A pyrophosphate-responsive gadolinium(III) MRI contrast agent

This study shows that the relaxivity and optical properties of functionalised lanthanide‐DTPA‐bis‐amide complexes (lanthanide=Gd³⁺ and Eu³⁺, DTPA=diethylene triamine pentaacetic acid) can be successfully modulated by addition of specific anions, without direct Ln³⁺/anion coordination. Zinc(II)‐dipicolylamine moieties, which are known to bind strongly to phosphates, were introduced in the amide “arms” of these ligands, and the interaction of the resulting Gd–Zn₂ complexes with a range of anions was screened by using indicator displacement assays (IDAs). Considerable selectivity for polyphosphorylated species (such as pyrophosphate and adenosine‐5′‐triphosphate (ATP)) over a range of other anions (including monophosphorylated anions) was apparent. In addition, we show that pyrophosphate modulates the relaxivity of the gadolinium(III) complex, this modulation being sufficiently large to be observed in imaging experiments. To establish the binding mode of the pyrophosphate and gain insight into the origin of the relaxometric modulation, a series of studies including UV/Vis and emission spectroscopy, luminescence lifetime measurements in H₂O and D₂O, ¹⁷O and ³¹P NMR spectroscopy and nuclear magnetic resonance dispersion (NMRD) studies were carried out.     

Manganese(II)-containing MRI contrast agent employing a neutral and non-macrocyclic ligand

The ligand N,N'-bis(2-pyridylmethyl)-bis(ethylacetate)-1,2-ethanediamine (debpn) coordinates divalent transition metal ions in either a pentadentate or hexadentate fashion. The coordination number correlates with the ionic radius of the metal ion, with larger cations being heptacoordinate as assessed by solid-state analysis. With Mn(II), the debpn ligand is hexadentate and remains bound to the oxophilic metal ion, even when dissolved in water. The ligand's incomplete coordination of the manganous ion allows water molecules to coordinate to the metal center. These two properties, coupled with the high paramagnetism associated with the S = 5/2 metal center, enable [Mn(debpn)(H(2)O)](ClO(4))(2) to serve as a stable and effective magnetic resonance imaging contrast agent despite the ligand's lack of both a macrocyclic component and an anionic charge.     

Mechanistic studies of a calcium-dependent MRI contrast agent

Intracellular Ca(2+) plays an important role in signal transduction, and we are developing new MRI techniques to study its regulation in living animals. We have reported on an MRI contrast agent (DOPTA-Gd) where the relaxivity of the complex is controlled by the presence or absence of the divalent ion Ca(2+). By structurally modulating inner-sphere access of water to a chelated Gd(3+) ion, we observe a substantial and reversible change in T(1) upon the addition of Ca(2+) and not other divalent ions. Luminescence lifetime and NMRD measurements of the complex have been acquired, and several parameters contribute to the Ca(2+) dependent relaxivity change of DOPTA-Gd. The number of inner-sphere water molecules is more than doubled after the Ca(2+) concentration is increased. This finding strongly supports the proposed conformational change of DOPTA-Gd when Ca(2+) is bound. Relaxometric measurements confirm these results and provide an indication that second-sphere water molecules are probably responsible for paramagnetic relaxation enhancement in the absence of Ca(2+). After Ca(2+) is bound to DOPTA-Gd, the molecule undergoes a substantial conformational change that opens up the hydrophilic face of the tetraazacyclododecane macrocycle. This change dramatically increases the accessibility of chelated Gd(3+) ion to bulk solvent. The design of this class of calcium-activated MR contrast agent was based primarily on the assumption that the number of coordinated inner-sphere water molecules would be the dominating factor in observed relaxivity measurements. This result has been confirmed; however, careful mechanistic studies reveal that additional factors are involved in this process.     

