Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain. Upon interaction with Ca2+, they exhibit high and reversible relaxivity changes in buffered solution or in a model of the brain extracellular medium. These efficient Ca2+ magnetic resonance imaging sensors might open new perspectives in functional molecular imaging
Here we report on a dual-modal (19) F and (1) H MRI paramagnetic probe with a self-immolative linker, Gd-DOMF-Gal. The enzymatic conversion of this probe by β-galactosidase resulted in a simultaneous turning on of the fluorine signal and changed ability of the Gd(3+) complex to modulate the (1) H MR signal intensity of the surrounding water molecules. A versatile imaging platform for monitoring a variety of enzymes by (19) F and (1) H MRI using this molecular design is proposed.
Contrast agents for magnetic resonance imaging (MRI) that exhibit sensitivity toward specific ions or molecules represent a challenging but attractive direction of research. Here a Gd 3þ complex linked to an aminobis(methylenephosphonate) group for chelating Ca 2þ was synthesized and investigated. The longitudinal relaxivity (r 1 ) of this complex decreases during the relaxometric titration with Ca 2þ from 5.76 to 3.57 mM -1 s -1 upon saturation. The r 1 is modulated by changes in the hydration number, which was confirmed by determination of the luminescence emission lifetimes of the analogous Eu 3þ complex. The initial in vivo characterization of this responsive contrast agent was performed by means of electrophysiology and MRI experiments. The investigated complex is fully biocompatible, having no observable effect on neuronal function after administration into the brain ventricles or parenchyma. Distribution studies demonstrated that the diffusivity of this agent is significantly lower compared with that of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA).
Calcium-sensitive MRI contrast agents can only yield quantitative results if the agent concentration in the tissue is known. The agent concentration could be determined by diffusion modeling, if relevant parameters were available. We have established an MRI-based method capable of determining diffusion properties of conventional and calcium-sensitive agents. Simulations and experiments demonstrate that the method is applicable both for conventional contrast agents with a fixed relaxivity value and for calcium-sensitive contrast agents. The full pharmacokinetic time-course of gadolinium concentration estimates was observed by MRI before, during and after intracerebral administration of the agent, and the effective diffusion coefficient D* was determined by voxel-wise fitting of the solution to the diffusion equation. The method yielded whole brain coverage with a high spatial and temporal sampling. The use of two types of MRI sequences for sampling of the diffusion time courses was investigated: Look-Locker-based quantitative T(1) mapping, and T(1) -weighted MRI. The observation times of the proposed MRI method is long (up to 20 h) and consequently the diffusion distances covered are also long (2-4 mm). Despite this difference, the D* values in vivo were in agreement with previous findings using optical measurement techniques, based on observation times of a few minutes. The effective diffusion coefficient determined for the calcium-sensitive contrast agents may be used to determine local tissue concentrations and to design infusion protocols that maintain the agent concentration at a steady state, thereby enabling quantitative sensing of the local calcium concentration.
A molecule bearing a macrocyclic DOTA-type chelator and an acyclic chelator based on the 5-aminoisophthalamide diethylenediaminetetraacid (5A-PADDTA) was synthesized by linking these two moieties via an amide bond. The ligand has the possibility to complex two identical or different lanthanide ions, depending on the desire for its potential application. Luminescence studies involving titrations of the Eu(3+) or Gd(3+) complex with Tb(3+) confirm the formation of heterometallic complexes, as well as the presence of different species in the solution. Comparative (1)H NMR spectra of the ligand, its Eu(3+) complex, and that containing both Eu(3+) and Tb(3+) proves the existence of respective monometallic or bimetallic species. NMR diffusion measurements on 5A-PADDTA as a model compound indicate the formation of aggregates upon the addition of Y(3+) (chosen as a diamagnetic analogue of lanthanide ions). Hydration values were calculated from the respective luminescence lifetime values. They show the dominance of a q = 1 species for both ions in monometallic complexes, or q = 1 and q = 2 species of ions in aggregated complexes, for DOTA and 5A-PADDTA chelators, respectively.
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