A bifunctional chelator featuring the DOTAM-Gly-l-Phe-OH structural subunit: en route toward homo- and heterobimetallic lanthanide(III) complexes as PARACEST MRI contrast agents

A new synthesis of a bifunctional chelator possessing DOTAM-Gly-l-Phe-OH and DO3A chelating cages interconnected by an oligoamide chain has been achieved via HBTU-mediated coupling from easily accessible building blocks. Both homo- and heterobimetallic lanthanide(III) complexes derived from this bifunctional chelator have been prepared in moderate yields. The CEST spectrum acquired for homobimetallic Eu³⁺ complex showed this molecule to be a promising PARACEST MRI contrast agent whereas the Eu³⁺/Tm³⁺ heterobimetallic complex lacked a useful CEST signal.     

Density-functional theory structures of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complexes for ions across the lanthanide series

The use of organically chelated lanthanides in diagnosis and treatment is a rapidly growing field in medicine. In order to gain a deeper understanding into the properties of these chelates, particularly spectroscopic, density-functional calculations have been performed on a series of lanthanide ions chelated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Based on the results of these calculations, it has been concluded that the local symmetry experienced by the chelated lanthanide ion may be treated as being axial, which will make the interpretation of their spectroscopic properties greatly simplified. It has also been suggested that the so-called "capping" water molecule at the ninth coordination position of the lanthanide is hydrogen bonded to the acetate oxygens of the sidearms, rather than coordinated as the ninth ligand of the lanthanide.     

Stabilities and Thermodynamic Properties of Ethylenediamine-di(o-Hydroxyphenylacetic Acid) Chelates of Tripositive Lanthanide Ions

The interaction between ethylenediamine-di(o-hydroxyphenylacetic acid) (EDDHA, H₄Z) and tripositive lanthanide ions has been investigated. The formation constants of the protonated chelates (LnHZ) and those of the normal chelates (LnZ^?) have been evaluated at various temperatures and at a constant ionic strength of 0.1(KNO₁). For LnHZ, the pH-titrimetric technique, and for LnZ^?, the mercury indicator electrode method were used. The enthalpy and entropy changes characterizing the formation of LnZ^? have been calculated at 25° and, these functions have been compared with the corresponding values of other lanthanide chelates with related chelating agents.     

Studies on beta-type reaction and kinetics of lanthanides with p-bromochloroarsenazo

The reaction behaviour of the β-type chelates of lanthanide ions (Ln³⁺) with p-bromochloroarsenazo (4-CAsA-pB) in 0.01 mol l⁻¹ HClO₄ solution has been studied systematically by a spectrophotometric method. All the lanthanide ions can form β-type chelates with p-bromochloroarsenazo. The maximum absorption wavelength is in the range 727–731 nm, the molar absorptivities are about 6.0 × 10⁴ – 9.0 × 10⁴ cm² mol⁻¹, the composition ratio of Ln³⁺ ions with 4-CAsA-pB is 1:2 and the actual combining ratio is 2:4. The optimum acidity range (ΔpH value) of the formation of β-type chelates has been obtained. Kinetic parameters, such as the reaction order and rate constants, have also been studied and a formation mechanism for the β-type chelates has been proposed.     

Quantum yields of luminescent lanthanide chelates and far-red dyes measured by resonance energy transfer.

Luminescent lanthanide chelates have unusual spectroscopic characteristics that make them valuable alternative probes to conventional organic fluorophores. However, fundamental parameters such as their quantum yield, and radiative and nonradiative decay rates have been difficult or impossible to measure. We have developed a simple and robust method based on resonance energy transfer to accurately measure these parameters. In addition, the excitation/emission process in lanthanide chelates involves several steps, and we are able to quantify each step. These include excitation of an organic antenna, transfer of energy from the antenna to lanthanide, and then lanthanide emission. Overall, the parameters show that lanthanide chelates can be efficient long-lived emitters, making them sensitive detection reagents and excellent donors in resonance energy transfer. The method is also shown to be applicable to photophysical characterization of red-emitting dyes, which are difficult to characterize by conventional means.     

"Asymmetric" catalysis by lanthanide complexes

Catalysis with lanthanide (Ln) complexes has been underestimated for long time, although Ln(III) complexes have great advantages as Lewis acid catalysts for "asymmetric" carbon-carbon bond-forming reactions. Lanthanide complexes are highly active in ligand-substitution reactions, especially with hard ligands. The association with substrates and dissociation of products are achieved fast enough for high catalyst efficiency. The asymmetric catalysis of organic reactions can be greatly advanced by the use of Ln complexes with chiral ligands such as binaphthol (binol). Ln(II) complexes are good reducing agents, which can be used in a wide variety of synthetically important reactions; when chiral ligands are used, many of these reactions are highly stereoselective. In the context of "green chemistry", the development of asymmetric Ln catalysts, and their recyclable use, is of increasing importance. This review gives an overview of the most recent developments in catalysis with lanthanide(II) and lanthanide(III) complexes.     

