Design, Synthesis and Characterization of Zinc-sensitive or dual-modal Probes for Optical and Magnetic Resonance Imaging

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Dokumentart: Dissertation
Date: 2021-04-27
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Chemie
Advisor: Scheffler, Klaus (Prof. Dr.)
Day of Oral Examination: 2021-03-11
DDC Classifikation: 540 - Chemistry and allied sciences
Other Keywords:
Lanthanide complex, molecular imaging, Luminescence, paraCEST, Zinc-sensitive
License: Publishing license including print on demand
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Optical imaging (OI) and magnetic resonance imaging (MRI) are powerful molecular imaging techniques widely used in biomedicine and neuroscience. To date, various image-contrast-enhancing molecular sensors have been developed to improve the functional and anatomical visualization of body structures and fluids. Zn(II) plays a fundamental role in many essential biological processes. The noninvasive determination of Zn(II) concentration fluctuations is of paramount importance for understanding its biological role and improve early-stage disease detection. To the best of our knowledge, the OI/MRI combined imaging sensors are much less studied. Aiming to expand research in this field, the efforts towards preparing Ln(III)-based probes sensitive to Zn(II) for MRI/OI dual-modal imaging are described in this thesis. The first part of this thesis begins with an introduction of non-responsive optical probes EuL1-2 consisting of a DO3A-based reporting moiety linked to a Tyr-derived chromophore. Further structural modifications of EuL1-2 include the introduction of a Zn-sensitive DPA moiety, resulting in the Zn-sensitive probes EuL3-4. These novel compounds exhibited strong selectivity to Zn(II) over other studied cations, and demonstrated an up to 7-fold luminescence enhancement. The induced luminescence change enables establishing EuL3-4 as viable Zn-chemosensors for biological applications. Based on the first project on optical probes, the Gd(III) analogues of EuL3-4, GdL3-4, were prepared and evaluated by means of NMR. It showed that both complexes displayed negligible sensitivity to Zn(II) in r1 relaxivity. In order to improve the sensitivity, GdL3-4 were subjected to further modifications. Thus, the phenolic OH group was converted into phenoxyacetic acid providing GdL5-6. These modifications led to a large r1 relaxivity enhancement (~280%) upon the addition of Zn(II) under physiologically relevant conditions. The detailed evaluation of GdL5-6 properties by means of various NMR experiments in HEPES, PBS, HSA and serum accompanied by MRI phantoms, evidenced their outstanding sensitivity to Zn(II). This makes GdL5-6 complexes potential agents for biological applications. In the third part, I focused on combining two different OI and MRI modalities into one entity. Thus, a trimacrocyclic chelator L7 bridged by DA18C6 moiety was designed and synthesized. Its dinuclear Eu(III) complex Eu2L7 displayed a CEST effect, which is typical for EuDOTAM-Gly. Upon metalation of the remaining DA18C6 chelator with Tb(III), the complex converted into a hetero-multinuclear Eu2L7Tb. This mixed lanthanide complex showed interesting emission properties at different excitation wavelengths. Overall, this system paves the way towards the development of bimodal imaging probes with controlled properties.

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