Synthesis and evaluation of a high relaxivity manganese(II)-based MRI contrast agent

The manganese(II) ion has many favorable properties that lead to its potential use as an MRI contrast agent: high spin number, long electronic relaxation time, labile water exchange. The present work describes the design, synthesis, and evaluation of a novel Mn(II) complex (MnL1) based on EDTA and also contains a moiety that noncovalently binds the complex to serum albumin, the same moiety used in the gadolinium based contrast agent MS-325. Ultrafiltration albumin binding measurements (0.1 mM, pH 7.4, 37 degrees C) indicated that the complex binds well to plasma proteins (rabbit: 96 +/- 2% bound, human: 93 +/- 2% bound), and most likely to serum albumin (rabbit: 89 +/- 2% bound, human 98 +/- 2% bound). Observed relaxivities (+/- 5%) of the complex were measured (20 MHz, 37 degrees C, 0.1 mM, pH 7.4) in HEPES buffer (r(1) = 5.8 mM(-)(1) s(-)(1)), rabbit plasma (r(1) = 51 mM(-)(1) s(-)(1)), human plasma (r(1) = 46 mM(-)(1) s(-)(1)), 4.5% rabbit serum albumin (r(1) = 47 mM(-)(1) s(-)(1)), and 4.5% human serum albumin (r(1) = 48 mM(-)(1) s(-)(1)). The water exchange rate was near optimal for an MRI contrast agent (k(298) = 2.3 +/- 0.9 x 10(8) s(-)(1)). Variable temperature NMRD profiles indicated that the high relaxivity was due to slow tumbling of the albumin-bound complex and fast exchange of the inner sphere water. The concept of a high relaxivity Mn(II)-based contrast agent was validated by imaging at 1.5 T. In a rabbit model of carotid artery injury, MnL1 clearly delineated both arteries and veins while also distinguishing between healthy tissue and regions of vessel damage.     

A responsive particulate MRI contrast agent for copper(I): a cautionary tale

A responsive MION-based MRI contrast agent for the detection of copper(I) is presented. Induced agglomeration of azide and acetylene-functionalized magnetite nanoparticles via Cu(I)-catalysed Huisgen cycloaddition leads to significant decrease in longitudinal relaxivity due to the slow exchange of water molecules trapped within the cluster with bulk solvent. Agglomeration leads to an initial two-fold increase followed by a sharp and almost complete loss in transverse relaxivity for clusters larger than 200 nm in size. The decrease in r(2) for clusters reaching the static dephasing regime has two significant implications for particulate responsive MRI contrast agents. First, the maximum increase in r(2) is barely two-fold, second, since r(2) does not increase continuously with increasing cluster size, the r(1)/r(2) ratio cannot be used to determine the concentration of an analyte ratiometrically.     

Ensemble preprocessing of near-infrared (NIR) spectra for multivariate calibration

Preprocessing of raw near-infrared (NIR) spectral data is indispensable in multivariate calibration when the measured spectra are subject to significant noises, baselines and other undesirable factors. However, due to the lack of sufficient prior information and an incomplete knowledge of the raw data, NIR spectra preprocessing in multivariate calibration is still trial and error. How to select a proper method depends largely on both the nature of the data and the expertise and experience of the practitioners. This might limit the applications of multivariate calibration in many fields, where researchers are not very familiar with the characteristics of many preprocessing methods unique in chemometrics and have difficulties to select the most suitable methods. Another problem is many preprocessing methods, when used alone, might degrade the data in certain aspects or lose some useful information while improving certain qualities of the data. In order to tackle these problems, this paper proposes a new concept of data preprocessing, ensemble preprocessing method, where partial least squares (PLSs) models built on differently preprocessed data are combined by Monte Carlo cross validation (MCCV) stacked regression. Little or no prior information of the data and expertise are required. Moreover, fusion of complementary information obtained by different preprocessing methods often leads to a more stable and accurate calibration model. The investigation of two real data sets has demonstrated the advantages of the proposed method.     

