Dendrimeric gadolinium chelate with fast water exchange and high relaxivity at high magnetic field strength

The synthesis and relaxivity properties of a new dendrimeric Gd chelate, Gd-TREN-bisHOPO-TAM-Asp-Asp2-12OH, are presented. The macromolecule demonstrates improved water solubility due to its 12 terminal hydroxyl groups and improved relaxivity due to its optimal water exchange rate and slower molecular tumbling. Unprecedented high relaxivity (r1p = 18 mM-1 s-1) is observed at high magnetic field (90 MHz), an important advance in the development of contrast agents for the next generation of MRI scanners.     

Paramagnetic liposomes: inner versus outer membrane relaxivity of DPPC liposomes incorporating lipophilic gadolinium complexes

Proton relaxometric properties of unilamellar DPPC liposomes embedding an amphiphilic paramagnetic chelate (Gd-DTPA-BC(14)A) in both layers of the phospholipid membrane or only in the external one are compared. The results show that the membrane's water permeability is able to quench the effect of the paramagnetic complexes located in the internal layer of DPPC liposomes, leading thus to an apparent lower global relaxivity.     

The dynamics of water exchange in gadolinium DOTA complexes studied by transition path sampling and potential of mean force methods

The mechanism of water exchange at the Gd centre of the two isomers of [Gd(iii)DOTA](-) (gadolinate(1-), [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetato(4-)-N1,N4,N7,N10,O1,O4,O7,O10]) has been explored using transition path sampling and potential of mean force methods to sample those regions of phase space inaccessible to standard molecular dynamics simulation. We find that there are definite differences in the details of the solvent rearrangement accompanying the exchange of the capping water molecule for the two isomers. We conclude that these solvent effects, rather than any differences in the binding energy of the capping water, are central in determining the exchange rate. We find that the potential of mean force studies yield absolute and relative rates of water exchange for the two isomers that are in good agreement with experiment.     

pH-dependent modulation of relaxivity and luminescence in macrocyclic gadolinium and europium complexes based on reversible intramolecular sulfonamide ligation

A series of macrocyclic Eu, Gd, and Tb complexes has been prepared in which the intramolecular ligation of a beta-arylsulfonamide nitrogen is rendered pH-dependent, giving rise to changes in the hydration state, q, at the lanthanide center. In complexes based on DO3A, variation of the p-substituent in the arylsulfonamide moiety determines the apparent protonation constant log K(MLH) with values of 5.7, 6.4, and 6.7 for the -CF(3), -Me, and -OMe substituents, respectively. Introduction of three beta-carboxyalkyl substituents, alpha to three ring nitrogens, inhibits displacement of the bound water by added protein and also suppresses intermolecular binding by endogenous anions (lactate, HCO(3)(-)). Measurements of the pH dependence of the form and intensity of the Eu complexes revealed that intramolecular carboxylate coordination occurred competitively. This was reduced either by enhancing the electron density at the sulfonamide nitrogen or by enlarging the chelate ring from 7--8. Amplification of the relaxivity changes in the pH range 8--5 occurred on protein binding, and over the pH range 7.4--6.8 a 48% change in relaxivity was defined for [Gd.3a] (298 K, 65.6 MHz) in 50% human serum solution.     

Albumin binding, relaxivity, and water exchange kinetics of the diastereoisomers of MS-325, a gadolinium(III)-based magnetic resonance angiography contrast agent

The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl] diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography (MRA). MS-325 consists of two slowly interconverting diastereoisomers, A and B (65:35 ratio), which can be isolated at pH > 8.5 (TyeklAr, Z.; Dunham, S. U.; Midelfort, K.; Scott, D. M.; Sajiki, H.; Ong, K.; Lauffer, R. B.; Caravan, P.; McMurry, T. J. Inorg. Chem. 2007, 46, 6621-6631). MS-325 binds to human serum albumin (HSA) in plasma resulting in an extended plasma half-life, retention of the agent within the blood compartment, and an increased relaxation rate of water protons in plasma. Under physiological conditions (37 degrees C, pH 7.4, phosphate buffered saline (PBS), 4.5% HSA, 0.05 mM complex), there is no statistical difference in HSA affinity or relaxivity between the two isomers (A 88.6 +/- 0.6% bound, r1 = 42.0 +/- 1.0 mM(-1) s(-1) at 20 MHz; B 90.2 +/- 0.6% bound, r1 = 38.3 +/- 1.0 mM(-1) s(-1) at 20 MHz; errors represent 1 standard deviation). At lower temperatures, isomer A has a higher relaxivity than isomer B. The water exchange rates in the absence of HSA at 298 K, kA298 = 5.9 +/- 2.8 x 10(6) s(-1), kB298 = 3.2 +/- 1.8 x 10(6) s(-1), and heats of activation, DeltaHA = 56 +/- 8 kJ/mol, DeltaHB = 59 +/- 11 kJ/mol, were determined by variable-temperature 17O NMR at 7.05 T. Proton nuclear magnetic relaxation dispersion (NMRD) profiles were recorded over the frequency range of 0.01-50 MHz at 5, 15, 25, and 35 degrees C in a 4.5% HSA in PBS solution for each isomer (0.1 mM). Differences in the relaxivity in HSA between the two isomers could be attributed to the differing water exchange rates.     