Chelation and radiolytic determination of lanthanides with 2,2′-oxybis-[ethyliminodi/acetic/ acid]

A quantitative study of the interaction of some lanthanide ions with 2,2-oxybis-[ethyliminodi /acetic/ acid] or 2,2-bis [aminoethyl]ether-tetraacetic acid /BAETA/ was carried out. Stability constants of the lanthanide chelates containing 11 ratio of metal to ligand were determined. A discussion of the variation of the metal chelates stability constants in the lanthanide series is given. Radiolysis of the formed chelates has also been investigated both in presence and in absence of oxygen. A radiolytic degradation mechanism is proposed and discussed.     

Investigations into whole water, prototropic and amide proton exchange in lanthanide(III) DOTA-tetraamide chelates

Lanthanide(III) chelates of DOTA-tetraamide ligands have been an area of particular interest since the discovery that water exchange kinetics are dramatically affected by the switch from acetate to amide side-chain donors. More recently these chelates have attracted interest as potential PARACEST agents for use in MRI. In this paper we report the results of studies using chemical exchange saturation transfer (CEST) and some more recently reported chelates to re-examine the exchange processes in this class of chelate. We find that the conclusions of Parker and Aime are, for the most part, solid; water exchange is slow and a substantial amount of prototropic exchange occurs in aqueous solution. The extent of prototropic exchange increases as the pH increases above 8, leading to higher relaxivities at high pH. However, amide protons are found to contribute only a small amount to the relaxivity at high pH.     

Osmotically Shrunken LIPOCEST Agents: An Innovative Class of Magnetic Resonance Imaging Contrast Media Based on Chemical Exchange Saturation Transfer

The peculiar properties of osmotically shrunken liposomes acting as magnetic resonance imaging–chemical exchange saturation transfer (MRI–CEST) contrast agents have been investigated. Attention has been primarily devoted to assessing the contribution arising from encapsulated and incorporated paramagnetic lanthanide(III)‐based shift reagents in determining the chemical shift of the intraliposomal water protons, which is a relevant factor for generating the CEST contrast. It is demonstrated that a highly shifted resonance for the encapsulated water can be attained by increasing the percentage of the amphiphilic shift reagent incorporated in the liposome bilayer. It is also demonstrated that the shift contribution arising from the bulk magnetic susceptibility can be optimized through the modulation of the osmotic shrinkage. In terms of sensitivity, it is shown that the saturation transfer efficiency can be significantly improved by increasing the size of the vesicle, thus allowing a high number of exchangeable protons to be saturated. In addition, the role played by the intensity of the saturating radiofrequency field has also been highlighted.     

Time-resolved high-performance liquid chromatography fluorescence detector using a nanosecond pulsed light source for detecting lanthanide-chelated compounds

We have constructed a time-resolved fluorescence detection (TRFD) system for the analysis of amino compounds with high-performance liquid chromatography (HPLC) using lanthanide ion chelates. In order to carry out time-resolved measurements, we have employed a nanosecond pulsed xenon-arc lamp as an excitation light source. Amino compounds derivatized by isothiocyanobenzyl-EDTA (IEDTA) with the lanthanide chelate are mixed with an enhancer solution in a post-column manner and detected by TRFD. Taking advantage of a property of the long fluorescence lifetime of the lanthanide chelates, high selectivity against background fluorescence was achieved. In order to demonstrate the usefulness of TRFD, fundamental performance tests were carried out. Details of the system are also described.     

Studying "invisible" excited protein states in slow exchange with a major state conformation

Ever since its initial development, solution NMR spectroscopy has been used as a tool to study conformational exchange. Although many systems are amenable to relaxation dispersion approaches, cases involving highly skewed populations in slow chemical exchange have, in general, remained recalcitrant to study. Here an experiment to detect and characterize "invisible" excited protein states in slow exchange with a visible ground-state conformation (excited-state lifetimes ranging from ～5 to 50 ms) is presented. This method, which is an adaptation of the chemical exchange saturation transfer (CEST) magnetic resonance imaging experiment, involves irradiating various regions of the spectrum with a weak B(1) field while monitoring the effect on the visible major-state peaks. The variation in major-state peak intensities as a function of frequency offset and B(1) field strength is quantified to obtain the minor-state population, its lifetime, and excited-state chemical shifts and line widths. The methodology was validated with (15)N CEST experiments recorded on an SH3 domain-ligand exchanging system and subsequently used to study the folding transition of the A39G FF domain, where the invisible unfolded state has a lifetime of ～20 ms. Far more accurate exchange parameters and chemical shifts were obtained than via analysis of Carr-Purcell-Meiboom-Gill relaxation dispersion data.     

