Endeavor toward Redox-Responsive Transition Metal Contrast Agents Based on the Cross-Bridge Cyclam Platform.

We present the synthesis and characterization of a series of Mn(III), Co(III), and Ni(II) complexes with cross-bridge cyclam derivatives (CB-cyclam = 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) containing acetamide or acetic acid pendant arms. The X-ray structures of [Ni(CB-TE2AM)]Cl2·2H2O and [Mn(CB-TE1AM)(OH)](PF6)2 evidence the octahedral coordination of the ligands around the Ni(II) and Mn(III) metal ions, with a terminal hydroxide ligand being coordinated to Mn(III). Cyclic voltammetry studies on solutions of the [Mn(CB-TE1AM)(OH)]2+ and [Mn(CB-TE1A)(OH)]+ complexes (0.15 M NaCl) show an intricate redox behavior with waves due to the MnIII/MnIV and MnII/MnIII pairs. The Co(III) and Ni(II) complexes with CB-TE2A and CB-TE2AM show quasi-reversible features due to the CoIII/CoII or NiII/NiIII pairs. The [Co(CB-TE2AM)]3+ complex is readily reduced by dithionite in aqueous solution, as evidenced by 1H NMR studies, but does not react with ascorbate. The [Mn(CB-TE1A)(OH)]+ complex is however reduced very quickly by ascorbate following a simple kinetic scheme (k0 = k1[AH-], where [AH-] is the ascorbate concentration and k1 = 628 ± 7 M-1 s-1). The reduction of the Mn(III) complex to Mn(II) by ascorbate provokes complex dissociation, as demonstrated by 1H nuclear magnetic relaxation dispersion studies. The [Ni(CB-TE2AM)]2+ complex shows significant chemical exchange saturation transfer effects upon saturation of the amide proton signals at 71 and 3 ppm with respect to the bulk water signal.

Effect of Magnetic Anisotropy on the 1H NMR Paramagnetic Shifts and Relaxation Rates of Small Dysprosium(III) Complexes.

We present a detailed analysis of the 1H NMR chemical shifts and transverse relaxation rates of three small Dy(III) complexes having different symmetries (C3, D2 or C2). The complexes show sizeable emission in the visible region due to 4F9/2 → 6HJ transitions (J = 15/2 to 11/2). Additionally, NIR emission is observed at ca. 850 (4F9/2 → 6H7/2), 930 (4F9/2 → 6H5/2), 1010 (4F9/2 → 6F9/2), and 1175 nm (4F9/2 → 6F7/2). Emission quantum yields of 1-2% were determined in aqueous solutions. The emission lifetimes indicate that no water molecules are present in the inner coordination sphere of Dy(III), which in the case of [Dy(CB-TE2PA)]+ was confirmed through the X-ray crystal structure. The 1H NMR paramagnetic shifts induced by Dy(III) were found to be dominated by the pseudocontact mechanism, though, for some protons, contact shifts are not negligible. The analysis of the pseudocontact shifts provided the magnetic susceptibility tensors of the three complexes, which were also investigated using CASSCF calculations. The transverse 1H relaxation data follow a good linear correlation with 1/r6, where r is the distance between the Dy(III) ion and the observed proton. This indicates that magnetic anisotropy is not significantly affecting the relaxation of 1H nuclei in the family of complexes investigated here.

Thermodynamic Stability of Mn(II) Complexes with Aminocarboxylate Ligands Analyzed Using Structural Descriptors.

We present a quantitative analysis of the thermodynamic stabilities of Mn(II) complexes, defined by the equilibrium constants (log KMnL values) and the values of pMn obtained as -log[Mn]free for total metal and ligand concentrations of 1 and 10 µM, respectively. We used structural descriptors to analyze the contributions to complex stability of different structural motifs in a quantitative way. The experimental log KMnL and pMn values can be predicted to a good accuracy by adding the contributions of the different motifs present in the ligand structure. This allowed for the identification of features that provide larger contributions to complex stability, which will be very helpful for the design of efficient chelators for Mn(II) complexation. This issue is particularly important to develop Mn(II) complexes for medical applications, for instance, as magnetic resonance imaging (MRI) contrast agents. The analysis performed here also indicates that coordination number eight is more common for Mn(II) than is generally assumed, with the highest log KMnL values generally observed for hepta- and octadentate ligands. The X-ray crystal structure of [Mn2(DOTA)(H2O)2], in which eight-coordinate [Mn(DOTA)]2- units are bridged by six-coordinate exocyclic Mn(II) ions, is also reported.