Synthesis of a tricyclic tetraazatriacetic ligand for gadolinium(III) as potential contrast agent for MRI

A tricyclic tetraazatriacetic compound, which is a rigidified derivative of PCTA12 ligand with a cyclohexylene bridge replacing an ethylene one, was prepared. Two synthetic routes have been investigated, both of them implying a common functionalized triamine intermediate. Whatever the route, four synthetic steps were necessary to obtain the target tricyclic ligand. The more effective one (Route B) led to the desired compound in 19% overall yield from the triamine intermediate. The corresponding gadolinium complex of 1/1 stoichiometry was then prepared in order to evaluate it as potential contrast agent for MRI.     

Preparation and in vitro evaluation of GdDOTA-(BOM)4; a novel angiographic MRI contrast agent

A novel Gd(III) complex, GdDOTA-(BOM)4, has been prepared by a simple three-step procedure. The complex showed high T1-relaxivity values in serum albumin solutions, blood and plasma, resulting from high affinity for serum albumin. The T1-relaxivity in plasma, 67.4 s-1 mM-1 (20 MHz, 37 degrees C), makes it a promising candidate for angiographic applications of MRI.     

Synthesis and characterization of a redox- and light-sensitive MRI contrast agent

A redox- and light-sensitive, T₁-weighted magnetic resonance imaging (MRI) contrast agent, which tethers a spiropyran (SP)/merocyanine (MC) motif to a Gd-DO3A moiety was synthesized and characterized. When in the dark, the probe is in its MC form, which has an r₁ relaxivity of 2.51 m M⁻¹ s⁻¹ (60 MHz, 37 °C). After irradiation with visible light or mixing with NADH, the probe experiences an isomerization and the r₁ relaxivity decreased 18% and 26%, respectively. Additionally, the signal intensity in MRI showed an observable decrease after the compound was mixed with NADH.     

Synthesis and relaxometric studies of a dendrimer-based pH-responsive MRI contrast agent

The design of effective pH responsive MRI contrast agents is a key goal in the development of new diagnostic methods for conditions such as kidney disease and cancer. A key factor determining the effectiveness of an agent is the difference between the relaxivity of the "on" state compared to that of the "off" state. In this paper, we demonstrate that it is possible to improve the pH-responsive action of a low molecular weight agent by conjugating it to a macromolecular construct. The synthesis of a bifunctional pH responsive agent is reported. As part of that synthetic pathway we examine the Ing-Manske reaction, identifying an undesirable by-product and establishing effective conditions for promoting a clean and effective reaction. Reaction of the bifunctional pH responsive agent with a G5-PAMAM dendrimer yielded a product with an average of 96 chelates per dendrimer. The relaxivity of the dendrimer conjugate rises from 10.8 mM(-1) s(-1) (pH 9) to 24.0 mM(-1) s(-1) (pH 6) per Gd(3+) ion. This more than doubles the relaxivity pH response, Deltar(1), of our agent from just 51 % for the original low molecular weight chelate to 122 % for the dendrimer.     

Tensile deformation of polyamide (PA) 6 probed by rheo-optical near-infrared (NIR) spectroscopy

A rheo-optical near-infrared (NIR) spectroscopy, based on the combination of NIR spectroscopy and mechanical analysis, was applied to polyamide (PA) 6 samples consisting of bundled amorphous chains. Sets of strain-dependent NIR spectra as well as tensile stress of dried and wet treated PA 6 samples were collected during the mechanical elongation of the samples. The spectra were then subjected to two-dimensional (2D) correlation analysis to elucidate fine features of the spectral changes. An asynchronous correlation peak develops between the bands at 2355 and 2300 nm due to the combination modes of CH₂ groups arising from the rubbery amorphous chain and rigid crystalline lamella of the dried PA 6, respectively. It therefore indicates that during the tensile deformation, the orientation of the amorphous chain is induced first to cause the elastic deformation. Further elongation results in the rotation of the crystalline lamella connected with the amorphous chain. This correlation intensity apparently increases by the wet treatment, suggesting that water molecule in the PA 6 disrupts the H-bonding interaction between the adjacent polymer chains and thus makes the polymer more flexible. Accordingly, it is likely the H-bonding between the polymer chains works in a manner somewhat similar to cross-linked polymers, which substantially effects on the mechanical property of the PA 6.     

