Molecular recognition of sugars by lanthanide (III) complexes of a conjugate of N,N‐bis[2‐[bis[2‐(1, 1‐dimethylethoxy)‐2‐oxoethyl]amino]ethyl]glycine and phenylboronic acid

A novel conjugate of phenylboronic acid and an Ln(DTPA) derivative, in which the central acetate pendant arm was replaced by the methylamide of L ‐lysine, was synthesized and characterized. The results of a fit of variable ¹⁷O NMR data and a ¹H NMRD profile show that the water residence lifetime of the Gd(III) complex (150 ns) is shorter than that of the parent compound Gd(DTPA)^2? (303 ns). Furthermore, the data suggest that several water molecules in the second coordination sphere of Gd(III) contribute to the relaxivity of the conjugate. The Ln(III) complexes of this conjugate are highly suitable for molecular recognition of sugars. The interaction with various sugars was investigated by ¹¹B NMR spectroscopy. Thanks to the thiourea function that links the phenylboronic acid targeting vector with the DTPA derivative, the interactions are stronger than that of phenylboronic acid itself. In particular, the interaction with N‐propylfructosamine, a model for the glucose residue in glycated human serum albumin (HSA), is very strong. Unfortunately, the complex also shows a rather strong interaction with hexose‐free HSA (K_A = 705 ± 300). Copyright © 2007 John Wiley & Sons, Ltd.     

Bifunctional Gd(III) and Tb(III) chelates based on a pyridine–bis(iminodiacetate) platform,suitable optical probes and contrast agents for magnetic resonance imaging

To study the physicochemical properties of lanthanide complexes derived from a bifunctional chelating agent based on a PMN‐tetraacetic acid moiety {PMN‐tetraacetic acid (1): [2,6‐pyridinediylbis(methylene nitrilo)‐tetraacetic acid]}, 4‐carboxylic acid substituted pyridine derivative (2) was synthesized. This ligand forms heptadentate (N₃O₄) Ln(III) complexes (Ln = Gd, Eu, Tb), with two water molecules completing the inner coordination sphere of the metal. The parameters that govern the relaxivity of the Gd(III) complex and the luminescence of Eu(III) and Tb(III) complexes were obtained by ¹⁷O and ¹H NMR studies and time‐resolved fluorescence experiments, respectively. The gadolinium and terbium complexes show interesting properties either for MRI or FOR optical imaging; that is, for the Gd complex, a high proton relaxivity (r₁ = 6.4 s^?1 mm ^?1 at 20 MHz) with short water residence time (τ_M = 38.5 ns); for the Tb complex, a luminescence lifetime of 1.22 ms at room temperature and a luminescence quantum yield of 10%. The kinetic stability of these complexes toward blood protein, cation or bioactive oxyanion was also examined. The Gd(2)(H₂O)₂ complex does not interact with human serum albumin, but undergoes a transmetalation reaction with Zn(II) in a phosphate buffer solution (pH 7.4), rather similar to that of Gd–DTPA–BMA(H₂O). On the other hand, as observed for Eu and Tb complexes, these chelates do not form ternary complexes with bidentate anions such as l ‐lactate, citrate or carbonate. Finally, a phosphatidylserine‐specific hexapeptide (TLVSSL) was grafted on Gd or Tb chelates, and the Gd–peptide conjugate was used in vitro for targeting apoptotic cells. Copyright © 2014 John Wiley & Sons, Ltd.     

