13 results on '"Starke, Miriam"'
Search Results
2. 64Cu tumor labeling with hexadentate picolinic acid‐based bispidine immunoconjugates.
- Author
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Kubeil, Manja, Neuber, Christin, Starke, Miriam, Arndt, Claudia, Rodrigues Loureiro, Liliana, Hoffmann, Lydia, Feldmann, Anja, Bachmann, Michael, Pietzsch, Jens, Comba, Peter, and Stephan, Holger
- Subjects
ANTIBODY-toxin conjugates ,RADIOCHEMICAL purification ,ANIMAL experimentation ,STEM cells ,LABORATORY rats ,ETHYLENEDIAMINETETRAACETIC acid - Abstract
Discussed are two picolinate appended bispidine ligands (3,7‐diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis‐pyridine derivative, which are all known to strongly bind CuII. The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with 64CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the 64Cu‐bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both 64Cu‐labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl‐NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS‐functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor‐bearing mice showed specific accumulation of the 64Cu‐labeled TMs in PSCA‐ and FAP‐overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. First-Generation Bispidine Chelators for ²¹³BiIII Radiopharmaceutical Applications
- Author
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Bruchertseifer, Frank, Comba, Peter, Martin, Bodo, Morgenstern, Alfred, Notni, Johannes, Starke, Miriam, and Wadepohl, Hubert
- Subjects
Medizin - Abstract
Hepta- and octadentate bispidines (3,7-diazabicyclo[3.3.1]nonane, diaza-adamantane) with acetate, methyl-pyridine, and methyl-picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate BiIII coordination chemistry. Crystal structure and solution spectroscopic data (NMR spectroscopy and mass spectrometry) confirm that the rigid and relatively large bispidine cavity with an axially distorted geometry is well suited for BiIII and in all cases forms nine-coordinate complexes; this is supported by an established hole size and shape analysis. It follows that nonadentate bispidines probably will be more suited as bifunctional chelators for ²¹³BiIII-based radiopharmaceuticals. However, two isomeric picolinate-/acetate-based heptadentate ligands already show very efficient complexation kinetics with ²¹³BiIII at ambient temperature and kinetic stability that is comparable with the standard ligands used in this field. The experimentally determined hydrophilicities (log D₇.₄ values) show that the BiIII complexes reported are relatively hydrophilic and well suited for medicinal applications. We also present a very efficient and relatively accurate method to compute charge distributions and hydrophilicities, and this will help to further optimize the systems reported here.
- Published
- 2020
4. First‐Generation Bispidine Chelators for 213 Bi III Radiopharmaceutical Applications
- Author
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Bruchertseifer, Frank, primary, Comba, Peter, additional, Martin, Bodo, additional, Morgenstern, Alfred, additional, Notni, Johannes, additional, Starke, Miriam, additional, and Wadepohl, Hubert, additional
- Published
- 2020
- Full Text
- View/download PDF
5. Synthese und Charakterisierung neuer Bispidin- Liganden und ihrer Metall-Komplexe für die radiopharmazeutische Anwendung
- Author
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Starke, Miriam
- Subjects
540 Chemistry and allied sciences - 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.
- Published
- 2019
6. First‐Generation Bispidine Chelators for 213BiIII Radiopharmaceutical Applications.
- Author
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Bruchertseifer, Frank, Comba, Peter, Martin, Bodo, Morgenstern, Alfred, Notni, Johannes, Starke, Miriam, and Wadepohl, Hubert
- Published
- 2020
- Full Text
- View/download PDF
7. Optimization of Hexadentate Bispidine Ligands as Chelators for 64 CuII PET Imaging
- Author
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Comba, Peter, primary, Starke, Miriam, additional, and Wadepohl, Hubert, additional
- Published
- 2018
- Full Text
- View/download PDF
8. Bispidines for radiopharmaceuticals
- Author
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Comba, Peter, primary, Kerscher, Marion, additional, Rück, Katharina, additional, and Starke, Miriam, additional
- Published
- 2018
- Full Text
- View/download PDF
9. Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions
- Author
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Comba, Peter, primary, Jermilova, Una, additional, Orvig, Chris, additional, Patrick, Brian O., additional, Ramogida, Caterina F., additional, Rück, Katharina, additional, Schneider, Christina, additional, and Starke, Miriam, additional
