Design, synthesis and evaluation of smart probes for magnetic resonance imaging - calcium selective contrast agents for tracking of neural activity
Final Report Abstract
The aim of this project was to develop 'smart' biochemical functional markers, in particular macrocyclic contrast agents that are sensitive to local change in extracellular calcium. Their utilization could enable detection of neuronal activity in real time by translating it into changes in MR contrast. The direct visualization of neural activation, independent of the state of the vascular system, could lead to the introduction of novel type of functional magnetic resonance imaging (fMRI) methodology. We have successfully synthesized several macrocyclic lanthanide complexes which possess calcium chelators. A wide range of convenient synthetic routes was applied to obtain the monomacrocyclic complexes. Moreover, a new synthetic route for preparation of bismacrocyclic chelates is developed. It should be expected that it overcomes usual difficulties in the preparation of these complex systems. Following their preparation, the structural, physicochemical and biophysical characterization of new agents was performed. The majority alter their magnetic properties along with changes of calcium concentration. In addition to the T1 responsive agents, the first example of a calcium-sensitive PARACEST agent was developed and thoroughly studied. Certain systems did not respond to varying Ca2+ concentrations. Nevertheless, due to the presence of chromophores in their final structures, these molecules showed great potential to be used as multimodal agents for simultaneous MR and optical imaging, or for optical imaging at two different wavelengths. Further sophisticated in vitro experiments using a system that mimics living tissue by growing fibroblast cells culture embedded in a gel matrix are currently being performed and their results will be reported in due course. Initial findings reveal a change in T1 upon the alteration of relevant extracellular Ca2+ concentrations. The potential for ultimate in vivo MRI application of these agents will be established soon. The initial set of in vivo experiments has been performed and published, while further characterization is ongoing where optimized protocols and procedures for MRI pulse sequences and data analysis are applied. To achieve the final goal, a strong interplay between chemistry, biology, medicine, and engineering is necessary. Various chemistry disciplines such as inorganic, coordination, organic, medicinal, or biochemistry, along with spectroscopy, are central to this research and play a crucial role offering many valuable findings for the future.
Publications
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"In Vivo Characterization of a Smart MRI Agent That Displays an Inverse Response to Calcium Concentration". ACS Chem. Neurosci. 2010, 1, 819-828
I. Mamedov, S. Canals, J. Henig, M. Beyerlein, Y. Murayama, H. A. Mayer, N. K. Logothetis, G. Angelovski
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"Synthesis and Characterization of Dinuclear Heterometallic Lanthanide Complexes Exhibiting MRI and Luminescence Response." Dalton Trans. 2010, 39, 5721-5727
I. Mamedov, T. N. Parac-Vogt, N. K. Logothetis, G. Angelovski
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"A straightforward and convenient pathway for the synthesis of functional bismacrocyclic ligands." Tetrahedron Lett. 2011, 52, 1619-1622
P. Kadjane, N. K. Logothetis, G. Angelovski
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"An arylphosphonate appended macrocyclic platform for lanthanide based bimodal imaging agents." Chem. Commun. 2011, 47, 11534-11536
M. P. Placidi, J. Engelmann, L. S. Natrajan, N. K. Logothetis, G. Angelovski
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"Calcium-Responsive Paramagnetic CEST Agents". Bioorg. Med. Chem. 2011, 19, 1097-1105
G. Angelovski, T. Chauvin, R. Pohmann, N. K. Logothetis, E. Tóth
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"Cation-Responsive MRI Contrast Agents Based on Gadolinium(lll)". Curr. Inorg. Chem. 2011, 1, 76-90
G. Angelovski, I. Mamedov
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"Structure-related Variable Responses of Calcium Sensitive MRI Probes." Org. Biomol. Chem. 2011, 9, 5816-5824
I. Mamedov, N. K. Logothetis, G. Angelovski
