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Synthese und Charakterisierung neuer Bispidin- Liganden und ihrer Metall-Komplexe für die radiopharmazeutische Anwendung

Starke, Miriam

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Abstract

Nuclear medicine offers various approaches and methods for using radiation for the diagnosis and therapy of different diseases, e.g. cancer. Imaging techniques such as positron emission tomography (PET) or therapeutic procedures such as radioimmunotherapy (RIT) use so-called tracers in which radio¬nuclides are linked to biomolecules as vector moieties (e.g. peptides or antibodies). These vectors specifically bind to the target tissue and allow imaging of a tumor in the body or inducing death of cancer cells. When using metallic radionuclides, these tracers contain a bifunctional chelator (BFC) which forms a stable complex and connects the metal ion to the desired vector. Due to the versatility of radiometals and their facile insertion into tracers by choosing a suitable BFC, the development and improvement of BFCs has become a constantly growing field of research. High stability of the metal-chelator complex is one of the major criteria for radio¬pharmaceutical application.

The work presented in this thesis is focused on the synthesis and experimental investigation of bispidine ligands, which form stable complexes with metal ions such as CuII, and thus represent suitable BFCs for the use in 64Cu positron emission tomography. Based on bispidine B1, which was already investigated for 64Cu-PET, ligand B2 was developed by substituting one of the pyridines with a pyridazine moiety and consequently reducing intraligand strain caused by pyridine-α-hydrogen atoms upon coordination. This was done in order to optimize the CuII complex geometry and enhance its stability. Coordination of B2 to CuII, NiII and ZnII was investigated, and comparison of CuII-B1 with CuII-B2 by different analytical methods did not show the expected increase in complex stability. The results suggest that the stabilizing effect of the optimized geometry is offset by the lower basicity and inferior donor properties of the modified substituent.

In the second part of this thesis, the promising chelator B4 was further developed into a 64Cu-PET tracer. B4 was functionalized at position C9-OH with a para-isothiocyanatobenzyl group (p-NCS-Bn) and linked to a peptide (TATE). Preliminary radiolabeling experiments of the functionalized ligand show its stability against EDTA as competing ligand, and give reason to expect promising in vitro and in vivo experiments of the ligand-peptide conjugate. The third part covers the investigation of heptadentate bispidine ligands for BiIII, whose isotopes 212Bi und 213Bi are suited for radiotherapy. Initially, DFT geometry optimizations were performed on BiIII complexes of various ligands with pyridyl, picolinate, carboxylate or phosphonate substituents at the tertiary amines of the bispidine platform. Of these, B7-B9 were synthesized and, as well as the literature-known octa¬dentate B3, were reacted with BiIII at room temperature. Single crystals of all complexes were obtained, and the X-ray structural analyses show either dimerization or coordination of a nitrate counter ion, resulting in coordination numbers of eight or nine. These findings suggest that the metal center is not coordinatively saturated with the hepta- and octadentate bispidines, and that therefore nonadentate bispidines could be a suitable choice for BiIII complexation.

Item Type: Dissertation
Supervisor: Comba, Prof. Dr. Peter
Date of thesis defense: 12 July 2019
Date Deposited: 23 Aug 2019 06:20
Date: 2019
Faculties / Institutes: Fakultät für Chemie und Geowissenschaften > Institute of Inorganic Chemistry
Subjects: 540 Chemistry and allied sciences
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