Hetero-tripodal hydroxypyridonate gadolinium complexes: syntheses, relaxometric properties, water exchange dynamics, and human serum albumin binding

The synthesis and relaxometric properties of hetero-tripodal hydroxypyridonate-terephthalamide gadolinium (Gd(3+)) chelates with differing structural features for probing human serum albumin (HSA) interactions are reported. The Gd(3+) complexes are divided into two series. The first series (3-5) features a benzyl derivative connected to the hydroxypyridonate (HOPO) moiety. The second series of complexes (6-10) has the common feature of a poly(ethylene glycol) (PEG) attached to the terephthalamide (TAM) moiety and is nonbenzylated. The water exchange of the complexes is in the fast exchange regime with rates (k(ex)) in the range 0.45-1.11 x 10(8) s(-1). The complexes have a moderate interaction with HSA with association constants (K(A)'s) in the range 0.7-8.6 x 10(3) M(-1). Protein binding results in an enhancement in proton relaxivity from 7.7-10.4 mM(-1) s(-1) (r(1p)) to 15-29 mM(-1) s(-1) (r(1p)(b)). It is concluded that the interaction of the complexes with HSA (i) is enhanced by the presence of benzyl groups, (ii) is entropically driven, and (iii) results in a lower hydration number (q).     

Highly soluble tris-hydroxypyridonate Gd(III) complexes with increased hydration number, fast water exchange, slow electronic relaxation, and high relaxivity

The design, synthesis, and relaxivity properties of highly soluble TACN-capped trishydroxypyridonate-Gd(III) complexes are presented. Molecular mechanics modeling was used to help design a complex capable of possessing three water molecules in the inner metal coordination sphere, an attractive property for high-relaxivity MRI contrast agents. The measured relaxivities of 13.1 and 12.5 mM-1 s-1 (20 MHz, 298 K) for two TACN-capped complexes are among the highest known relaxivities of low-molecular weight Gd complexes and are consistent with three coordinated waters, an extremely fast water exchange rate, and long electronic relaxation time. Luminescence measurements to confirm the number of coordinated water molecules for the first time in the HOPO series are also discussed.     

Towards the rational design of MRI contrast agents: a practical approach to the synthesis of gadolinium complexes that exhibit optimal water exchange

The gadolinium(iii) complex of S-SSSS-NO(2)BnDOTMA exhibits water exchange kinetics that are optimal for use in high relaxivity or targeted contrast agents. However, the synthesis of this ligand is hampered by the steric encumbrance imparted upon the cyclen ring by the nitrobenzyl substituent. A relatively simple modification has been used to enable the synthesis of larger quantities of a bifunctional ligand that retains similar fast water exchange properties. The gadolinium complex of S-SSS-NO(2)BnDO3MA-1A is shown to retain the rapid water exchange kinetics characteristic of a twisted square antiprismatic (TSAP) coordination geometry (tau(M)= 6 +/- 0.4 ns).     

Structure, stability and relaxivity of trinuclear triangular complexes

The self-assembly of a carbonylpyridine-based heptadentate ligand with Ln(III) results in the formation of triangular trinuclear europium complexes, which exhibit interesting luminescent properties in the solid state and in solution. With a view to developing multimodal responsive systems, we report here the preparation and characterisation of analogous complexes with Gd(III). The X-ray crystal structure of Gd(3)L2(3) indeed reveals the isostructurality with the Eu(III) complexes. A combination of (1)H NMRD and variable temperature studies yields the parameters elucidating the exchange of coordinated water and relaxivity properties. Conveniently, the competitive spectrophotometric titrations with EDTA and NTA are used to determine the thermodynamic stability constants of the europium complexes in aqueous media. In addition, the exchange reaction with EDTA is monitored with NMR and fluorimetry. The interactions of the Eu(III) trinuclear complex with some potentially interfering ligands are qualitatively investigated by means of luminescence titrations.     