Entrapment of a neutral Tm(III)‐based complex with two inner‐sphere coordinated water molecules into PEG‐stabilized vesicles: towards an alternative strategy to develop high‐performance LipoCEST contrast agents for MR imaging

Chemical exchange saturation transfer (CEST) probes issued from the encapsulation of a water proton paramagnetic shift reagent into the inner aqueous volume of lipid vesicles provide an emerging class of frequency‐selective contrast agents with huge potential in the field of molecular magnetic resonance imaging (MRI). This work deals with the generation of such LipoCEST agents properly designed to optimize, under isotonic conditions, the chemical shift offset of the intra‐liposomal water protons as well as the number of exchangeable protons under reasonably low radiofrequency (RF) fields of saturation. The strategy lies in the loading of poly(ethylene glycol)‐stabilized nanosized liposomes with uncharged lanthanide chelates, binding more than one water molecule in the first hydration sphere, exemplified here by [Tm(III)–DO3A (H₂O)₂] complex. The key properties of the probes are demonstrated by complementary NMR investigations. The residence lifetime of the water molecules coordinated to the lanthanide center was outstandingly short (9.5 ± 0.2 ns from ¹⁷O NMR), and indeed relevant for effective LipoCEST responsiveness. The ¹H NMR CEST spectra (7.01 T magnetic field) prove that the theoretically expected optimal sensitivity can be approximated in the nanomolar concentration range, at reasonably low RF presaturation pulses (6.7–12 μT) and saturation frequency offsets of the intra‐liposomal water protons beyond 10 ppm, making possible selective irradiation in biological environment. CEST‐MRI images (7.01 T magnetic field and 10–12 μT RF pulse) explicitly confirm the interest of these newly conceived LipoCEST agents, indeed among the most efficient ones developed so far under isosmotic conditions. Copyright © 2014 John Wiley & Sons, Ltd.     

Pharmacokinetic and in vivo evaluation of a self‐assembled gadolinium(III)‐iron(II) contrast agent with high relaxivity

A high‐molecular weight tetrametallic supramolecular complex [(Ln‐DTPA‐phen)₃Fe]^? (Ln = Gd, Eu, La) has been obtained upon self‐assembly around one iron(II) ion of three 1,10‐phenantroline‐based molecules substituted in 5′‐position with the polyaminocarboxylate diethylenetriamine‐N,N,N′,N′,N′‐pentaacetate, DTPA‐phen^4?. The ICP‐MS measurements indicated that the lanthanide:iron ratio is 3:1. Photoluminescence spectra of [Eu‐DTPA‐phen]^? and of [(Eu‐DTPA‐phen)₃Fe]^? are nearly identical, implying that the first coordination sphere of the lanthanide(III) ion has not been changed upon coordination of phenantroline unit to iron(II) ion. NMRD measurements revealed that at 20 MHz and 310 K the relaxivity of the [(Gd‐DTPA‐phen)₃Fe]^? is equal to 9.5 ± 0.3 s^?1 mM^?1 of Gd (28.5 s^?1 per millimole per liter of complex) which is significantly higher than that for Gd‐DTPA (3.9 s^?1 mM^?1). The pharmacokinetic parameters of [(Gd‐DTPA‐phen)₃Fe]^? in rats indicate that the elimination of [(Gd‐DTPA‐phen)₃Fe]^? is significantly slower than that of Gd‐DTPA and is correlated with a reduced volume of distribution. The low volume of distribution and the longer elimination time (T_e1/2) suggest that the agent is confined to the blood compartment, so it could have an important potential as a blood pool contrast agent. The biodistribution profile of [(Gd‐DTPA‐phen)₃Fe]^? 2 h after injection indicates significantly higher concentrations of [(Gd‐DTPA‐phen)₃Fe]^? as compared with Gd‐DTPA in kidney, liver, lungs, heart and spleen. The images obtained on rats by MR angiography show the enhancement of the abdominal blood vessels. The signal intensity reaches a maximum of 55% at 7 min post‐contrast and remains around 25% after 90 min. MRI‐histomorphological correlation studies of [Gd‐DTPA‐phen]^? and [(Gd‐DTPA‐phen)₃Fe]^? showed that both agents displayed potent contrast enhancement in organs including the liver. The necrosis avidity tests indicated that, in contrast to the [Gd‐DTPA‐phen]^? precursor complex, the supramolecular complex [(Gd‐DTPA‐phen)₃Fe]^? exhibits necrosis avidity. Copyright © 2006 John Wiley & Sons, Ltd.     

