Activatable 19F MRI Nanoparticle Probes for the Detection of Reducing Environments

¹⁹F magnetic resonance imaging (MRI) probes that can detect biological phenomena such as cell dynamics, ion concentrations, and enzymatic activity have attracted significant attention. Although perfluorocarbon (PFC) encapsulated nanoparticles are of interest in molecular imaging owing to their high sensitivity, activatable PFC nanoparticles have not been developed. In this study, we showed for the first time that the paramagnetic relaxation enhancement (PRE) effect can efficiently decrease the ¹⁹F NMR/MRI signals of PFCs in silica nanoparticles. On the basis of the PRE effect, we developed a reduction‐responsive PFC‐encapsulated nanoparticle probe, FLAME‐SS‐Gd³⁺ (FSG). This is the first example of an activatable PFC‐encapsulated nanoparticle that can be used for in vivo imaging. Calculations revealed that the ratio of fluorine atoms to Gd³⁺ complexes per nanoparticle was more than approximately 5.0×10², resulting in the high signal augmentation.     

Gadolinium(III)–fluorescein complex as a dual modal probe for MRI and fluorescence zinc sensing

A bimodal imaging Gd–Zpy probe based on magnetic resonance imaging and fluorescence sensing has been synthesized and characterized. Gd–Zpy features a bright green emission and a turn-on fluorescent response manner with high sensitivity for Zn²⁺ in aqueous solution and is able to luminescent imaging intracellular Zn²⁺ levels within living cells. It exhibits a 130% increase of the longitudinal relaxation time and a 115% increase of transverse relaxive time upon addition of Zn²⁺. The results demonstrated that the incorporating of the fluorescein dye having the efficient chelators within a high-spin Gd³⁺ system was a powerful approach to achieve dual modal probes for MRI and fluorescence sensing.     

Nuclear spin relaxation study of aqueous raffinose solution in the presence of a gadolinium contrast agent

Paramagnetic enhancement of nuclear spin-lattice relaxation rates (PREs) was measured in aqueous solution of the trisaccharide raffinose in the presence of a gadolinium(III) complex, GdDTPA-BMA, used as a magnetic resonance imaging contrast agent. The relaxation enhancement of aqueous protons was measured over a broad range of magnetic fields, using field-cycling apparatus in addition to conventional spectrometers. The nuclear magnetic relaxation dispersion profile thus obtained was interpreted with a recently developed model, allowing for both inner- and outer-sphere relaxation. The relaxation enhancement for the carbon-13 nuclei in raffinose was studied under high-resolution conditions at three magnetic fields, whereas the sugar proton PRE was measured at two fields. The PRE of the sugar nuclei could be interpreted in a consistent way, assuming that it was caused by the outer-sphere mechanism. The electron spin relaxation was found to be a less important source of modulation of the electron-nuclear dipole-dipole interaction than the mutual translational diffusion.     

Out-cage metal ion coordination by novel benzoazacrown bisamides with carboxyl,pyridyl and picolinate pendant arms

A new series of macrocyclic diamides with carboxyl, pyridyl and picolinate pendant arms have been synthesized and the stability constants of their complexes with Ni²⁺, Cu²⁺, Zn²⁺, Cd²⁺, Pb²⁺ in water were determined. Complexes with a stoichiometry of 1 : 1 (M: L) were found for all ligands with the exception of 15-membered crown ethers with one pendant carboxyl or pyridine group. The ligand containing two picolinate backbone groups exhibits the highest values of the stability constants for all studied cations (logβ_ML?=?12.5–15.7). X-ray study of free ligands showed that the introduction of benzene and amide fragments into the macrocyclic moiety provides a flatten open structure of the ligand. The crystallographic analysis of Cu²⁺ and Zn²⁺ complexes revealed the external coordination of the metal atom by amine N atoms of the macrocycle and heteroatoms of the pendant groups.     