A general approach to the design of high-performance near-infrared (NIR) D-π-A type fluorescent dyes

A four-step method is presented as a general guideline for design of high performance NIR absorbing/emitting dyes.     

Self-modeling curve resolution (SMCR) analysis of near-infrared (NIR) imaging data of pharmaceutical tablets

The idea of quality by design (QbD) has been proposed in pharmaceutical field. QbD is a systematic approach to control the product performance based on the scientific understanding of the product quality and its manufacturing process. In the present study, near-infrared (NIR) imaging is utilized as a tool to achieve this concept. A practical use of a chemometrics technique called self-modeling curve resolution (SMCR) is demonstrated with NIR imaging analysis of pharmaceutical tablets containing two ingredients, a soluble active ingredient, pentoxifylline (PTX), and an insoluble excipient, palmitic acid. Concentration profiles obtained by SMCR reveal that the homogenous distribution of chemical ingredients strongly depends on the grinding time and that its process plays a central role in quantitative control, say sustained-release of PTX. In addition, pure component spectra by SMCR indicate a sequential change of specific NIR peak intensities following the increase of the grinding time. The spectra change shows a molecular structure change related to its crystallinity during grinding process. Accordingly, this study clearly demonstrates that NIR imaging combined with SMCR can be a powerful tool to reveal chemical or physical mechanism induced by the manufacturing process of pharmaceutical products and that it may be a solid solution for QbD of pharmaceutical products.     

Re(I) sensitised near-infrared lanthanide luminescence from a hetero-trinuclear Re2Ln array

The trinuclear complexes Re2Ln (Ln = Nd, Yb or Er) contain two Re(I) tricarbonyl units linked to a DTPA binding site via 2,2'-bipyridyl ligands; Ln(III)-centred emission is sensitised by the Re(I) MLCT excited states.     

Tensile deformation of isotactic polypropylene (iPP) and iPP-nanocomposite studied by rheo-optical near-infrared (NIR) spectroscopy

Tensile deformations of isotactic polypropylene (iPP) and its nanocomposite were examined by a rheo-optical characterization technique based on near-infrared (NIR) spectroscopy to derive the submolecular-level understanding of the deformation mechanism during a tensile test. Sets of NIR spectra of the iPP samples were collected by using an acousto-optic tunable filter (AOTF) NIR spectrometer coupled with a tensile testing machine as an excitation device. Mechanical deformation of the samples was readily captured as strain-dependent NIR spectra. However, the main feature of the NIR spectra was overwhelmed by the contribution from the baseline change due to the substantial decrease in the sample thickness and subsequent change in the NIR light scattering. The variation of the spectral feature suggests that the deformation of the iPP involves the elongation of the rubbery amorphous chains prior to the displacement of the crystalline lamellae, providing elastic and subsequent plastic deformations during the tensile testing. In addition, it is revealed that the nanoclay layers dispersed within the iPP matrix restrict the elongation of the amorphous chains. Such interaction makes iPP hard and brittle, so that it yields no obvious ductile fracture during the tensile deformation.     

Magnetically modified bentonite as a possible contrast agent in MRI of gastrointestinal tract

A composite of iron oxide nanoparticles and mineral matrix has been studied by XRD, Mössbauer spectroscopy, and TEM. Magnetite and superparamagnetic magnetite have been identified by Mössbauer spectroscopy in the nanocomposite. A relationship between the hyperfine parameters and iron oxide particle size has been confirmed by TEM. The optimal concentration of “magnetite—bentonite” composite, when the MRI signal is fully reduced, was found for using this composite as a negative contrast agent.     

Recombinant HDL-like nanoparticles: a specific contrast agent for MRI of atherosclerotic plaques

A new contrast agent for MRI based on recombinant HDL-like nanoparticles has been prepared. It shows a great potential as a contrast agent for atherosclerotic plaques in a relative short time (24 h post-injection) as it is selective for the plaques and is an endogenous molecule. It also can distinguish between different types of plaques as the enhancement obtained is different, depending on plaque composition.