Towards MRI contrast agents responsive to Ca(II) and Mg(II) ions: metal‐induced oligomerization of dota–bisphosphonate conjugates

In magnetic resonance imaging (MRI), paramagnetic complexes are utilized as contrast agents. Much attention has been paid to the development of new contrast agents responsive to pH, temperature or concentration of various components of body liquids. We report a new type of MRI probe sensing the concentrations of calcium and magnesium in biological media. The ligand do3ap^BP combines a dota‐like chelator with a bisphosphonate group. In the complex, the Gd(III ) ion is entrapped in the macrocyclic cavity whereas the bisphosphonate group is not coordinated and therefore is available for coordination with endogenous metal ions. In the presence of metal ions, Gd–do3ap^BP appears to show formation of coordination oligomers leading to an unprecedented increase in r₁ up to 200–500%. The extremely high relaxivity response makes this type of compound interesting for further studies as MRI ion‐responsive probes for biomedical research. Copyright © 2010 John Wiley & Sons, Ltd.     

Nanoparticle‐based PARACEST agents: the quenching effect of silica nanoparticles on the CEST signal from surface‐conjugated chelates

Silica nanoparticles of average diameter 53 ± 3 nm were prepared using standard water‐in‐oil microemulsion methods. After conversion of the surface Si–OH groups to amino groups for further conjugation, the PARACEST agent, EuDOTA–(gly)₄^? was coupled to the amines via one or more side‐chain carboxyl groups in an attempt to trap water molecules in the inner‐sphere of the complex. Fluorescence and ICP analyses showed that ~1200 Eu³⁺ complexes were attached to each silica nanoparticle, leaving behind excess protonated amino groups. CEST spectra of the modified silica nanoparticles showed that attachment of the EuDOTA–(gly)₄^? to the surface of the nanoparticles did not result in a decrease in water exchange kinetics as anticipated, but rather resulted in a complete elimination of the normal Eu³⁺‐bound water exchange peak and broadening of the bulk water signal. This observation was traced to catalysis of proton exchange from the Eu³⁺‐bound water molecule by excess positively charged amino groups on the surface of the nanoparticles. Copyright © 2012 John Wiley & Sons, Ltd.     

The pH sensitivity of –NH exchange in LnDOTA–tetraamide complexes varies with amide substituent

The amide proton exchange rates in various lanthanide(III) DOTA–tetraamide complexes were investigated by CEST as a function of variable chemical structures and charges on the amide substituents. Comparisons were made between YbDOTA–(gly)₄^? (Yb‐1), YbDOTA–(NHCH₂PO₃)₄^5? (Yb‐2) and YbDOTA–(NHCH₂PO₃Et₂)₄³⁺ (Yb‐3). The general shapes of the CEST vs pH profiles were similar for the three complexes but they showed maximum CEST intensities at different pH values, pH 8.3, 8.8 and 6.9 for Yb‐1, Yb‐2 and Yb‐3, respectively. This indicates that a more negatively charged substituent on the amide helps stabilize the partial positive charge on the amide nitrogen and consequently more base is required to catalyze proton exchange. The chemical shifts of the –NH protons in Yb‐1 and Yb‐2 were similar (?17 ppm) while the –NH proton in Yb‐3 was at ?13 ppm. This shows that the crystal field produced by the amide oxygen donor atoms in Yb‐3 is substantially weaker than that in the other two complexes. In an effort to expand the useful range of pH values that might be measured using these complexes as CEST agents, the shapes of the CEST vs pH curves were also determined for two thulium(III) complexes with much larger hyperfine shifted –NH proton resonances. The ratio of CEST from –NH exchange in Tm‐1 compared with CEST from –NH exchange in Tm‐3 was found to be linear over an extended pH range, from 6.3 to 7.4. This demonstrates a potential advantage of using mixtures of lanthanide(III) DOTA–tetraamides for mapping tissue pH by use of ratiometric CEST imaging. Copyright © 2011 John Wiley & Sons, Ltd.     