Zn^2＋ Recognition by Two New Bipyridine Ligands

IntroductionThehighsensitivityandselectivityofmolecularfluores cenceorluminescencehavebeenwidelyutilizedinmonitoringH+ ,Ca2 + ,Na+ ,Mg2 + ,andotherimportantcationoran ionionsinbiologicalorenvironmentalsystems.Duetothesensitiveresponseofluminescenceuponmicroenviromentalchanges (e .g .polarityofsolvent,pH ,thepresenceofions) ,bipyridinecomplexesofRe(I)andRu(II)withmetaltoligandchargetransferexcitedstatesconstitutealargefami lyofchemicalsensors.1 5Intheseprobingmolecules ,theco operationofthe…     

Metal Complexes of Free Radicals. Part II: Identification and structures of radical complexes of alkaline earth metals and zinc

The formation of chelate complexes between free radicals and closed-shell metal ions is observed by ESR. spectroscopy. High resolution spectra of 1:1 complexes formed between the radical anion of glyoxal-bis-(N-t-butylimine) (GLIR) and Mg²⁺, Ca²⁺ and Zn²⁺ are completely analysed. The complexes formed in dimethoxyethane or tetrahydrofuran solutions are Ca(GLIR)⁺, Mg(GLIR)X, Zn (GLIR)X and Zn(GLIR)Y^?₂, where X = Cl^?, Br^?, I^?, and Y = CN^?, NCS^?. The formation of the heterometallic, binuclear cyanide-bridged complex Zn(GLIR)Fe(CN)₆^3? is also described. Isotropic coupling constants are given for protons and ¹⁴N in GLIR as well as for the metal nuclei and magnetic nuclei in the groups X and Y. Stabilities, structures and ESR. parameters of these radical complexes are discussed.     

Effects of Ligand Chain Length and Terminal N-Alkylation on the Protonation Constants and Stability Constants of Some Transition Metal Complexes of Linear Tetraaza and Pentaaza Ligands

A number of terminal N-alkylated linear tetraaza and pentaaza ligands were prepared. Their ligand protonation constants and some transition and post-transition metal (Ni²⁺, Cu²⁺, Zn²⁺, and Cd²⁺) complex stability constants were determined by potentiometric titration methods. In general, methylation and ethylation at the terminal nitrogen atoms caused the corresponding ligand nitrogen basicity to increase; however, the corresponding metal complex stabilities were decreased compared to the non-alkylated structural analogs, presumably due to a steric effect.     

Coexistence of Spin–Lattice Relaxation and Phonon-Bottleneck Processes in GdIII–Phthlocyaninato Triple-Decker Complexes under Highly Diluted Conditions

Gd³⁺ complexes have been shown to undergo unusual slow magnetic relaxation processes similar to those of single-molecule magnets (SMMs), even though Gd³⁺ does not exhibit strong magnetic anisotropy. To reveal the origin of the slow magnetic relaxation of Gd³⁺ complexes, we have investigated the magnetic properties and heat capacities of two Gd³⁺-phthalocyaninato triple-decker complexes, one of which has intramolecular Gd³⁺–Gd³⁺ interactions and the other does not. It was found that the Gd³⁺–Gd³⁺ interactions accelerate the magnetic relaxation processes. In addition, magnetically diluted samples, prepared by doping a small amount of the Gd³⁺ complexes into a large amount of diamagnetic Y³⁺ complexes, underwent dual magnetic relaxation processes. A detailed dynamic magnetic analysis revealed that the coexistence of spin–lattice relaxation and phonon-bottleneck processes is the origin of the dual magnetic relaxation processes.     

Luminescence of Eu3+ and Tb3+ Complexes of Two Macrobicyclic Ligands Derived from a Tetralactam Ring and a Chromophoric Antenna

