Influence of calcium-induced aggregation on the sensitivity of aminobis(methylenephosphonate)-containing potential MRI contrast agents

A novel class of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenecarboxylic) acid (DO3A)-based lanthanide complexes with relaxometric response to Ca(2+) was synthesized, and their physicochemical properties were investigated. Four macrocyclic ligands containing an alkyl-aminobis(methylenephosphonate) side chain for Ca(2+)-chelation have been studied (alkyl is propyl, butyl, pentyl, and hexyl for L(1), L(2), L(3), and L(4), respectively). Upon addition of Ca(2+), the r(1) relaxivity of their Gd(3+) complexes decreased up to 61% of the initial value for the best compounds GdL(3) and GdL(4). The relaxivity of the complexes was concentration dependent (it decreases with increasing concentration). Diffusion NMR studies on the Y(3+) analogues evidenced the formation of agglomerates at higher concentrations; the aggregation becomes even more important in the presence of Ca(2+). (31)P NMR experiments on EuL(1) and EuL(4) indicated the coordination of a phosphonate to the Ln(3+) for the ligand with a propyl chain, while phosphonate coordination was not observed for the analogue bearing a hexyl linker. Potentiometric titrations yielded protonation constants of the Gd(3+) complexes. log K(H1) values for all complexes lie between 6.12 and 7.11 whereas log K(H2) values are between 4.61 and 5.87. Luminescence emission spectra recorded on the Eu(3+) complexes confirmed the coordination of a phosphonate group to the Ln(3+) center in EuL(1). Luminescence lifetime measurements showed that Ca-induced agglomeration reduces the hydration number which is the main cause for the change in r(1). Variable temperature (17)O NMR experiments evidenced high water exchange rates on GdL(1), GdL(2), and GdL(3) comparable to that of the aqua ion.     

Dual-functional probes towards in vivo studies of brain connectivity and plasticity

A Gd(3+) based paramagnetic dextran conjugate has been developed, which enables the tracking of neuroanatomical connectivity in the brain by both MR and optical imaging. Cell studies and subsequent in vivo experiments in rodents demonstrate efficient internalisation and transport properties of the new tracer molecule.     

Synthesis and characterization of lanthanide complexes of DO3A-alkylphosphonates

Eight DO3A-based lanthanide(III) complexes bearing ester protected and unprotected phosphonate groups at variable distances from the macrocyclic moiety have been synthesized and analyzed. The ligands were made by straightforward four-step synthetic procedures and purified with preparative RP-HPLC, after which they were used to prepare gadolinium(III) and europium(III) complexes. Relaxometric experiments were performed on the Gd(III) complexes at 300 MHz, varying the pH of the solutions or the concentration of human serum albumin (HSA). It was found that when the pH of the medium was changed from neutral to pH 4 the longitudinal relaxivity of GdDO3A-ethylphosphonate and GdDO3A-propylphosphonate complexes increased by 50% and 60%, respectively. Diethyl esters of these complexes did not change longitudinal relaxivity in the same pH range but their transverse relaxivity increased upon binding to HSA. 31P NMR experiments on Eu(III) complexes showed a change in the chemical shift of both acid complexes in the same region where the highest relaxivity changes were observed and proved the stability of the complexes in the investigated pH range, while no shift was observed for the diester complexes. Luminescence studies on europium(III) complexes additionally supported observations obtained by NMR methods. The change in the form of the luminescence emission spectra, and the reduction in the q value upon addition of HSA proved the ternary adduct formation between the charge neutral diester complexes and HSA. Similarly, the change in the emission spectra showing a phosphonate bound structure at pH 7 to a species where the phosphonate oxygen is not coordinated at pH 4 in parallel with the increase of q value is supporting the hypothesis that the deprotonation of phosphonates is the main reason for the distinct relaxivity change from slightly acidic to the neutral solution media.     

Static and dynamic stability modeling of a capacitive FGM micro-beam in presence of temperature changes

Stability of a functionally graded (FG) micro-beam, based on modified couple stress theory (MCST), subjected to nonlinear electrostatic pressure and thermal changes regarding convection and radiation, is the main purpose of this paper. It is assumed that the functionally graded beam, made of metal and ceramic, follows the volume fraction definition and law of mixtures, and its properties change as an exponential function through its thickness. By changing the ceramic constituent percent of the bottom surface, five different types of the micro-beams are investigated. The static pull-in voltages in presence of temperature changes are obtained by using step-by-step linearization method (SSLM) and, by adapting Runge–Kutta approach, the dynamic pull-in voltages are obtained numerically. Though the temperature distribution through the thickness of FG micro-beam (due to its too small measurement) is considered uniform, owing to the different thermal expansions of layers, temperature changes cause deflection in the micro-beam, and consequently affect pull-in values. Hence the profound effects of different material constituent over the pull-in voltages are illustrated and it is graphically displayed that how in some cases neglecting components of the couple stress leads to inaccurate results.     

Structure-related variable responses of calcium sensitive MRI probes

A new series of Gd(3+) complexes based on DO3A (GdL(1)-GdL(4)) was synthesized and investigated. They possess side chains with different structures which determine their varying binding properties and response towards endogenous metal ions, measured by changes in the longitudinal relaxivity (r(1)). GdL(4) exhibits the highest selectivity toward Ca(2+) in comparison to the other complexes, with up to a 63% increase of the r(1). GdL(2) and GdL(3) also respond to different Ca(2+) concentration ranges, however with a lower selectivity since the r(1) changes are also observed in the presence of other cations such as Mg(2+), Zn(2+) or Cu(2+). Assessment of the hydration number (q) via luminescence lifetime measurements confirmed that the change in q is responsible for the r(1) response for all the complexes.