In vitro characterization of phosphatidylglyceroglycerol‐based thermosensitive liposomes with encapsulated 1H MR T1‐shortening gadodiamide

Thermosensitive liposomes (TSL) with encapsulated proton (¹H) magnetic resonance (MR) contrast agents have been proposed for noninvasive online temperature monitoring during tumor treatment using chemotherapy combined with hyperthermia (HT). The technique exploits the fact that water exchange between the TSL interior and exterior is increased and/or the encapsulated ¹H MR contrast agent is released near the gel‐to‐liquid crystalline phase transition temperature (T_m) of TSL and thus shortens the ¹H MR relaxation time of tissue. In this work, newly developed, phosphatidylglyceroglycerol (DPPGOG)‐based TSL with encapsulated ¹H MR longitudinal relaxation time (T₁)‐shortening gadodiamide (Gd‐DTPA‐BMA) were characterized in vitro by measuring the temperature dependence of the T₁ of these gadodiamide‐containing DPPGOG‐TSL samples between 30 and 50°C. The measurements revealed that the T₁ nonlinearly slightly decreased with increasing temperature from 30 to 37°C, mainly due to increased water exchange between the gadodiamide‐containing DPPGOG‐TSL interior and exterior with the exception of negligible gadodiamide release. This implies that gadodiamide‐containing DPPGOG‐TSL were stable at temperatures ≤37°C, which was also confirmed by an independent stability study. From 37 to 44°C, the T₁ nonlinearly markedly decreased with increasing temperature since encapsulated gadodiamide was rapidly released. Above 44°C, gadodiamide was completely released and the T₁ was directly proportional to temperature while heated from 44 to 50°C and cooled from 50 to 30°C, respectively. Additionally, gadodiamide release was theoretically quantified and this calculated concentration was consistent with the actually released amount directly obtained from the cooling course of empty DPPGOG‐TSL with completely released gadodiamide. Copyright © 2008 John Wiley & Sons, Ltd.     

Modulation of water exchange in Eu(III) DOTA–tetraamide complexes: considerations for in vivo imaging of PARACEST agents

Modulation of water exchange in lanthanide(III)–DOTA type complexes has drawn considerable attention over the past two decades, particularly because of their application as contrast agents for magnetic resonance imaging. LnDOTA–tetraamide complexes display unusually slow water exchange kinetics and this chemical property offers an opportunity to use these complexes as a new type of contrast agent based upon the chemical exchange saturation transfer (CEST) mechanism. Six new DOTA–tetraamide ligands having side‐chain amide arms with varying hydrophobicity and polarity were prepared and the water exchange characteristic of complexes formed with europium(III) complexes were investigated. The results show that introduction of steric bulk into the amide side‐chain arms of the europium(III) complexes not only favors formation of the mono‐capped twisted square antiprism coordination isomers, the isomer that is generally less favourable for CEST, but also accelerates water exchange in the mono‐capped square antiprism isomers. However, converting single methyl groups on these bulky arms to carboxyl or carboxyl ethyl esters results in a rather dramatic decrease in water exchange rates, about 50‐fold. Thus, steric bulk, polarity and hydrophobicity of the amide side‐chains each contribute to organization of water molecules in the second hydration sphere of the europium(III) ion and this in turn controls water exchange in these complexes. Copyright © 2009 John Wiley & Sons, Ltd.     

Influence of molecular parameters and increasing magnetic field strength on relaxivity of gadolinium‐ and manganese‐based T1 contrast agents

Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r₁) and transverse (r₂) relaxivity as a function of applied field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally. The field‐dependent relaxivities of a panel of gadolinium and manganese complexes with different molecular parameters, water exchange rates, rotational correlation times, hydration state, etc. were measured to confirm that measured relaxivities were consistent with theory. The design tenets previously stressed for optimizing r₁ at low fields (very slow rotational motion; chelate immobilized by protein binding; optimized water exchange rate) do not apply at higher fields. At 1.5T and higher fields, an intermediate rotational correlation time is desired (0.5–4 ns), while water exchange rate is not as critical to achieving a high r₁. For targeted applications it is recommended to tether a multimer of metal chelates to a protein‐targeting group via a long flexible linker to decouple the slow motion of the protein from the water(s) bound to the metal ions. Per ion relaxivities of 80, 45, and 18 mM ^?1 s^?1 at 1.5, 3 and 9.4 T, respectively, are feasible for Gd³⁺ and Mn²⁺ complexes. Copyright © 2009 John Wiley & Sons, Ltd.     