Two macrobicyclic ligands derived from an 18‐membered tetralactam ring and 2,2′‐bipyridine or 2,6‐bis(pyrazol‐1‐yl)pyridine moieties, 1 and 2 , respectively, form stable complexes with Gd^III, Eu^III, and Tb^III ions in aqueous solution. The ligand‐based luminescence is retained in the Gd^III cryptates, whereas this radiative deactivation is quenched in the Eu^III and Tb^III cryptates by ligand‐to‐metal energy transfer, resulting in the usual metal‐centered emission spectra. Singlet‐ and triplet‐state energies, emission‐decay lifetimes, and luminescence yields were measured. [Tb⊂ 1 ]³⁺ cryptate shows a long luminescence lifetime (τ=1.12 ms) and a very high metal luminescence quantum yield (Φ=0.25) in comparison with those reported in the literature for Tb³⁺ complexes sensitized by a bipyridine chromophore. By comparison to [Ln⊂ 1 ]³⁺, [Ln⊂ 2 ]³⁺ presents markedly lower luminescence properties, due to worse interaction between the 2,6‐bis(pyrazol‐1‐yl)pyridine unit and the metal ion. Moreover, the luminescent metal and the triplet ligand energy levels of [Eu⊂ 2 ]³⁺ do not match. The effects of H₂O molecules coordinated to the metal centre and of thermally activated decay processes on nonradiative deactivation to the ground‐state are also reported.     

Synthesis,characterization, speciation and biological studies on metal chelates of 1-benzoyl(1,2,4-triazol-3-yl)thiourea

Proton-ligand association constants of 1-benzoyl(1,2,4-triazol-3-yl)thiourea (BTTU) and its complex formation constants with some bivalent metal ions Ni(II), Co(II), Mn(II), Zn(II), and Cu(II), have been determined potentiometrically in 50% EtOH–H₂O and 0.1 M NaNO₃. The complexes formed in solution have a stoichiometry of 1:1 and 1:2 [M:L], where M represents the metal ion and L the BTTU ligand. The corresponding thermodynamic parameters are derived and discussed. The complexes are stabilized by enthalpy changes and the results suggest that complexation is an enthalpy-driven process. The effects of metal ion, ionic radius, electronegativity, and nature of ligand on the formation constants are discussed. The formation constants of the complexes with 3d transition metals follow the order Mn²⁺ < Co²⁺ < Ni²⁺ < Cu²⁺ > Zn²⁺. The metal complexes were synthesized and characterized by elemental analyses, conductance, IR, ¹H NMR, and magnetic measurements. The low magnetic moment of 0.11 BM for the Cu(II) complex is suggestive of dimerization through Cu–Cu interaction. The concentration distribution diagrams of the complexes were evaluated. The ligands and their metal complexes have been screened in vitro against some bacteria and fungi.     

Metal complexes with macrocyclic ligands. Part XXXVI. Thermodynamic and kinetic studies of bivalent and trivalent metal ions with 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

NMR, potentiometric, and UV/VIS measurements were run to study the protonation and the In³⁺ and Cu²⁺ stability constants of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (do3a, L). The protonation of do3a follows the typical scheme with two high and several low log K_H values. Between pH 11 and 13, the protonation mainly occurs at the N-atom, which is not substituted by an acetate side chain. The In³⁺ complex is not appreciably protonated even at low pH values (pH ? 1.7), whereas [CuL] can add up to three protons in acidic solution to give the species [CuLH], [CuLH₂], and [CuLH₃], the stability of which was determined. The formation rates of the Y³⁺, Gd³⁺, Ga³⁺, and In³⁺ complexes with do3a were measured using a pH-stat technique, whereas that of Cu²⁺, being faster, was followed on a stopped-flow spectrophotometer. In all cases, the reaction scheme implies the rapid formation of partially protonated intermediates, which rearrange themselves to the final product in the rate-determining process. ([MLH])_in, an intermediate, in which the metal ion probably is coordinated by two amino acetate groups, proved to be the reactive species for Y³⁺, Gd³⁺, and Ga³⁺. The formation of [Cu(do3a)] was interpreted by postulating that either ([CuLH])_in or ([CuLH])_in, and ([CuLH₂])_in are the reactive complexes. The rates of dissociation of the Y³⁺, Gd³⁺, and Cu²⁺ complexes with do3a were studied spectrophotometrically. For Y³⁺ and Gd³⁺, arsenazo III was used as a scavenger, whereas for Cu²⁺ the absorption associated with d-d* transition was followed. For [Y(do3a)] and [Gd(do3a)], the rate law follows the kinetic expression k_obsd ? k₀ + k₁[H⁺]. The dissociation of [Cu(do3a)] goes through the proton-independent dissociation of [CuLH₃], which is the main species at low pH.     