Europium(III) macrocyclic complexes with alcohol pendant groups as chemical exchange saturation transfer agents

Paramagnetic lanthanide(III) complexes that contain hyperfine-shifted exchangeable protons offer considerable advantages over diamagnetic molecules as chemical exchange saturation transfer (CEST) agents for MRI. As part of a program to investigate avenues to improve the sensitivity of such agents, the CEST characteristics of europium(III) macrocyclic complexes having appended hydroxyethyl groups were investigated. The CEST spectrum of the asymmetrical complex, EuCNPHC3+, shows five distinct peaks for each magnetically nonequivalent exchangeable proton in the molecule. The CEST spectra of this complex were fitted to NMR Bloch theory to yield exchange rates between each of six exchanging proton pools (five on the agent plus bulk water). Exchange between the Eu3+-bound hydroxyl protons and bulk water protons was slow in dry acetonitrile but accelerated incrementally upon stepwise addition of water. In pure water, exchange was too fast to observe a CEST effect. The utility of this class of europium(III) complex for CEST imaging applications is ultimately limited by the small chemical shifts induced by the hydroxyl-appended ligands of this type and the resulting small Deltaomega values for the exchangeable hydroxyl protons.     

Lanthanide(III) complexes that contain a self-immolative arm: potential enzyme responsive contrast agents for magnetic resonance imaging

Enzyme-responsive MRI-contrast agents containing a "self-immolative" benzylcarbamate moiety that links the MRI-reporter lanthanide complex to a specific enzyme substrate have been developed. The enzymatic cleavage initiates an electronic cascade reaction that leads to a structural change in the Ln(III) complex, with a concomitant response in its MRI-contrast-enhancing properties. We synthesized and investigated a series of Gd(3+) and Yb(3+) complexes, including those bearing a self-immolative arm and a sugar unit as selective substrates for β-galactosidase; we synthesized complex LnL(1), its NH(2) amine derivatives formed after enzymatic cleavage, LnL(2), and two model compounds, LnL(3) and LnL(4). All of the Gd(3+) complexes synthesized have a single inner-sphere water molecule. The relaxivity change upon enzymatic cleavage is limited (3.68 vs. 3.15 mM(-1) s(-1) for complexes GdL(1) and GdL(2), respectively; 37 °C, 60 MHz), which prevents application of this system as an enzyme-responsive T(1) relaxation agent. Variable-temperature (17)O NMR spectroscopy and (1)H NMRD (nuclear magnetic relaxation dispersion) analysis were used to assess the parameters that determine proton relaxivity for the Gd(3+) complexes, including the water-exchange rate (k(ex)(298), varies in the range 1.5-3.9×10(6) s(-1)). Following the enzymatic reaction, the chelates contain an exocyclic amine that is not protonated at physiological pH, as deduced from pH-potentiometric measurements (log K(H)=5.12(±0.01) and 5.99(±0.01) for GdL(2) and GdL(3), respectively). The Yb(3+) analogues show a PARACEST effect after enzymatic cleavage that can be exploited for the specific detection of enzymatic activity. The proton-exchange rates were determined at various pH values for the amine derivatives by using the dependency of the CEST effect on concentration, saturation time, and saturation power. A concentration-independent analysis of the saturation-power-dependency data was also applied. All these different methods showed that the exchange rate of the amine protons of the Yb(III) complexes decreases with increasing pH value (for YbL(3), k(ex)=1300 s(-1) at pH 8.4 vs. 6000 s(-1) at pH 6.4), thereby resulting in a diminution of the observed CEST effect.     

Oxidative Conversion of a Europium(II)‐Based T1 Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging

The Eu^II complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) tetra(glycinate) has a higher reduction potential than most Eu^II chelates reported to date. The reduced Eu^II form acts as an efficient water proton T₁ relaxation reagent, while the Eu^III form acts as a water‐based chemical exchange saturation transfer (CEST) agent. The complex has extremely fast water exchange rate. Oxidation to the corresponding Eu^III complex yields a well‐defined signal from the paraCEST agent. The time course of oxidation was studied in vitro and in vivo by T₁‐weighted and CEST imaging.     

Luminescence studies on europium-strontium phthalate system

New lanthanide luminescence materials were prepared. The main component lanthanide chelates generally need a relatively high content of rare earth. Inorganic luminescence materials only need low rare earth concentration using doped method. Similarly, lanthanide chelates can be added to complex matrix by doped method. In this way, low rare earth concentration emission was successful in the lanthanide chelates system as well. The influence of europium ion concentration on luminescence intensities was discussed. When the europium ion weight in the complex is only about 0.6%, the sample exhibits good luminescence properties. The fluorescence, Fourier transform infrared spectra, micro-Raman and electron spin resonance spectra of the samples were measured. And a possible luminescence mechanism was suggested by the inorganic doped mechanism and the luminescence of lanthanide complexes together.     