Lanthanide ion (III) complexes of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraaminophosphonate for dual biosensing of pH with chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS)

Relaxivity‐based magnetic resonance of phosphonated ligands chelated with gadolinium (Gd³⁺) shows promise for pH imaging. However instead of monitoring the paramagnetic effect of lanthanide complexes on the relaxivity of water protons, biosensor (or molecular) imaging with magnetic resonance is also possible by detecting either the nonexchangeable or the exchangeable protons on the lanthanide complexes themselves. The nonexchangeable protons (e.g. –CH_x, where 3 ≥ x ≥ 1) are detected using a three‐dimensional chemical shift imaging method called biosensor imaging of redundant deviation in shifts (BIRDS), whereas the exchangeable protons (e.g. –OH or –NH_y, where 2 ≥ y ≥ 1) are measured with chemical exchange saturation transfer (CEST) contrast. Here we tested the feasibility of BIRDS and CEST for pH imaging of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraaminophosphonate (DOTA‐4AmP^8?) chelated with thulium (Tm³⁺) and ytterbium (Yb³⁺). BIRDS and CEST experiments show that both complexes are responsive to pH and temperature changes. Higher pH and temperature sensitivities are obtained with BIRDS for either complex when using the chemical shift difference between two proton resonances vs using the chemical shift of a single proton resonance, thereby eliminating the need to use water resonance as reference. While CEST contrast for both agents is linearly dependent on pH within a relatively large range (i.e. 6.3–7.9), much stronger CEST contrast is obtained with YbDOTA‐4AmP^5? than with TmDOTA‐4AmP^5?. In addition, we demonstrate the prospect of using BIRDS to calibrate CEST as new platform for quantitative pH imaging. Copyright © 2014 John Wiley & Sons, Ltd.     

Relaxivity enhancement of aquated Tris(β‐diketonate)gadolinium(III) chelates by confinement within ultrashort single‐walled carbon nanotubes

Ultrashort single‐walled carbon nanotubes loaded with gadolinium ions (gadonanotubes) have been previously shown to exhibit extremely high T₁‐weighted relaxivities (>100 mm ^?1 s^?1). To further examine the effect of nanoconfinement on the relaxivity of gadolinium‐based contrast agents for magnetic resonance imaging, a series of ultrashort single‐walled carbon nanotube (US‐tube) materials internally loaded with gadolinium chelates have been prepared and studied. US‐tubes were loaded with Gd(acac)₃ · 2H₂O, Gd(hfac)₃ · 2H₂O, and Gd(thd)₃ (acac = acetylacetone, hfac = hexafluoroacetylacetone, thd = tetramethylheptanedione). The longitudinal relaxivities of the prepared materials determined at 25°C in a 1.5 T field were 103 mm ^?1 s^?1 for Gd(acac)₃ · 2H₂O@US‐tubes, 105 mm ^?1 s^?1 for Gd(hfac)₃ · 2H₂O@US‐tubes and 26 mm ^?1 s^?1 for Gd(thd)₃@US‐tubes. Compared with the relaxivities obtained for the unloaded chelates (<10 mm ^?1 s^?1) as well as accounting for the T₁ reduction observed for the empty US‐tubes, the boost in relaxivity for chelate‐loaded US‐tubes is attributed to confinement within the nanotube and depends on the number of coordinated water molecules. Copyright © 2014 John Wiley & Sons, Ltd.     