Relaxivity and water exchange studies of a cationic macrocyclic gadolinium(III) complex

We conducted relaxometric and water exchange studies of the cationic [Gd((S,S,S,S)-THP)(H2O)]3+ complex (THP 1,4,7,10-tetrakis(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane). While the NMRD profiles obtained are typical for DOTA-like complexes (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), variable-temperature 7O NMR investigations revealed a relatively high water exchange rate (k(298)(ex) = 1.89 x 10(7) s(-1)). These results differ from those reported for other cationic tetraamide macrocyclic Gd(III) complexes, which exhibit characteristically low exchange rates. Since the low exchange rates are attributed partially to the geometry of the M isomer (square antiprismatic) in the tetraamide derivatives, the atypical water exchange rate observed in [Gd((S,S,S,S)-THP-(H2O)]3+ may result from a twisted square antiprismatic structure in this complex and from the relatively high steric strain at the water coordination site as a result of the presence of methyl groups at the alpha-position with respect to the Gd(III)-bound O atoms of THP.     

Thin film analysis of gadolinium iron oxide and gadolinium iron by a combined ion exchange X-ray fluorescence method

Summary The composition of thin gadolinium iron oxide and alloy films of limited size (weighing from 500 to 2000g and ranging from 0.7 to 2.3 nm in thickness) was determined by first collecting and simultaneously concentrating gadolinium and iron ions from very dilute solutions on ion-exchange resin-loaded paper disks, and then analyzing the concentrated samples by X-ray fluorescence. This method of analysis allows the preparation of standards by normal solution techniques without the problem of matrix effects.

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Zusammenfassung Die Zusammensetzung dünner Filme aus Gadolinium-Eisenoxid bzw. Gadolinium-Eisenlegierung (Gewicht: 500 bis 2000g; Dicke: 0,7 bis 2,3 nm) wurde bestimmt. Dazu wurden die Gadolinium- und Eisenionen aus sehr verdünnten Lösungen auf Filterscheiben angereichert, die mit Ionenaustauscherharz beladen waren. Die angereicherten Proben wurden dann durch Röntgenfluoreszenzmessung analysiert. Dieses Analysenverfahren eignet sich zur Herstellung von Standards durch gewöhnliche Lösungstechnik und vermeidet das Problem der Matrixeffekte.

     

Enhancement of relaxivity rates of Gd-DTPA complexes by intercalation into layered double hydroxide nanoparticles

In this paper we report the preparation and characterization of [Gd(dtpa)](2-) intercalated layered double hydroxide (LDH) nanomaterials. [Gd(dtpa)](2-) (gadolinium(III) diethylene triamine pentaacetate) was transferred into LDH by anionic exchange. The intercalation of [Gd(dtpa)](2-) into LDH was confirmed by X-ray diffraction for the new phase with the interlayer spacing of 3.5-4.0 nm and by FTIR for the characteristic vibration peaks of [Gd(dtpa)](2-). The morphology of the nanoparticles was influenced by the extent of [Gd(dtpa)](2-) loading, in which the poly-dispersity quality decreased as the [Gd(dtpa)](2-) loading was increased. Compared with the morphology of the original Mg(2)Al-Cl-LDH nanoparticles (hexagonal plate-like sheets of 50-200 nm), the modified LDH-Gd(dtpa) nanoparticles are bar-like with a width of 30-60 nm and a length of 50-150 nm. LDH-Gd(dtpa) was expected to have an increased water proton magnetic resonance relaxivity due to the intercalation of [Gd(dtpa)](2-) into the LDH interlayer that led to slower molecular anisotropic tumbling compared with free [Gd(dtpa)](2-) in solution. Indeed, LDH-nanoparticle suspension containing approximately 1.6 mM [Gd(dtpa)](2-) exhibits a longitudinal proton relaxivity r(1) of approximately 16 mM(-1) s(-1) and a transverse proton relaxivity r(2) of approximately 50 mM(-1) s(-1) at room temperature and a magnetic field of 190 MHz, which represents an enhancement four times (r(1)) and 12 times (r(2)) that of free [Gd(dtpa)](2-) in solution under the same reaction conditions. We have thus tailored LDH-nanoparticles into a novel contrast agent with strong relaxivity, promising for great potential applications in magnetic resonance imaging.     

Bimodal, dimetallic lanthanide complexes that bind to DNA: the nature of binding and its influence on water relaxivity

UV-visible titrations, (1)H NMRD experiments and molecular docking studies show that emissive anthraquinone appended dimetallic lanthanide complexes bind to DNA. The strength of binding and the observed relaxivity behaviour depend on the nature of the substituted anthraquinone core.     