The Complexation of Some Sodium Sulphophenyl Hydrazo-5-Pyrazolone Dyes Towards Trivalent Lanthanide Ions “Stability Constants”

Acid dissociation constants of substituted-5-pyrazolone dyes have been determined potentiometrically in 75% (v/v) dioxane-water mixture at 30°C and <0.1 ionic strength. The stability constants of their 1:1 and 1:2 chelates with tweleve trivalent lanthanide ions have been determined under the same conditions. The data were correlated and the results were taken to explain the stabilization of such. chelates by dative π -bonding between Ln (III) and the ligand.     

Preparation of lanthanide sulfide films by chemical vapor deposition using β-diketone chelates

Preparation of thin films of lanthanide (Ln) sulfides has been studied by the chemical vapor deposition (CVD) method, using metal -diketonato chelates with 2,2,6,6-tetramethyl-3,5-heptanedione and reactant H₂S gas as starting materials. Two kinds of sulfides, Ln₂O₂S oxysulfides and EuS monosulfide, were obtained as thin films at temperatures as low as 390–570 °C. The CVD method was confirmed to be suited for the above purpose.     

Preparation of lanthanide,thorium and uranium oxide films by chemical vapor deposition using β-diketone chelates

Preparation of thin film deposits of lanthanide, thorium and uranium oxides has been studied by chemical vapor deposition (CVD) method using -diketonate metal chelates with 2,2,6,6-tetramethyl-3,5-heptanedione and some reactant gases as starting materials. The deposition process was carried out using a special apparatus designed for the CVD method at atmospheric pressure and temperatures as low as 400–600°C.As a result, it was demonstrated that each chelate used was well suited for the above purpose by its high volatility and reactivity with the reactant, especially with water vapor.     

Synthesis and characterization of an organometallic Schiff base and its lanthanide chelates

Summary A Schiff base containing an organometallic substituent,N, N-[bis(ferrocenyl-1-oxo-3-methyl)propenyl]ethylenediamine (H₂ bfe) and its chelates with lanthanide(III), [Ln(bfe)]Cl·0–1H₂O (Ln=Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, or Lu) have been prepared and characterized by elemental analyses, i.r., u.v.,¹H n.m.r., molar conductance, and t.g. analysis. The ligand is a tetradentate species and coordinates to the central lanthanide ion by the oxygen and nitrogen with 11 stoichiometry. The chelates are 11 electrolytes.     

Fractional sublimation of the β-diketone chelates of the lanthanide and related elements

Various β-diketone chelates of Sc(III), Y(III), Th(IV), U(IV). U(VI), Zr(IV) and the lanthanides have been prepared, characterized and investigated to determine if they were volatile and stable. The ligands employed were acetylacetone(AA), trifluoroacetylacetone(TFAA), hexafluoroacetylacetone(HFAA), and dipivaloyl-methane(DPM). The chelates were sublimed in a fractional vacuum sublimator and the recrystallization temperature zones recorded for individual chelates. None of the lanthanide acetylacetonates arc volatile but the Sc(III), Th(IV), U(IV) and dioxouranium(VI) acetylacetonates are thermally stable and quite volatile below 150° at 1 mm mercury pressure. The lanthanide, Sc(III), Y(III), and dioxouranium(VI) trifluoroacetylacetonates are volatile and can be vacuum-sublimed below 150°, but are thermally unstable; only the Th(IV) chelate is sufficiently stable to be quantitatively recovered by sublimation. The Sc(III), Y(III), Th(IV), and lanthanide hexafluoroacetylacetonates are thermally stable and easily sublimed below 125° in vacua or at atmospheric pressure. All the dipivaloylmethanates studied were thermally stable and volatile and could be quantitatively recovered by vacuum sublimation below 140°.The volatility of the HFAA and DPM lanthanide chelates increased with an increase in atomic weight (a decrease in ionic radii) of the lanthanides. The lack of volatility observed for the lanthanide AA and TFAA chelates is attributed to the fact that only hydrates of the chelates were formed, which decomposed at elevated temperatures in vacuo to form basic polymeric compounds.Separations are proposed for numerous binary mixtures of the β-diketone chelates of the lanthanide and related elements. Recrystallization temperature zones are given for the following binary mixtures which were quantitatively resolved by the fractional sublimation technique; 118-88° for Nd(DPM)₃ and 84-48° for Tm(DPM)₃; 72-49° for Sc(DPM) and 120-88° for Pr(DPM); 128-79° for La(DPM)₃ and 79-47° for Yb(DPM)₃; 70-47° for Th(TFAA)₄ and 116-96° for Gd(TFAA)₃; 52-42° for Th(HFAA)₄ and 120-80° for La(HFAA)₃.