Mimicking 2,2′:6′,2′′:6′′,2′′′-quaterpyridine complexes for the light-driven hydrogen evolution reaction: synthesis,structural, thermal and physicochemical characterizations

The synthetic difficulties associated with quaterpyridine (qtpy) complexes have limited their use in the formation of various metallosupramolecular architectures in spite of their diverse structural and physicochemical properties. Providing a new facile synthetic route to the synthesis of functionalised qtpy mimics, we herein report the synthesis of three novel –NH₂ functionalized qtpy-like complexes 12–14 with the general formula M(C₁₆H₁₄N₁₂)(NO₃)₂ (M = Co(ii), Ni(ii) and Cu(ii)) in high yield and purity. Characterization of these complexes has been done by single crystal X-ray diffraction (SCXRD), thermogravimetric analysis, UV-Vis, infrared, mass spectrometry and cyclic voltammetry. As indicated by SCXRD, in all the synthesized complexes, the metal ions show a strongly distorted octahedral coordination geometry and typical hydrogen bonding networks involving DAT groups. In addition, complexes 12–14 have been analyzed as potential photocatalysts for hydrogen evolution reaction (HER) displaying good turnover numbers (TONs). Hydrogen produced from these photocatalysts can serve as the possible alternative for fossil fuels. To the best of our knowledge, this is the only study showcasing –NH₂ functionalized qtpy-like complexes of Co(ii), Ni(ii) and Cu(ii) and employing them as photocatalysts for HER. Thus, a single proposed strategy solves two purposes-one related to synthesis while second is related to our environment.

Facile synthesis of three novel –NH₂ functionalized qtpy-like complexes, their characterizations and study of their photocatalytic properties for hydrogen evolution reaction.     

How to determine the number of inner‐sphere water molecules in Lanthanide(III) complexes by 17O NMR spectroscopy. A technical note

Lanthanide(III) complexes of polyaminocarboxylates are widely used in MRI as contrast agents. The paramagnetic properties of the metal ion contribute to the increase of ¹H relaxation rates, while the chelate offers a stable binding with the metal. The number of water molecules, coordinated directly to the Ln(III) ion, is very important for the relaxivity and, thus, the efficacy of these contrast agents. Here, we describe convenient methods to determine this parameter by measurement of Ln(III)‐induced shifts of the water ¹⁷O NMR resonance. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis,crystal structures and,magnetic and photoluminescence properties of lanthanide-based metal–organic frameworks constructed with 2,5-dihydroxybenzene-1,4-dicarboxylic acid

Four new lanthanide(iii) coordination polymers (1–4) have been synthesized by using 2,5-dihydroxybenzene-1,4-dicarboxylate (Dhbdc, C₈H₆O₆²⁻) as a ligand and characterized by elemental analysis, infrared spectroscopy, TGA-DSC (Thermogravimetric Analysis-Differential Scanning Calorimetry) and single crystal X-ray diffraction studies. The isolated complexes include; [Ce(Dhbdc)(H₂O)₃Cl]_n (1) and [Ln(Dhbdc)_1.5(H₂O)₂]_n·3n(C₂H₆O)·nH₂O [Ln = Eu (2), Gd (3) and Tb (4)]. The structural analysis reveals that compound 1 is a two-dimensional polymer in which the cerium atoms are coordinated by six oxygen and two bridging chloride ions adopting a dodecahedral geometry. The compounds 2–4 are isomorphous and their extended structures consist of three-dimensional supramolecular frameworks encapsulating [001] channels occupied by the guest water and ethanol molecules. The metal atoms in 2–4 exhibit a square antiprism geometry. All these compounds have O–H⋯O hydrogen bonds originating from the coordinated water and solvent molecules that help to consolidate the structures. The compounds 1, 3 and 4 were investigated for magnetic properties and they exhibited weak antiferromagnetic coupling interactions between the lanthanides as per the Curie Weiss law. Anisotropic nature of 3 and 4 has been depicted as per magnetization versus field plots. Complex 4 behaves as a soft magnetic material as compared to 3. The luminescence studies indicate that compounds 2, 3 and 4 show ligand-centred fluorescence, which is significantly enhanced in the case of 4.

