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  Synthetic Modifications of Responsive MRI Contrast Agents-Development of Multifunctional Conjugates for Novel Class of fMRI [Synthetische Modifizierung von Intelligenten MRI Kontrastmitteln-Entwicklung von Multifunktionalen Verbindungen für eine neuartige Klasse von fMRI]

Vibhute, S. (2013). Synthetic Modifications of Responsive MRI Contrast Agents-Development of Multifunctional Conjugates for Novel Class of fMRI [Synthetische Modifizierung von Intelligenten MRI Kontrastmitteln-Entwicklung von Multifunktionalen Verbindungen für eine neuartige Klasse von fMRI]. PhD Thesis, Eberhard-Karls-Universität, Tübingen, Germany.

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Vibhute, S1, 2, Author           
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1Department Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497798              
2Max Planck Institute for Biological Cybernetics, Max Planck Society, Spemannstrasse 38, 72076 Tübingen, DE, ou_1497794              

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 Abstract: Magnetic resonance imaging (MRI) using contrast agents has been widely employed in diagnostic imaging and basic research. Mostly to increase MR image contrast, positively Gd3+ based contrast agents are being utilized. In order to better understand biological processes responsive (smart) contrast agents (SCAs) which are able to report physiological changes by altering the MR signal have been developed. To overcome challenges such as localization, quantification, low MR signal etc. during routine in vivo applications of SCAs, one of the strategies is to conjugate such agents to various functional molecules such as dendrimers, nanoparticles, proteins or fluorescent tags. To attach reported SCAs to functional molecules efficient synthetic modifications of such SCAs retaining crucial physico-chemical properties are needed. The first part of thesis describes preparation and characterization of pH sensitive SCAs appended with a phosphonate pendant arm and either an aliphatic (GdL1) or aromatic linker (GdL2). The longitudinal relaxivity of GdL1 and GdL2 increases by 146% and 31%, respectively, when the pH decreases from 9 to 5. These two SCAs were converted to the biotinylated systems GdL3 and GdL4 and their interaction with avidin was investigated. The fluorescence displacement assay and MRI E-titrations revealed a 3:1 binding mode of GdL3–4 to avidin with the binding affinity as high as that of the parent avidin–biotin complex. The high binding affinity was confirmed with MRI by a competitive assay. The avidin–GdL3–4 complexes thus obtained exhibit changes in both r1 and r2 that are pH dependent. The results reveal a new pathway for the modification and improvement of SCAs to make them more suitable for in vivo applications. The second part of thesis presents synthetic modification of a reported Ca2+ responsive bismacrocyclic contrast agent. Modified SCA (Gd2L5) was obtained by inserting an aromatic linking moiety carrying a primary amine group for further derivatization of it. With 1.2 equiv of Ca2+ Gd2L5 exhibited 97% increase in longitudinal relaxivity. This indicates the relaxivity property is well retained in Gd2L5. The amino group from the linker of L5 was converted into an isothiocyanate group to obtain L6 which widens the use of this ligand since its reactive group can be utilized for efficient functionalization of L6. This probe provides a new opportunity to append it to functional molecules suitable for in vivo applications through its linker. The last chapter describes the synthesis of L5 using solid phase synthetic methodology applying pthalamide/tert-butyl chemistry. This is the first report to obtain such a bismacrocycle on solid support. This strategy was attempted to minimize the time consuming laborious purifications of polar intermediates in the liquid phase approach. With the successful demonstration of synthesis of L5, Ca2+ responsive bismacrocyclic ligand L7 carrying two aromatic linkers on each macrocycle has been synthesized. This synthetic strategy should allow to produce a large number of synthetic analogues to get a library of molecules within short time. Moreover, structural modulation on solid phase allows to insert different linkers as well as suitable tags to improve its in vivo applicability. Overall, efficient and easy labeling of DO3A based multi targeted contrast agents with a wide range of functional molecules are possible using the aforementioned strategies. Furthermore, this study provides promising pathways to develop multimodal responsive imaging agents for better biomedical applications.

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 Dates: 201320132013-04-22
 Publication Status: Published in print
 Pages: 178
 Publishing info: Tübingen, Germany : Eberhard-Karls-Universität
 Table of Contents: -
 Rev. Type: -
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 Degree: PhD

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