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.

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, [BiCl], [BiCl] and [Bi(DMSO)], which show absorption maxima at 334, 326 and 279 nm due to P ← S 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.

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

We present a detailed analysis of the H NMR chemical shifts and transverse relaxation rates of three small Dy(III) complexes having different symmetries (, or ). The complexes show sizeable emission in the visible region due to F → H transitions ( = 15/2 to 11/2). Additionally, NIR emission is observed at ca.

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  values) and the values of pMn obtained as -log[Mn] 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 and pMn values can be predicted to a good accuracy by adding the contributions of the different motifs present in the ligand structure.

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.

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

Rigid derivatives of the acyclic ligand PDTA4- (HPDTA = propylenediamine-,,','-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 Mn complexes were determined using potentiometric and spectrophotometric titrations.

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

Investigating the relaxation of water H 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 H NMR relaxometry and theoretical calculations. These ligands include 1,4,7-triazacyclononane-1,4,7-triacetic acid (HNOTA) and three derivatives in which an acetate group is replaced by sulfonamide (HNO2ASAm), amide (HNO2AM), or pyridyl (HNO2APy) pendants.

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.

Mn Complexes Containing Sulfonamide Groups with pH-Responsive Relaxivity.

We present two ligands containing a -ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (HDPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (HNO2ASAm). These ligands were designed to provide a pH-dependent relaxivity response upon complexation with Mn in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn complexes were determined using potentiometric titrations complemented by spectrophotometric experiments.

Macrocyclic Pyclen-Based Gd 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 (HL) 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 position are protonated in the solid state, together with the exocyclic N atom and one of the carboxylate groups of the ligand.

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-HDO2APA) or trans (1,7-HDO2APA) positions. The stability constants of the Gd complexes with these two ligands are very similar, with log values of 16.98 and 16.

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 Yb ion in [Yb(DOTAM)] has profound consequences in the magnetic anisotropy and optical properties of the complex, as evidenced by H NMR and UV-vis spectroscopies. The pseudocontact shifts of H nuclei and the F ← F absorption band were found to be very sensitive to the nature of the axial ligand (MeOH, HO, MeOH, or F). The energy levels of the F and F manifolds in [Yb(DOTAM)(X)] (X = MeOH, HO, or dimethyl sulfoxide (DMSO)) and [Yb(DOTAM)F] 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.

Peroxidase Sensitive Amplifiable Probe for Molecular Magnetic Resonance Imaging of Pulmonary Inflammation.

An amplifiable magnetic resonance imaging (MRI) probe that combines the stability of the macrocyclic Gd-DOTAGA core with a peroxidase-reactive 5-hydroxytryptamide (5-HT) moiety is reported. The incubation of the complex under enzymatic oxidative conditions led to a 1.7-fold increase in at 1.

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 Gd and Eu complexes. This is mainly related to the important application of some Gd complexes as contrast agents in magnetic resonance imaging (MRI), and the intensive investigation of Eu 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.

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.

On the consequences of the stereochemical activity of the Bi(iii) 6s lone pair in cyclen-based complexes. The [Bi(DO3A)] case.

We report a detailed study of the structure of the [Bi(DO3A)] complex both in the solid state and in solution. The X-ray crystal structure of [Bi(DO3A)] evidences the octa-coordination of the Bi(iii) ion, which is directly coordinated to the four nitrogen atoms of the cyclen unit and three oxygen atoms of the carboxylate groups. The octa-coordination is completed by an oxygen atom of a neighboring carboxylate group, which bridges Bi(iii) ions thanks to μ2-η1:η1 coordination, resulting in the formation of a coordination polymer.

High-resolution Imaging of Myeloperoxidase Activity Sensors in Human Cerebrovascular Disease.

Progress in clinical development of magnetic resonance imaging (MRI) substrate-sensors of enzymatic activity has been slow partly due to the lack of human efficacy data. We report here a strategy that may serve as a shortcut from bench to bedside. We tested ultra high-resolution 7T MRI (µMRI) of human surgical histology sections in a 3-year IRB approved, HIPAA compliant study of surgically clipped brain aneurysms.

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-H 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-H Medo2 ampa) positions are reported. These ligands provide eight-coordination to the Ln ions, leaving a coordination position available for a water molecule that occupies a capping position in the twisted square antiprismatic polyhedron (1,4-H Medo2 ampa) or one of the positions of the square antiprism (1,7-H Medo2 ampa). The charge neutral [Gd(1,7-Medo2 ampa)] complex presents an unprecedentedly low water-exchange rate (k =8.

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.

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.

Stable Mn(2+), Cu(2+) and Ln(3+) complexes with cyclen-based ligands functionalized with picolinate pendant arms.

In this study we present the results of the equilibrium, dissociation kinetics, DFT and X-ray crystallographic studies performed on the complexes of metal ions of biomedical importance (Mn(2+), Cu(2+) and Gd(3+)) formed with octadentate ligands based on a cyclen platform incorporating two picolinate pendant arms (dodpa(2-) and Medodpa(2-)). The stability constants of the complexes were accessed by multiple methods (pH-potentiometry, direct and competition UV-vis spectrophotometry and (1)H-relaxometry). The stability constants of the complexes formed with dodpa(2-) and Medodpa(2-) do not differ significantly (e.

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.

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).

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.