Four new lanthanide(iii) coordination polymers (1–4) have been synthesized by using 2,5-dihydroxybenzene-1,4-dicarboxylate as a ligand and investigated for magnetic and photo-luminescence properties.     

Synthesis and characterization of new low‐molecular‐weight lysine‐conjugated Gd‐DTPA contrast agents

Various blood pool contrast agents (CAs), characterized by intravascular distribution, have been developed to assist contrast enhanced magnetic resonance angiography (MRA). Among these CAs, the DTPA derivatives conjugated to synthetic polypeptides, such as polylysine, represent attractive candidates for blood pool imaging. However, due to the presence of charged residues located on their backbone, these agents are retained in the kidneys and this compromises their long blood half‐life. In order to overcome this major drawback of the polylysine compounds, two new low‐molecular‐weight CAs were synthesized in the present work by conjugating four or six 1‐p‐isothiocyanatobenzyl‐DTPA moieties to tri‐ or penta‐Lys peptides [(Gd‐DTPA)₄Lys₃ and (Gd‐DTPA)₆Lys₅], respectively. All the –NH₂ groups of Lys were thus blocked by covalent conjugation to DTPA. The stability and relaxometric properties of these compounds, as well as their pharmacokinetic and biodistribution characteristics, were then evaluated. The half‐life in blood of these new polylysine derivatives, as determined in rats, is twofold longer than that of Gd‐DTPA. The compounds could thus be optimal blood pool markers for MRA, which typically uses fast acquisition times. The absence of positive molecular charge did not limit their retention in kidneys 2 h after administration. On the other hand, (Gd‐DTPA)₄Lys₃ is retained in kidneys to a lesser extent than (Gd‐DTPA)₆Lys₅. Their moderate retention in blood and their higher stability and relaxivity in comparison with Gd‐DTPA highlight these polylysine derivatives as optimal compared with previously developed polylysine compounds. Copyright © 2010 John Wiley & Sons, Ltd.     

Cellular labeling with Gd(III) chelates: only high thermodynamic stabilities prevent the cells acting as ‘sponges’ of Gd3+ ions

MR‐labeling of cells may be carried out by adding a Gd‐based contrast agent to the incubation media. The amount of gadolinium internalized in HTC and C6 cells upon incubation with Gd–DTPA–BMA is circa one order of magnitude higher than those found with Gd–DTPA, Gd–DOTA and Gd–HPDO3A, respectively. The comparison of relaxometric and mass spectrometry determinations allows us to establish that only a minor fraction of intact Gd–DTPA–BMA is internalized into the cells. Moreover the binding/uptake behavior shown by Gd–DTPA–BMA resembles that found when GdCl₃ is added to the incubation medium. We suggest that the lower stability of Gd–DTPA–BMA is responsible for a shift in the dissociation equilibrium that results in the net transfer of Gd³⁺ ions on the cell membrane followed by a slower internalization process. The transmetallation process is mediated by components of the incubation media, among which a dominant role is represented by phosphate anions. The uptake of Gd³⁺ ions is clearly reflected in the drastic decrease of cell viability observed for cells labeled with Gd–DTPA–BMA. Copyright © 2006 John Wiley & Sons, Ltd.     

Thermodynamic stability and kinetic inertness of a Gd–DTPA bisamide complex grafted onto gold nanoparticles

Gold nanoparticles coated by gadolinium (III) chelates (Au@DTDTPA) where DTDTPA is a dithiolated bisamide derivative of diethylenetriamine‐N,N,N′,N′′,N′′‐pentaacetic acid (DTPA), constituted contrast agents for both X‐ray computed tomography and magnetic resonance imaging. In an MRI context, highly stable Gd³⁺ complexes are needed for in vivo applications. Thus, knowledge of the thermodynamic stability and kinetic inertness of these chelates, when grafted onto gold nanoparticles, is crucial since bisamide DTPA chelates are usually less suited for Gd³⁺ coordination than DTPA. Therefore, these parameters were evaluated by means of potentiometric titrations and relaxivity measurements. The results showed that, when the chelates were grafted onto the nanoparticle, not only their thermodynamic stability but also their kinetic inertness were improved. These positive effects were correlated to the chelate packing at the nanoparticle surface that stabilized the corresponding Gd³⁺ complexes and greatly enhanced their kinetic inertness. Copyright © 2014 John Wiley & Sons, Ltd.     