Cooperative Luminescence and Cooperative Sensitisation Upconversion of Lanthanide Complexes in Solution.

Upconversion materials have led to various breakthrough applications in solar energy conversion, imaging, and biomedicine. One key impediment is the facilitation of such processes at the molecular scale in solution where quenching effects are much more pronounced. In this work, molecular solution-state cooperative luminescence (CL) upconversion arising from a Yb excited state is explored and the mechanistic origin behind cooperative sensitisation (CS) upconversion in Yb/Tb systems is investigated. Counterintuitively, the best UC performances were obtained for Yb/Tb ratios close to parity, resulting in the brightest molecular upconversion complexes with a quantum yield of 2.8×10-6 at a low laser power density of 2.86 W cm-2 .

Understanding the Effect of the Electron Spin Relaxation on the Relaxivities of Mn(II) Complexes with Triazacyclononane Derivatives.

Investigating the relaxation of water 1H nuclei induced by paramagnetic Mn(II) complexes is important to understand the mechanisms that control the efficiency of contrast agents used in diagnostic magnetic resonance imaging (MRI). Herein, a series of potentially hexadentate triazacyclononane (TACN) derivatives containing different pendant arms were designed to explore the relaxation of the electron spin in the corresponding Mn(II) complexes by using a combination of 1H NMR relaxometry and theoretical calculations. These ligands include 1,4,7-triazacyclononane-1,4,7-triacetic acid (H3NOTA) and three derivatives in which an acetate group is replaced by sulfonamide (H3NO2ASAm), amide (H2NO2AM), or pyridyl (H2NO2APy) pendants. The analogue of H3NOTA containing three propionate pendant arms (H3NOTPrA) was also investigated. The X-ray structure of the derivative containing two acetate groups and a sulfonamide pendant arm [Mn(NO2ASAm)]- evidenced six-coordination of the ligand to the metal ion, with the coordination polyhedron being close to a trigonal prism. The relaxivities of all complexes at 20 MHz and 25 °C (1.1-1.3 mM-1 s-1) are typical of systems that lack water molecules coordinated to the metal ion. The nuclear magnetic relaxation profiles evidence significant differences in the relaxivities of the complexes at low fields (<1 MHz), which are associated with different spin relaxation rates. The zero field splitting (ZFS) parameters calculated by using DFT and CASSCF methods show that electronic relaxation is relatively insensitive to the nature of the donor atoms. However, the twist angle of the two tripodal faces that delineate the coordination polyhedron, defined by the N atoms of the TACN unit (lower face) and the donor atoms of the pendant arms (upper face), has an important effect in the ZFS parameters. A twist angle close to the ideal value for an octahedral coordination (60°), such as that in [Mn(NOTPrA)]-, leads to a small ZFS energy, whereas this value increases as the coordination polyhedron approaches to a trigonal prism.

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers.

Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

Mn2+ Complexes Containing Sulfonamide Groups with pH-Responsive Relaxivity.

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (H3DPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H3NO2ASAm). These ligands were designed to provide a pH-dependent relaxivity response upon complexation with Mn2+ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn2+ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonations of the sulfonamide groups of the ligands are characterized by protonation constants of log KiH = 10.36 and 10.59 for DPASAm3- and HNO2ASAm2-, respectively. These values decrease dramatically to log KiH = 6.43 and 5.42 in the presence of Mn2+, because of the coordination of the negatively charged sulfonamide groups to the metal ion. The higher log KiH value in [Mn(DPASAm)]- is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)]- is six-coordinated. The X-ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N atom, the N atom of the sulfonamide group, and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)]- complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (<7.0). However, protonation of the sulfonamide group in [Mn(DPASAm)]- falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r1p = 3.8 mM-1 s-1 at pH 9.0 to r1p = 8.9 mM-1 s-1 at pH 4.0 (10 MHz, 25 °C).

Unexpected Trends in the Stability and Dissociation Kinetics of Lanthanide(III) Complexes with Cyclen-Based Ligands across the Lanthanide Series.