Long‐lived states in an intrinsically disordered protein domain

Long‐lived states (LLS) are relaxation‐favored spin population distributions of J‐coupled magnetic nuclei. LLS were measured, along with classical ¹H and ¹⁵N relaxation rate constants, in amino acids of the N‐terminal Unique domain of the c‐Src kinase, which is disordered in vitro under physiological conditions. The relaxation rates of LLS can probe motions and interactions in biomolecules. LLS of the aliphatic protons of glycines, with lifetimes approximately four times longer than their spin–lattice relaxation times, are reported for the first time in an intrinsically disordered protein domain. LLS relaxation experiments were integrated with 2D spectroscopy methods, further adapting them for studies on proteins. Copyright © 2013 John Wiley & Sons, Ltd.     

The effect of ligand donor atoms on ternary complex stability

Formation constants of mixed ligand complexes of Cu²⁺, Zn²⁺, Ni²⁺, Co²⁺, and Mn²⁺,with cyadine-5′-monophosphoric acid (CMP) and various primary ligands such as 1,10-phenanthroline(phen), glycylglycine(glygly) and salicylic acid (sal) have been determined in aqueous solution at 35°C and 0.1 M (KNO₃) by potentiomeric measurements. The acid dissociation constants of all the above mentioned ligands together with their 1 : 1 binary metal complex formation constants were also measured at 35°C. In general all the 1 : 1 binary complexes follow the Irving-Williams order of stability. Further the binary metal complexes of primary ligands are more stable than their ternary complexes with CMP. For ternary complexes, Δ(log K) values seem to change from positive to highly negative as the coordinating atoms of the primary ligands were varied from N,N to N,O^? to O^?O^?. The higher stability of ternary complexes involving phen is due to its Π-bonding interaction with the above metal ions and the relative decrease in the stability of other ternary systems is due to the coulombic repulsion of donor oxygen atoms of primary and secondary ligands. Thus for ternary complexes the stabilities follow a decreasing order of M-phen-CMP > M-glygly-CMP > M-sal-CMP.     

Synthesis and Characterization of Various Benzyl Diethylenetriaminepentaacetic Acids (dtpa) and Their Paramagnetic Complexes,Potential Contrast Agents for Magnetic Resonance Imaging

Four derivatives of diethylenetriaminepentaacetic acid (=3,6,9‐tris(carboxymethyl)‐3,6,9‐triazaundecanedioic acid (H₅dtpa)), potential contrast agents for magnetic resonance imaging (MRI), carrying benzyl groups at various positions of the parent structure were synthesized and characterized by a thorough multinuclear NMR study, i.e., the (S)‐ and (R)‐stereoisomers 1a and 1b of 4‐benzyl‐3,6,9‐tris(carboxymethyl)‐3,6,9‐triazaundecanedioic acid (H₅[(S)‐(4‐Bz)dtpa] and H₅[(R)‐(4‐Bz)dtpa], the diamide derivative N,N″‐bis[(benzylcarbamoyl)methyl]diethylenetriamine‐N,N′,N″‐triacetic acid (=3,9‐bis[2‐(benzylamino)‐2‐oxoethyl]‐6‐(carboxymethyl)‐3,6,9‐triazaundecanedioic acid; H₃[dtpa(BzA)₂]; 2 ), and the diester derivative N,N″‐bis{[(benzyloxy)carbonyl]methyl}diethylenetriamine‐N,N′,N″‐triacetic acid (=3,9‐bis[2‐(benzyloxy)‐2‐oxoethyl]‐6‐(carboxymethyl)‐3,6,9‐triazaundecanedioic acid; H₃[dtpa(BzE)₂]; 3 ). From the ¹⁷O‐NMR chemical shift of H₂O induced by their dysprosium complexes with ligands 1 – 3 , it was concluded that only one H₂O molecule is contained in the first coordination sphere of these lanthanide complexes. The rotational correlation times (τ_R) of the complexes were estimated from the ²H‐NMR longitudinal relaxation rate of the deuterated diamagnetic lanthanum complexes. The exchange time of the coordinated H₂O molecule (τ_M) was studied through the temperature dependence of the ¹⁷O‐NMR transverse relaxation rate. As compared to [Gd(dtpa)]²⁻, the H₂O‐exchange rate is faster for [Gd{(S)‐(4‐Bz)dtpa}]²⁻ and [Gd{(R)‐(4‐Bz)dtpa}]²⁻‐, slower for [Gd{dtpa(BzA)₂}], and almost identical for [Gd{dtpa(BzE)₂}]. The analysis of the ¹H‐relaxivity of the gadolinium complexes recorded from 0.02 to 300 MHz established that i) the relaxivity of [Gd{dtpa(BzE)₂}] is similar to that of [Gd(dtpa)]²⁻, ii) the slightly slower molecular rotation of [Gd{dtpa(BzA)₂}] induces a mild enhancement of its relaxivity, and iii) the marked increase of relaxivity of [Gd{(S)‐(4‐Bz)dtpa}]²⁻ and [Gd{(R)‐(4‐Bz)dtpa}]²⁻ mainly results from an apparently shorter distance between the gadolinium ion and the H₂O protons of the coordinated H₂O molecule.     

