Methylthiazolyl Tacn Ligands for Copper Complexation and Their Bifunctional Chelating Agent Derivatives for Bioconjugation and Copper-64 Radiolabeling: An Example with Bombesin
| Autor: | Véronique Patinec, Luís M. P. Lima, Nicolas Le Poul, Amaury Guillou, Raphaël Tripier, David Esteban-Gómez, Carlos Platas-Iglesias, Rita Delgado, Mark Bartholomä |
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| Přispěvatelé: | Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Departamento de Química Fundamental, Universidade da Coruña, Department of Nuclear Medicine, Saarland University [Saarbrücken] |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular 64Cu-labeling Potentiometric titration Molecular Conformation chemistry.chemical_element [CHIM.THER]Chemical Sciences/Medicinal Chemistry Conjugated system Ligands radiopharmaceutical 010402 general chemistry 01 natural sciences Inorganic Chemistry bifunctionalization chemistry.chemical_compound Piperidines [CHIM.COOR]Chemical Sciences/Coordination chemistry Chelation Physical and Theoretical Chemistry Bifunctional Chelating Agents Aza Compounds methylthiazolyl Bioconjugation [CHIM.ORGA]Chemical Sciences/Organic chemistry 010405 organic chemistry Water tacn Hydrogen-Ion Concentration Combinatorial chemistry Copper 0104 chemical sciences Copper Radioisotopes chemistry Isotope Labeling Quantum Theory Bombesin Chemical stability Copper-64 |
| Zdroj: | Inorganic Chemistry Inorganic Chemistry, American Chemical Society, In press, ⟨10.1021/acs.inorgchem.8b03280⟩ |
| ISSN: | 1520-510X 0020-1669 |
| DOI: | 10.1021/acs.inorgchem.8b03280 |
| Popis: | International audience; We present here the synthesis of two new bifunctionalized azachelators, no2th-EtBzNCS and Hno2th1tha, as bioconjugable analogues of two previously described di- and trimethylthiazolyl 1,4,7-triazacyclononane (tacn) ligands, no2th and no3th, for potential uses in copper-64 (64Cu) positron emission tomography imaging. The first one bears an isothiocyanate group on the remaining free nitrogen atom of the tacn framework, while the second one presents an additional carboxylic function on one of the three heterocyclic pendants. Their syntheses required regiospecific N-functionalization of the macrocycles. In order to investigate their suitability for in vivo applications, a complete study of their copper(II) chelation was performed. The acid–base properties of the ligands and their thermodynamic stability constants with copper(II) and zinc(II) cations were determined using potentiometric techniques. Structural studies were conducted in both solution and the solid state, consolidated by theoretical calculations. The kinetic inertness in an acidic medium of both copper(II) complexes was determined by spectrophotometry, while cyclic voltammetry experiments were performed to evaluate the stability at the copper(I) redox state. UV–vis, NMR (of the zinc complexes), electron paramagnetic resonance spectroscopy, and density functional theory studies showed excellent agreement between the solution structures of the complexes and their crystallographic data. These investigations unambiguously prove that these bifunctional derivatives display similar coordination properties as their no2th and no3th counterparts, opening the door to targeted bioapplications. The no2th-EtBzNCS and Hno2th1tha ligands were then conjugated to a bombesin antagonist peptide for targeting the gastrin-releasing peptide receptor (GRPr). To highlight the potential of the two chelators for radiopharmaceutical development, the 64Cu-radiolabeling properties, in vitro stability, and binding affinity to GRPr of the corresponding bioconjugates were determined. Altogether, the results of this work warrant the further development of 64Cu-based radiopharmaceuticals comprising our novel bifunctional chelators. |
| Databáze: | OpenAIRE |
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