We report a detailed study of the thermodynamic stability and dissociation kinetics of lanthanide complexes with two ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms linked to two nitrogen atoms of the macrocycle in either cis (1,4-H3DO2APA) or trans (1,7-H3DO2APA) positions. The stability constants of the Gd3+ complexes with these two ligands are very similar, with log KGdL values of 16.98 and 16.33 for the complexes of 1,4-H3DO2APA and 1,7-H3DO2APA, respectively. The stability constants of complexes with 1,4-H3DO2APA follow the usual trend, increasing from log KLaL = 15.96 to log KLuL = 19.21. However, the stability of [Ln(1,7-DO2APA)] complexes decreases from log K = 16.33 for Gd3+ to 14.24 for Lu3+. The acid-catalyzed dissociation rates of the Gd3+ complexes differ by a factor of ∼15, with rate constants (k1) of 1.42 and 23.5 M-1 s-1 for [Gd(1,4-DO2APA)] and [Gd(1,7-DO2APA)], respectively. This difference is magnified across the lanthanide series to reach a 5 orders of magnitude higher k1 for [Yb(1,7-DO2APA)] (1475 M-1 s-1) than for [Yb(1,4-DO2APA)] (5.79 × 10-3 M-1 s-1). The acid-catalyzed mechanism involves the protonation of a carboxylate group, followed by a cascade of proton-transfer events that result in the protonation of a nitrogen atom of the cyclen unit. Density functional theory calculations suggest a correlation between the strength of the Ln-Ocarboxylate bonds and the kinetic inertness of the complex, with stronger bonds providing more inert complexes. The 1H NMR resonance of the coordinated water molecule in the [Yb(1,7-DO2APA)] complex at 176 ppm provides a sizable chemical exchange saturation transfer effect thanks to a slow water exchange rate of (15.9 ± 1.6) × 103 s-1.

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.

Axial Ligation in Ytterbium(III) DOTAM Complexes Rationalized with Multireference and Ligand-Field ab Initio Calculations.

The nature of the axial ligand coordinated to the Yb3+ ion in [Yb(DOTAM)]3+ has profound consequences in the magnetic anisotropy and optical properties of the complex, as evidenced by 1H NMR and UV-vis spectroscopies. The pseudocontact shifts of 1H nuclei and the 2F5/2 ← 2F7/2 absorption band were found to be very sensitive to the nature of the axial ligand (MeOH, H2O, MeOH, or F-). The energy levels of the 2F5/2 and 2F7/2 manifolds in [Yb(DOTAM)(X)]3+ (X = MeOH, H2O, or dimethyl sulfoxide (DMSO)) and [Yb(DOTAM)F]2+ complexes were assigned from the analysis of the optical spectra and ab initio calculations based on CASSCF wave functions that considered dynamic correlation through perturbation theory (NEVPT2) and spin-orbit coupling effects. The magnetic anisotropies obtained with ab initio calculations are in good agreement with the experimental values derived from 1H NMR spectral data, though for the [Yb(DOTAM)(H2O)]3+ and [Yb(DOTAM)F]2+ complexes, the explicit inclusion of a few second-sphere water molecules is required to improve the calculated data. Crystal-field calculations show that the observed pseudocontact shifts do not correlate well with the crystal-field parameter B20, as predicted by Bleaney's theory. The change in the sign of the magnetic anisotropy from prolate (X = MeOH, H2O, or DMSO) to oblate in [Yb(DOTAM)F]2+ is related to the relative energies of the 4fz3 orbital and the 4fx3/4fy3 pair, which are affected by the coordination ability of the axial ligand.

Definition of the Labile Capping Bond Effect in Lanthanide Complexes.

Two macrocyclic ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms attached to two nitrogen atoms of the macrocycle either in trans (1,7-H3 Medo2 ampa = 2,2'-(7-((6-carboxypyridin-2-yl)methyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetic acid) or in cis (1,4-H3 Medo2 ampa) positions are reported. These ligands provide eight-coordination to the Ln3+ ions, leaving a coordination position available for a water molecule that occupies a capping position in the twisted square antiprismatic polyhedron (1,4-H3 Medo2 ampa) or one of the positions of the square antiprism (1,7-H3 Medo2 ampa). The charge neutral [Gd(1,7-Medo2 ampa)] complex presents an unprecedentedly low water-exchange rate (kex298 =8.8×103  s-1 ), whereas water exchange in [Gd(1,4-Medo2 ampa)] is three orders of magnitude faster (kex298 =6.6×106  s-1 ). These results showcase the labile capping bond phenomenon: A ligand occupying a capping position is hindered by the environment and thus is intrinsically labile.

Cyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) Coordination.