Synthesis, IR and NMR characterization and ion extraction properties of tetranonylcalix[4]resorcinol bearing acetylhydrazone groups

A series of new calix[4]resorcinarenes (rccc-isomer) and resorcinols functionalized by acetylhydrazone binding fragments have been synthesized. The IR and NMR data and stereochemical behaviour of hydrazones are reported and compared with the results of earlier investigations. The barriers of rotation of hydrazone fragments for some octahydrazone derivatives of calix[4]resorcinarenes and their resorcinol analogues have been determined by NMR-measurements. The complexing behaviour of bis- and octahydrazones has been studied by liquid-liquid extraction towards the s-metal ions (Li⁺, Na⁺, K⁺, Cs⁺ and Ca²⁺), p-metal ions (Pb²⁺), d-metal ions (Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, Cd²⁺ and Hg²⁺) and f-metal ions (La³⁺, Gd³⁺ and Lu³⁺). The stoichiometry of complexes and the extraction constants have been determined. It has been established that octahydrazones do not extract alkali metal cations but show excellent selectivity towards transition and soft heavy metal cations (especially Hg²⁺ or Pb²⁺).     

The Role of Equilibrium and Kinetic Properties in the Dissociation of Gd[DTPA‐bis(methylamide)] (Omniscan) at near to Physiological Conditions

[Gd(DTPA‐BMA)] is the principal constituent of Omniscan, a magnetic resonance imaging (MRI) contrast agent. In body fluids, endogenous ions (Zn²⁺, Cu²⁺, and Ca²⁺) may displace the Gd³⁺. To assess the extent of displacement at equilibrium, the stability constants of DTPA‐BMA^3? complexes of Gd³⁺, Ca²⁺, Zn²⁺, and Cu²⁺ have been determined at 37 °C in 0.15 M NaCl. The order of these stability constants is as follows: GdL≈CuL>ZnL?CaL. Applying a simplified blood plasma model, the extent of dissociation of Omniscan (0.35 mM [Gd(DTPA‐BMA)]) was found to be 17 % by the formation of Gd(PO₄), [Zn(DTPA‐BMA)]^? (2.4 %), [Cu(DTPA‐BMA)]^? (0.2 %), and [Ca(DTPA‐BMA)]^? (17.7 %). By capillary electrophoresis, the formation of [Ca(DTPA‐BMA)]^? has been detected in human serum spiked with [Gd(DTPA‐BMA)] (2.0 mM ) at pH 7.4. Transmetallation reactions between [Gd(DTPA‐BMA)] and Cu²⁺ at 37 °C in the presence of citrate, phosphate, and bicarbonate ions occur by dissociation of the complex assisted by the endogenous ligands. At physiological concentrations of citrate, phosphate, and bicarbonate ions, the half‐life of dissociation of [Gd(DTPA‐BMA)] was calculated to be 9.3 h at pH 7.4. Considering the rates of distribution and dissociation of [Gd(DTPA‐BMA)] in the extracellular space of the body, an open two‐compartment model has been developed, which allows prediction of the extent of dissociation of the Gd^III complex in body fluids depending on the rate of elimination of the contrast agent.     