A highly stable gadolinium complex with a fast, associative mechanism of water exchange

The stability and water exchange dynamics of gadolinium (GdIII) complexes are critical characteristics that determine their effectiveness as contrast agents for magnetic resonance imaging (MRI). A new heteropodal GdIII chelate, [Gd-TREN-bis(6-Me-HOPO)-(TAM-TRI)(H2O)2] (Gd-2), is presented which is based on a hydroxypyridinate (HOPO)-terephthalamide (TAM) ligand design. Thermodynamic equilibrium constants for the acid-base properties and the GdIII complexation strength of TREN-bis(6-Me-HOPO)-(TAM-TRI) (2) were measured by potentiometric and spectrophotometric titration techniques, respectively. The pGd of 2 is 20.6 (pH 7.4, 25 degrees C, I = 0.1 M), indicating that Gd-2 is of more than sufficient thermodynamic stability for in vivo MRI applications. The water exchange rate of Gd-2 (kex = 5.3(+/-0.6) x 107 s-1) was determined by variable temperature 17O NMR and is in the fast exchange regime - ideal for MRI. Variable pressure 17O NMR was used to determine the volume of activation (DeltaV) of Gd-2. DeltaV for Gd-2 is -5 cm3 mol-1, indicative of an interchange associative (Ia) water exchange mechanism. The results reported herein are important as they provide insight into the factors influencing high stability and fast water exchange in the HOPO series of complexes, potentially future clinical contrast agents.     

Glycoconjugates of gadolinium complexes for MRI applications

Examples of C-4 symmetric, medium MW conjugates incorporating 12 glucose or galactose groups linked via four dendritic wedges to a central Gd complex have been characterised; their enhanced relaxivity is interpreted in terms of effective motional coupling and large contributions from second sphere water molecules.     

Synthesis and relaxivity of polyamide paramagnetic metal complexes for magnetic resonance imaging

A new class of paramagnetic macromolecular magnetic resonance imaging contrast agents has been developed. Eight new polyamide ligands were synthesized by copolymerization of ethylenediaminetetraacetic acid dianhydride or diethylenetriaminepentaacetic acid dianhydride and diamine monomers. Their gadolinium(III), manganese(II) and iron(III) complexes were also synthesized. All polyamide ligands and metal complexes were characterized by ¹H nuclear magnetic resonance, infrared spectra and elemental analyses. Relaxivity studies showed that the polyamide paramagnetic metal complexes had obviously higher relaxation effectiveness as compared to corresponding simple monomeric paramagnetic metal complexes.     

Arrangement of tris(phthalocyaninato) gadolinium triple-decker complexes with multi-octyloxy groups on water surface

A series of five carefully designed tris(phthalocyaninato) gadolinium triple-decker complexes [Pc(R)8]Gd[Pc(R')8]Gd[Pc(R')8] (R=R'=R'=H; R=R'=H, R'=OC8H17; R=R'=H, R'=OC8H17; R=H, R'=R'=OC8H17; R=R'=R'=OC8H17) (1-5) were prepared and the film forming properties on water surface were systematically investigated. The limited mean molecular area obtained by pi-A isotherms revealed an "edge-on" conformation for all these compounds. UV-vis absorption spectra showed red-shifted Q bands, indicating the formation of J aggregates and effective intermolecular interaction in solid film. Phthalocyanine rings were found to take tilted orientation with respect to the normal of substrate according to the polarized absorption spectroscopic measurements. Low angle X-ray diffraction results provide direct evidence and therefore clearly clarify the point, for the first time, that unsymmetrical triple-decker molecules pack on the water surface with the unsubstituted phthalocyanine ring set close to the water surface and the substituted phthalocyanine ligand with octyloxy groups lies on the top.     

Determination of gadolinium in river water by SPE preconcentration and ICP-MS

An analytical scheme was developed for the determination of Gd-diethylenetriaminepentaacetate (Gd-DTPA), Gd and the other rare earth elements (REE) in river water by inductively coupled plasma (quadrupole) mass spectrometry (ICP-Q-MS). The preconcentration step was essential, since the limits of detection of this multielemental analytical technique are higher than the trace concentrations of the interesting elements in river water.Solid phase extraction (SPE) with different commercially available complexing agents (Chelex 100, Toyopearl and ethylhexylphosphates) was employed for the preconcentration of REE. The investigations revealed that complex stability (varying in dependence of the pH value) has a strong influence on the degree of the enrichment of Gd-DTPA. Based on acidified water samples (pH<3) a procedure using ethylhexylphosphates was proposed for the preconcentration of Gd and REE from surface water samples. For this purpose C₁₈-cartridges loaded with ethylhexylphosphates were used, resulting in an enrichment factor of 40.     

Hindered rotation and exchange in trimethylsilylanilides

A series of trimethylsilylanilides were prepared and characterized as amide—imidate mixtures. Low temperature NMR spectra reveal both hindered rotation and exchange processes for the formanilides and benzanilides and exchange for the acetanilides. Isomer ratios and free energies of activation are reported and used to postulate a mechanism for the exchange process.