Aiming to develop new copper chelates for application in nuclear medicine we report two new chelators, te1th and te2th, based on a cyclam backbone mono-N- or di-N1,N8-functionalized by methylthiazolyl arms. The acid-base properties of both ligands were investigated as well as their coordination chemistry, especially with Cu(2+), when possible in aqueous solution and in the solid state. Single-crystal X-ray diffraction structures of complexes were determined. Stability constants of the copper(II) and zinc(II) complexes showed that the complexes of both ligands with Cu(2+) are thermodynamically very stable, and they exhibit an important selectivity for Cu(2+) over Zn(2+). The kinetic inertness in acidic medium of both copper(II) complexes was evaluated revealing a quite good resistance to dissociation (the half-life times of complexes with te1th and te2th are 50.8 and 5.8 min, respectively, in 5 M HCl and 30 °C). The coordination geometry of the metal center in the complexes was established in aqueous solution based on UV-visible, electron paramagnetic resonance (EPR) spectroscopy, DFT studies, and NMR by using the zinc(II) complex analogues. The [Cu(te1th)](2+) and [Cu(te2th)](2+) complexes adopt trans-I and trans-III configurations both in the solid state and in solution, while the [Zn(te2th)](2+) complex crystallizes as the cis-V isomer but exists in solution as a mixture of trans-III and cis-V forms. Cyclic voltammetry experiments in acetonitrile point to a relatively easy reduction of [Cu(te2th)](2+) in acetonitrile solution (Epc = -0.41 V vs NHE), but the reduced complex does not undergo dissociation in the time scale of our electrochemical experiments. The results obtained in these studies revealed that despite the limited solubility of its copper(II) chelate, te2th is an attractive chelator for Cu(2+) that provides a fast complexation process while forming a complex with a rather high thermodynamic stability and kinetic inertness with respect to dissociation even upon electrochemical reduction.

Complexation of Ln(3+) Ions with Cyclam Dipicolinates: A Small Bridge that Makes Huge Differences in Structure, Equilibrium, and Kinetic Properties.

The coordination properties toward the lanthanide ions of two macrocyclic ligands based on a cyclam platform containing picolinate pendant arms have been investigated. The synthesis of the ligands was achieved by using the well-known bis-aminal chemistry. One of the cyclam derivatives (cb-tedpa(2-)) is reinforced with a cross-bridge unit, which results in exceptionally inert [Ln(cb-tedpa)](+) complexes. The X-ray structures of the [La(cb-tedpa)Cl], [Gd(cb-tedpa)](+), and [Lu(Me2tedpa)](+) complexes indicate octadentate binding of the ligands to the metal ions. The analysis of the Yb(3+)-induced shifts in [Yb(Me2tedpa)](+) indicates that this complex presents a solution structure very similar to that observed in the solid state for the Lu(3+) analogue. The X-ray structures of [La(H2Me2tedpa)2](3+) and [Yb(H2Me2tedpa)2](3+) complexes confirm the exocyclic coordination of the metal ions, which gives rise to coordination polymers with the metal coordination environment being fulfilled by oxygen atoms of the picolinate groups and water molecules. The X-ray structure of [Gd(Hcb-tedpa)2](+) also indicates exocyclic coordination that in this case results in a discrete structure with an eight-coordinated metal ion. The nonreinforced complexes [Ln(Me2tedpa)](+) were prepared and isolated as chloride salts in nonaqueous media. However, these complexes were found to undergo dissociation in aqueous solution, except in the case of the complexes with the smallest Ln(3+) ions (Ln(3+) = Yb(3+) and Lu(3+)). A DFT investigation shows that the increased stability of the [Ln(Me2tedpa)](+) complexes in solution across the lanthanide series is the result of an increased binding energy of the ligand due to the increased charge density of the Ln(3+) ion.

Lanthanide(III) complexes with a reinforced cyclam ligand show unprecedented kinetic inertness.

Lanthanide(III) complexes of a cross-bridged cyclam derivative containing two picolinate pendant arms are kinetically inert in very harsh conditions such as 2 M HCl, with no dissociation being observed for at least 5 months. Importantly, the [Ln(dota)](-) complexes, which are recognized to be extremely inert, dissociate under these conditions with lifetimes in the range ca. 1 min to 12 h depending upon the Ln(3+) ion. X-ray diffraction studies reveal octadentate binding of the ligand to the metal ion in the [Eu(cb-tedpa)](+) complex, while (1)H and (13)C NMR experiments in D2O point to the presence of a single diastereoisomer in solution with a very rigid structure. The structure of the complexes in the solid state is retained in solution, as demonstrated by the analysis of the Yb(3+)-induced paramagnetic shifts.

Unravelling the 6sp ← 6s absorption spectra of Bi(III) complexes.

