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 new bimodal and multivalent dendritic contrast agent (CA) that targets the protein avidin was prepared and characterized. The tripartite lysine core was used to link the ligand biotin, the fluorescent dye, and the dendron carrying GdDOTA (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelates for amplification of the magnetic resonance imaging (MRI) signal. The longitudinal relaxivity of this dendrimeric CA was greater than those of its GdDOTA chelate and most of the common commercial agents at the investigated high magnetic field (7 T). The capacity of the dendrimeric CA to bind to the target protein was confirmed by fluorescence measurements upon its treatment with NeutrAvidin–agarose gel or NeutrAvidin-coated microspheres and the results were compared with those of its monomeric analogue. The fluorescence intensity of monomer-treated targets was found to be greater than that from those treated with dendrimeric CA; however, a several-fold increase in the MRI signal was observed on the same samples treated with the dendrimeric CA. The inductively coupled plasma mass spectrometry analysis of the digested samples indicated somewhat higher Gd3+ content and hence slightly better binding of monomeric versus dendrimeric CA. This bimodal and multivalent targeted probe opens an avenue for the preparation of new nanosized CAs that allow high-resolution MRI of various targets, such as cellular receptors or specific cellular populations
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