Determination and comparison of the stability constants of some bivalent ion complexes of 5,7-dichloro-, 5,7-dibromo-, and 5,7-dinitro-8-Hydroxyquinoline and their N-oxides

The stability constants of complexes of Mn⁺⁺, Fe⁺⁺, Co⁺⁺, Ni⁺⁺, Cu⁺⁺, Zn⁺⁺, Cd⁺⁺ and UO with 5,7-dichloro-, 5,7-dibromo- and 5,7-dinitro-8-hydroxyquinoline and their corresponding N-oxides have been determined in 75 + 25 v/v dioxan + water medium at 35°C in presence of 0.20 M sodium perchlorate by pH-titration technique as given by IRVING and Rossotti. A possible explanation for the observed orders of the stability constants of the metal complex with the different ligands, and of the complexes of a particular ligand with different metal ions is also proposed.     

Imino- and bis-imino-pyridines with N-ter-butyl-N-aminoxyl group: synthesis, oxidation and use as ligand towards M ( Mn, Ni, Zn) and Gd

Imino- and bis-iminopyridine ligands bearing N-ter-butylhydroxy groups were synthesized by the condensation reaction between a N-ter-butylhydroxy substituted aniline and 2-formylpyridine, 2-acetylpyridine and 2,6-bis-acetylpyridine. The N-ter-butylaminoxy radicals obtained after oxidation using PbO₂ or Ag₂O were studied by EPR spectroscopy in solution. Indeed, complete decomposition was observed during isolation of these radical derivatives. The N-ter-butylhydroxy substituted ligands obtained were complexed with Mn²⁺, Ni²⁺, Zn²⁺ and Gd³⁺ salts; the obtained complexes were characterized and oxidized to give the aminoxy analogs, which were studied using IR, UV and EPR spectroscopies.     

CATALYTIC HYDROLYSIS OF P-NITROPHENYL PICOLNATE BY BIOXOCYLAM ZINC(II) COMPLEXES IN MICELLAR SOLUTION

The effects of dioxocyclam Zn³ ion complexes in micellar solution on ihe hydrolysis of PNPP have been investigated in this paper. Second order rate constants of Ihe hydrolysis of PNPP catalyzed by dio*ocyclam Zn²⁺ion complexes at various pH and the deprotonation constants of H₂ cooriinated to the dioxocyclam Zn²⁺ion complexes pKwere determined kinetically, and the catalytic mechanism was discussed. The results unexpectedly showed that the activation was much larger for Itpophilic ligand under miccllar condition than for bydrophilic ligands under non-miccllar conditions, indicating the dioxocyclam Zn²⁺ ion complex to be an excellent model of carbonic anhydnue.     

ADDUCTS OF THEOBROMINE WITH 3d METAL PERCHLORATES

Abstract

Adducts of theobromine (tbH) with 3d metal perchlorates (Mⁿ⁺ = Cr^3-. Mn²⁺, Fe²⁺, Fe³⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn^2- I here prepared by refluxing mixtures of the Iigand and a metal salt in ethyl acetate-triethyl orthoformate. The new complexes invariably involve 2: 1 molar ratios of tbH to metal ion and are apparently monomeric with terminal tbH ligands binding riaa ring nitrogen (N9 or Nl). The Mn²⁺, Cu²⁺ and Zn^2- complexes are distorted tetrahedral, involving tuo tbH and two unidentate perchlorato ligands in the first coordination sphere of the metal ion. The remaining metal(II) complexes (Fe, Co, Ni) were obtained as monohydrates. These compounds are pentacoordinated of the [M(tbH)₂(OClO₃)₂(OH₂)] type, containing one aqua ligand in addition to the tbH and perchlorato ligands. The Cr³⁺ and Fe³⁺ complexes are low-symmetry hexacoordinated, with two tbH ligands. two unidentate and one bidentate chelating perchlorate Iigands.