We report a spectroscopic and computational study that investigates the absorption spectra of Bi(III) complexes, which often show an absorption band in the UV region (∼270-350 nm) due to 6sp ← 6s transitions. We investigated the spectra of three simple complexes, [BiCl5]2-, [BiCl6]3- and [Bi(DMSO)8]3+, which show absorption maxima at 334, 326 and 279 nm due to 3P1 ← 1S0 transitions. Theoretical calculations based on quasi-degenerate N-electron valence perturbation theory to second order (QD-NEVPT2) provide an accurate description of the absorption spectra when employing CAS(2,9) wave functions. We next investigated the absorption spectra of the [Bi(NOTA)] complex (H3NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid), which forms ternary complexes [Bi(NOTA)X]- (X = Cl, Br or I) in the presence of excess halide in aqueous solutions. Halide binding has an important impact on the position of the 3P1 ← 1S0 transition, which shifts progressively to longer wavelengths from 282 nm ([Bi(NOTA)]) to 298 nm (X = Cl), 305 nm (X = Br) and 325 nm (X = I). Subsequent QD-NEVPT2 calculations indicate that this effect is related to the progressive stabilization of the spin-orbit free states associated with the 6s16p1 configuration on increasing the covalent character of the metal-ligand(s) bonds, rather than with significant differences in spin-orbit coupling (SOC). These studies provide valuable insight into the coordination chemistry of Bi(III), an ion with increasing interest in targeted alpha therapy due to the possible application of bismuth isotopes bismuth-212 (212Bi, t1/2 = 60.6 min) and bismuth-213 (213Bi, t1/2 = 45.6 min).

Solution structure of Ln(III) complexes with macrocyclic ligands through theoretical evaluation of 1H NMR contact shifts.

Herein, we present a new approach that combines DFT calculations and the analysis of Tb(III)-induced (1)H NMR shifts to quantitatively and accurately account for the contact contribution to the paramagnetic shift in Ln(III) complexes. Geometry optimizations of different Gd(III) complexes with macrocyclic ligands were carried out using the hybrid meta-GGA TPSSh functional and a 46 + 4f(7) effective core potential (ECP) for Gd. The complexes investigated include [Ln(Me-DODPA)](+) (H(2)Me-DODPA = 6,6'-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid, [Ln(DOTA)(H(2)O)](-) (H(4)DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), [Ln(DOTAM)(H(2)O)](3+) (DOTAM = 1,4,7,10- tetrakis[(carbamoyl)methyl]-1,4,7,10-tetraazacyclododecane), and related systems containing pyridyl units (Ln = Gd, Tb). Subsequent all-electron relativistic calculations based on the DKH2 approximation, or small-core ECP calculations, were used to compute the (1)H hyperfine coupling constants (HFCCs) at the ligand nuclei (A(iso) values). The calculated A(iso) values provided direct access to contact contributions to the (1)H NMR shifts of the corresponding Tb(III) complexes under the assumption that Gd and Tb complexes with a given ligand present similar HFCCs. These contact shifts were used to obtain the pseudocontact shifts, which encode structural information as they depend on the position of the nucleus with respect to the lanthanide ion. An excellent agreement was observed between the experimental and calculated pseudocontact shifts using the DFT-optimized geometries as structural models of the complexes in solution, which demonstrates that the computational approach used provides (i) good structural models for the complexes, (ii) accurate HFCCs at the ligand nuclei. The methodology presented in this work can be classified in the context of model-dependent methods, as it relies on the use of a specific molecular structure obtained from DFT calculations. Our results show that spin polarization effects dominate the (1)H A(iso) values. The X-ray crystal structures of [Ln(Me-DODPA)](PF(6))·2H(2)O (Ln = Eu or Lu) are also reported.

Lanthanide(III) complexes with ligands derived from a cyclen framework containing pyridinecarboxylate pendants. The effect of steric hindrance on the hydration number.

Two new macrocyclic ligands, 6,6'-((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2DODPA) and 6,6'-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb(DODPA)](PF6)·H2O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (q) obtained from luminescence lifetime measurements in aqueous solution of the Eu(III) and Tb(III) complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H2Me-DODPA are q = 0. The structure of the complexes in solution has been investigated by 1H and 13C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb(III) complex [Λ(λλλλ)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb(III)-induced paramagnetic 1H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd(Me-DODPA)]+ are typical of a complex with q = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd(DODPA)]+ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature 17O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd(DODPA)]+. The results show that this system is endowed with a relatively fast water exchange rate k(ex)(298) = 58 × 10(6) s(­1).