The Gd3+ complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid mono(p‐isothiocyanatoanilide) conjugated to inulin: a potential stable macromolecular contrast agent for MRI

Reaction of DOTA–NCSA [1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid mono(p‐isothiocyanatoanilide)] with O‐(aminopropyl)inulin (degree of polymerization 25) provided a chelate that formed a kinetically extremely stable Gd³⁺ complex. No transmetalation was observed with Zn²⁺. The conjugate has a relaxivity of 21.7 s^?1 m m ^?1 at 20 MHz and 37 °C, and each molecule of the inulin carries on average 35 Gd³⁺ ions. The parameters governing the relaxivity of this material and of a low‐molecular‐weight model compound prepared by conjugation of DOTA–NCSA and propylamine were evaluated by investigation of their water ¹H longitudinal relaxation rate enhancements at different magnetic fields (NMRD) and by studying variable temperature ¹⁷O NMR data. The high relaxivity of the inulin conjugate can be ascribed to the efficient slowing down of the molecular tumbling by this carrier. The rotational correlation time at 37 °C of this material is 1460 ps, whereas that of the model compound is 84 ps. Furthermore, both complexes do not interact significantly with human serum albumin, as shown by their NMRD profiles, and do not undergo transmetallation by zinc ions. The inulin conjugate thus has potential for application as a contrast agent for MRI, particularly as a blood pool agent. Copyright © 2011 John Wiley & Sons, Ltd.     

Coordination properties of N,N′-bis(5-methylsalicylidene)-2-hydroxy-1,3-propanediamine with d- and f-electron ions: crystal structure,stability in solution,spectroscopic and spectroelectrochemical studies

Template reaction between 5-methylsalicylaldehyde and 2-hydroxy-1,3-propanediamine in the presence of copper ion led to dinuclear and mononuclear copper(ii) complexes [Cu₂L(CH₃COO)(CH₃OH)](CH₃OH) (1) and [CuHL](CH₃OH) (2), where H₃L is N,N′-bis(5-methylsalicylidene)-2-hydroxy-1,3-propanediamine. The result of the reactions between 5-methylsalicylaldehyde and 2-hydroxy-1,3-propanediamine in the presence of lanthanide ions and/or copper(ii) ion was N,N′-bis(5-methylsalicylidene)-2-hydroxy-1,3-propanediamine (H₃L B) or [CuHL](CH₃OH) (2), respectively. Structures of the compounds were determined by single-crystal X-ray diffraction and physicochemical methods. The microstructures and phase compositions of crystals were studied by scanning electron microscopy (SEM). In dinuclear complex [Cu₂L(CH₃COO)(CH₃OH)](CH₃OH) (1), two copper(ii) ions are bond to one H₃L ligand and one acetate ion. Coordination modes of the two copper centers are different: the geometry of copper 1 is almost ideal square-planar, while that for copper 2 can be described as tetragonal pyramidal. In complex [CuHL](CH₃OH) (2), the copper(ii) ion is four coordinated and the coordination, rather than square-planar, can be described as flattened tetrahedral. Formation of complexes between copper(ii) or lanthanide ions with N,N′-bis(5-methylsalicylidene)-2-hydroxy-1,3-propanediamine (H₃L) was also studied in solution by pH potentiometry. It should be mentioned that the complexes of lanthanide ions exist only in solution. Additionally, the salen-type ligand H₃L and its dinuclear and mononuclear copper(ii) complexes were studied by cyclic voltammetry, and their spectroelectrochemical properties were examined.

The self-assembled metal-promoted synthesis and properties of N,N′-bis(5-methylsalicylidene)-2-hydroxy-1,3-propanediamine (H₃L) complexes with d- and f-metal ions are described.