- Published
- 2017
- Full Text
- View/download PDF
10. Optimization of Hexadentate Bispidine Ligands as Chelators for 64CuII PET Imaging.
- Author
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Comba, Peter, Starke, Miriam, and Wadepohl, Hubert
- Subjects
- *
PYRIDAZINES , *LIGANDS (Chemistry) , *TERTIARY amines , *SINGLE crystals , *CRYSTAL structure - Abstract
The coordination chemistry of the hexadentate bispidine ligand L1 with three pyridine, one pyridazine, and two tertiary amine donors with CuII and ZnII is reported. The substitution of one of the two cis-disposed pyridine donors in-plane with the two tertiary amines of the bispidine backbone by a pyridazine group was predicted to substantially reduce distortion from planarity of the tetradentate subunit and therefore was assumed to lead to higher CuII complex stability. The X-ray single-crystal structures of the ZnII and CuII complexes, which are in excellent agreement with the DFT- and MM-optimized structures, confirmed this prediction but indicated that deviation from planarity is appreciable. This also emerges from solution spectroscopy (UV/Vis/NIR and EPR of the CuII complex), which indicated that the in-plane ligand field is only slightly increased. The geometric parameters together with the lower basicity of pyridazine versus pyridine (pKa=2.33 vs. 5.23) are also in agreement with an only slightly more negative redox potential of the CuII/I couple (E0=-780 vs. -760 mV, MeCN, vs. Fc/Fc+), and the potentiometrically determined CuII stability constant with L1 is slightly lower than that with the parent ligand L2 (log K=12.7 vs. 14.5). Therefore, modification of the donor groups is a more promising approach to increasing the stabilities of these complexes and yields 64CuII chelators that outperform known hexadentate bispidine ligands. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
11. 64 Cu tumor labeling with hexadentate picolinic acid-based bispidine immunoconjugates.
- Author
-
Kubeil M, Neuber C, Starke M, Arndt C, Rodrigues Loureiro L, Hoffmann L, Feldmann A, Bachmann M, Pietzsch J, Comba P, and Stephan H
- Subjects
- Animals, Rats, Humans, Mice, Tissue Distribution, Radiopharmaceuticals chemistry, Ligands, Male, Positron-Emission Tomography, Coordination Complexes chemistry, Bridged Bicyclo Compounds, Heterocyclic, Picolinic Acids chemistry, Copper Radioisotopes chemistry, Rats, Wistar, Immunoconjugates chemistry, Immunoconjugates pharmacokinetics
- Abstract
Discussed are two picolinate appended bispidine ligands (3,7-diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis-pyridine derivative, which are all known to strongly bind Cu
II . The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with64 CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the64 Cu-bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both64 Cu-labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl-NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS-functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor-bearing mice showed specific accumulation of the64 Cu-labeled TMs in PSCA- and FAP-overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)- Published
- 2024
- Full Text
- View/download PDF
12. Optimization of Hexadentate Bispidine Ligands as Chelators for 64 Cu II PET Imaging.
- Author
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Comba P, Starke M, and Wadepohl H
- Abstract
The coordination chemistry of the hexadentate bispidine ligand L
1 with three pyridine, one pyridazine, and two tertiary amine donors with CuII and ZnII is reported. The substitution of one of the two cis-disposed pyridine donors in-plane with the two tertiary amines of the bispidine backbone by a pyridazine group was predicted to substantially reduce distortion from planarity of the tetradentate subunit and therefore was assumed to lead to higher CuII complex stability. The X-ray single-crystal structures of the ZnII and CuII complexes, which are in excellent agreement with the DFT- and MM-optimized structures, confirmed this prediction but indicated that deviation from planarity is appreciable. This also emerges from solution spectroscopy (UV/Vis/NIR and EPR of the CuII complex), which indicated that the in-plane ligand field is only slightly increased. The geometric parameters together with the lower basicity of pyridazine versus pyridine (pKa =2.33 vs. 5.23) are also in agreement with an only slightly more negative redox potential of the CuII/I couple (Eo =-780 vs. -760 mV, MeCN, vs. Fc/Fc+ ), and the potentiometrically determined CuII stability constant with L1 is slightly lower than that with the parent ligand L2 (log K=12.7 vs. 14.5). Therefore, modification of the donor groups is a more promising approach to increasing the stabilities of these complexes and yields64 CuII chelators that outperform known hexadentate bispidine ligands., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2018
- Full Text
- View/download PDF
13. Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions.
- Author
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Comba P, Jermilova U, Orvig C, Patrick BO, Ramogida CF, Rück K, Schneider C, and Starke M
- Abstract
The synthesis of the octadentate bispidine ligand bearing two picolinic acid pendant arms (H
2 bispa2 ), and its coordination chemistry with radionuclides relevant for nuclear medicine, namely indium(III) (111 In), lutetium(III) (177 Lu), and lanthanum(III) (as surrogate for225 Ac), are reported. The non-radioactive metal complexes of the N6 O2 -type bispa ligand were characterized by1 H and13 C NMR spectroscopy, elemental analysis, mass spectrometry and single-crystal X-ray analysis. Experimental structural data, computational analysis, complex stabilities determined by potentiometric titration, and "radiostabilities" determined by competition studies in the presence of human serum reveal complex stabilities of H2 bispa2 comparable to those of the macrocyclic "gold standard" DOTA. After an incubation time of 1 day, 86 and 87 % of [177 Lu(bispa2 )]+ and [177 Lu(DOTA)]- , respectively, remain intact. Importantly, unlike DOTA, H2 bispa2 is radiolabeled quantitatively with111 InIII and225 AcIII under ambient conditions, which is an essential aspect when working with heat-sensitive antibodies as targeting vectors. In the case of111 InIII , room temperature radiolabeling of H2 bispa2 yields molar activities as high as 70 MBq nmol-1 within 10 minutes. These are promising results for radiopharmaceutical applications of H2 bispa2 ., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
- Full Text
- View/download PDF
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