Rigid versions of PDTA4- incorporating a 1,3-diaminocyclobutyl spacer for Mn2+ complexation: stability, water exchange dynamics and relaxivity.

Rigid derivatives of the acyclic ligand PDTA4- (H4PDTA = propylenediamine-N,N,N',N'-tetraacetic acid) were prepared by functionalization of a 1,3-diaminocyclobutyl spacer. The new ligands contain either four acetate groups attached to the central scaffold (H4L1) or incorporate pyridyl (H2L2) or propylamide (H2L3) units replacing two of the carboxylate groups. The ligand protonation constants and the stability constants of their Mn2+ complexes were determined using potentiometric and spectrophotometric titrations. The stability of the [Mn(L1)]2- complex was found to be significantly higher than that of the flexible [Mn(PDTA)]2- derivative (log KMnL = 10.78 and 10.01, respectively). A detailed study of the 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O NMR measurements evidence that the [Mn(L1)]2- and [Mn(L2)] complexes display a hydration equilibrium in solution involving a seven-coordinate species with an inner-sphere water molecule and a six-coordinate species that lacks a coordinated water molecule. As a result the 1H relaxivities of these complexes are somewhat lower than that of [Mn(EDTA)]2- and related systems. The introduction of propylamide groups in [Mn(L3)] shifts the hydration equilibrium to the seven-coordinate species, which results in a 1H relaxivity (r1p = 3.7 mM-1 s-1 at 22 MHz and 25 °C) exceeding that of [Mn(EDTA)]2- (r1p = 3.3 mM-1 s-1 at 22 MHz and 25 °C). The parameters that control the relaxivities in this family of complexes were determined by simultaneous fitting of the experimental 1H NMRD and 17O NMR data (transverse relaxation rates and chemical shifts), with the aid of computational studies performed at the DFT and CASSCF/NEVPT2 levels. These studies provide detailed insight of the parameters that control the efficiency of these relaxation agents at the molecular level.

In situ decellularization of a large animal saccular aneurysm model: sustained inflammation and active aneurysm wall remodeling.

OBJECTIVE: To investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation. METHODS: 18 New Zealand White rabbits were randomized 2:1 to receive endoluminal sodium dodecyl sulfate infusion (SDS, 1% solution, 45 min) following elastase or elastase-only treatment (control). All aneurysms were measured by digital subtraction angiography every 2 weeks. Every 2 weeks, three of the rabbits (two elastase + SDS, one control) underwent MRI, followed by contrast injection with myeloperoxidase (MPO)-sensing contrast agent. MRI was repeated 3 hours after contrast injection and the enhancement ratio (ER) was calculated. Following MRI, aneurysms were explanted and subjected to immunohistopathology. RESULTS: During follow-up MRI, the average ER for SDS-treated animals was 1.63±0.20, compared with 1.01±0.06 for controls (p<0.001). The width of SDS-treated aneurysms increased significantly in comparison with the elastase aneurysms (47% vs 20%, p<0.001). Image analysis of thin sections showed infiltration of MPO-positive cells in decellularized aneurysms and surroundings through the 12-week observation period while control tissue had 5-6 times fewer cells present 2 weeks after aneurysm creation. Immunohistochemistry demonstrated the presence of MPO-positive cells surrounding decellularized lesions at early time points. MPO-positive cells were found in the adventitia and in the thrombi adherent to the aneurysm wall at later time points. CONCLUSIONS: In situ decellularization of a large animal model of saccular aneurysms reproduces features of unstable aneurysms, such as chronic inflammation (up to 12 weeks) and active aneurysm wall remodeling, leading to continued growth over 8 weeks.

Water exchange in lanthanide complexes for MRI applications. Lessons learned over the last 25 years.

The water exchange rates of water molecules coordinated to the metal ion in lanthanide complexes have been profusely investigated during the last 25 years, especially in the case of Gd3+ and Eu3+ complexes. This is mainly related to the important application of some Gd3+ complexes as contrast agents in magnetic resonance imaging (MRI), and the intensive investigation of Eu3+ complexes as contrast agent candidates providing contrast through the chemical exchange saturation transfer mechanism (CEST). Both applications require a fine tunning of the exchange rate of the coordinated water molecule to yield optimal response. Herein we review the progress made in this field to control water exchange in a rational way through ligand design, providing relationships between the observed trends, the structures of the complexes and the mechanisms responsible for the water exchange reaction.