vascular system much longer than anticipated but is cleared slowly via renal filtration.

Macrocyclic Pyclen-Based Gd3+ Complex with High Relaxivity and pH Response.

We report the synthesis and characterization of the macrocyclic ligand 2,2'-((2-(3,9-bis(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-6-yl)ethyl)azanediyl)diacetic acid (H4L) and several of its complexes with lanthanide ions. The structure of the free ligand was determined using X-ray diffraction measurements. Two N atoms of the pyclen moiety in the trans position are protonated in the solid state, together with the exocyclic N atom and one of the carboxylate groups of the ligand. The relaxivity of the Gd3+ complex was found to increase from 6.7 mM-1 s-1 at pH 8.6 to 8.5 mM-1 s-1 below pH ≈ 6.0. Luminescence lifetime measurements recorded from H2O and D2O solutions of the Eu3+ complex evidence the presence of a single complex species in solution at low pH (∼5.0) that contains two inner-sphere water molecules. DFT calculations suggest that the coordination environment of the Ln3+ ion is fulfilled by the four N atoms of the pyclen unit, two oxygen atoms of the macrocyclic acetate groups, and an oxygen atom of an exocyclic carboxylate group. The two inner-sphere water molecules complete coordination number nine around the metal ion. At high pH (∼9.3), the lifetime of the excited 5D0 level of Eu3+ displays a biexponential behavior that can be attributed to the presence of two species in solution with hydration numbers of q = 0 and q = 1. The 1H NMR and DOSY spectra recorded from solutions of the Eu3+ and Y3+ complexes reveal a structural change triggered by pH and the formation of small aggregates at high pH values.

The Ligand Cap Affects the Coordination Number but Not Necessarily the Affinity for Anions of Tris-Bidentate Europium Complexes.

To evaluate the effect of ligand geometry on the coordination number, number of inner-sphere water molecules, and affinity for anions of the corresponding lanthanide complex, six tris-bidentate 1,2-hydroxypyridonate (HOPO) europium(III) complexes with different cap sizes were synthesized and characterized. Wider or more flexible ligand caps, such as in EuIII-TREN-Gly-HOPO and EuIII-3,3-Gly-HOPO, enable the formation of nine-coordinate europium(III) complexes bearing three inner-sphere water molecules. In contrast, smaller or more rigid caps, such as in EuIII-TREN-HOPO, EuIII-2,2-Li-HOPO, EuIII-3,3-Li-HOPO, and EuIII-2,2-Gly-HOPO, favor eight-coordinate europium(III) complexes that have only two inner-sphere water molecules. Notably, there is no correlation between the number of inner-sphere water molecules and the affinity of the Eu(III) complexes for phosphate. Some q = 2 (EuIII-TREN-HOPO, EuIII-3,3-Li-HOPO, and EuIII-2,2-Gly-HOPO) and some q = 3 (EuIII-TREN-Gly-HOPO) complexes have no affinity for anions, whereas one q = 2 complex (EuIII-2,2-Li-HOPO) and one q = 3 complex (EuIII-3,3-Gly-HOPO) have a high affinity for phosphate. For the latter two systems, each inner-sphere water molecule is replaced with a phosphate anion, resulting in the formation of EuLPi2 and EuLPi3 adducts, respectively.

Tripyridinophane Platform Containing Three Acetate Pendant Arms: An Attractive Structural Entry for the Development of Neutral Eu(III) and Tb(III) Complexes in Aqueous Solution.

We report a detailed characterization of Eu3+ and Tb3+ complexes derived from a tripyridinophane macrocycle bearing three acetate side arms (H3tpptac). Tpptac3- displays an overall basicity (∑ log KiH) of 24.5, provides the formation of mononuclear ML species, and shows a good binding affinity for Ln3+ (log KLnL = 17.5-18.7). These complexes are also thermodynamically stable at physiological pH (pEu = 18.6, pTb = 18.0). It should be noted that the pGd value of Gd-tpptac (18.4) is only slightly lower than that of commercially available MRI contrast agents such as Gd-dota (pGd = 19.2). Moreover, a very good selectivity for these ions over the endogenous cations (log KCuL = 14.4, log KZnL = 12.9, and log KCaL = 9.3) is observed. The X-ray structure of the terbium complex shows the metal coordinated by the nine N6O3 donor set of the ligand and one inner-sphere water molecule. DFT calculations result in two Eu-tpptac structures with similar bond energies (ΔE = 0.145 eV): one structure in which the water is coordinated to the metal ion and one structure in which the water molecule is farther away from the ion, bound to the ligand with an OH-π bond. By detailed luminescence experiments, we demonstrate that the europium complex in aqueous solution presents a hydration equilibrium between nine-coordinate, dehydrated [Eu-tpptac]0 and ten-coordinate, monohydrated [Eu-tpptac(H2O)]0 species. A similar trend is observed for the terbium complex. Despite the presence of this hydration equilibrium, the H3tpptac ligand sensitizes Eu3+ and Tb3+ luminescence efficiently in buffered water at physiological pH. Particularly, the terbium complex displays a long excited-state lifetime of 2.24 ms and an overall quantum yield of 33% with a brightness of 3600 M-1 cm-1. Such features of Ln3+ complexes of H3tpptac indicate that this platform appears to be particularly appealing for the further development of luminescent lanthanide labels.