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The design and synthesis of selective copper(II) chelators
Havlík, Jan ; Kotek, Jan (advisor) ; Holzhauser, Petr (referee)
Title: Design and synthesis of selective copper(II) chelators Author: Jan Havlík Department: Department of Inorganic Chemistry, Faculty of Science Supervisor: assoc. prof. RNDr. Jan Kotek, Ph.D. Supervisor's e-mail address: modrej@natur.cuni.cz The aim of this work was to prepare selective copper(II) chelators. Within the frame of this thesis were synthesized 13 compounds, from which 7 are new. All compounds were fully characterized by NMR spectroscopy and mass spectrometry. Copper(II) complex of synthesized ligand 1,11-bis(methylphosphinic acid)cyclam, (1,11-dipin), was studied in thermodynamic and formation/decomplexation studies. For 1,11-dipin-copper(II) complex were determined values of rate constants and activation parameters. Keywords: selective chelator, copper, cyclam derivatives, macrocyclic ligands, methylphosphonate, methylphosphinate
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Ditopic ligand based on 1,4,7-triazacyclononane
Kačmarčík, Jaroslav ; Kubíček, Vojtěch (advisor) ; Kotek, Jan (referee)
The radioisotopes 64 Cu and 68 Ga are used in radiomedicine and imaging (PET) due to their properties. The metal ion must be complexed with a suitable ligand forming a stable and kinetically inert complex. The aim of this bachelor thesis was to synthesize polydentate ligand based on the TACN macrocycle, followed by the preparation of its gallium (III) and copper (II) complexes. Based on the dependence of absorbance A on the wavelength λ, d-d transitions in the VIS (λ = 440 - 800 nm) region and CT transitions with transitions on the aromatic cycle in the UV region (λ = 220 - 380 nm) for the [Cu(L)] were also observed. The [Cu(L)] complex was studied by UV-VIS titration. The complex [Ga(L)] was also synthesized, but its further characterization and study of coordination properties were not carried out. Key words: macrocyclic ligands, complexes, stability, radiomedicine, PET
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Zirconium ternary complexes with fluoride anions
Zach, Kamil - Lukáš ; Kubíček, Vojtěch (advisor) ; Schulz, Jiří (referee)
Modern medicine uses non-invasive imaging methods for diagnostic purposes. Positron emission tomography is one of them. During the examination, the patient is injected with a radiopharmaceutical that is accumulated in tissue abnormalities and emits detectable radiation during its nuclear decay. The world's most commonly used radionuclide for these purposes is the radioisotope 18 F. The biodistribution of the fluoride ion itself is not very specific, so the radioisotope is usually bound to the structure of bioactive molecules. The actual preparation of these molecules is very challenging, so new labeling methods are currently being sought. One of the new possibilities is the preparation of labeled ternary complexes. In this work, the preparation of two polyazamacrocyclic ligands, H3NOTA and H3PCTA, which have acetate arms attached to their skeleton via aliphatic nitrogen atoms, is described. Zirconium complexes were prepared with these ligands. Subsequently, coordination and dissociation studies of fluoride ions to the prepared complexes were carried out. The measurements were monitored with a fluoride ion selective electrode. Both kinetic and thermodynamic aspects of coordination and decoordination were investigated in the measurements. Furthermore, characterization of the prepared ternary...
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Macrocycles and complexation of large metal cations
Faltejsek, Jan ; Hermann, Petr (advisor) ; Drahoš, Bohuslav (referee)
In the last years, radioisotopes of heavy elements from the bottom of the Periodic Table have been increasingly used in nuclear medicine with focus on alpha-therapy. These large metal ions demand ligands fulfilling their special requirements. Complexes of polyazamacrocyclic ligands have been used in radiomedicine for a long time as diagnostic and therapeutic agents. This work aims to con- tribute to understanding of coordination chemistry of large macrocycles toward large metal ions. Thus, this work deals with structural studies, formation and decomplexation kinetics of Ln(III)-H4pyta complexes employing X-ray solid-state and solution NMR/UV-Vis spectroscopic data. The H4pyta is a 18-membered hexaazamacrocycle formed by two pyridine units and four amine groups which are modified with four acetate pendant arms. In the solid state, several isomeric complexes were structu- rally characterized. Large Ln(III) ions form decacoordinated species with two and two acetates on each side of the macrocyclic N6-plane. Small Ln(III) binds the ligand in a nonadentate fashion with one pendant non-coordinated. In the middle of lanthanide series, both isomers were characterized for several Ln(III) ions. Formation of the complexes takes place in a three-step mechanism with fast formation of an out-of-cage intermediate...
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Ligand design for medicinal applications
Paúrová, Monika ; Kotek, Jan (advisor) ; Trávníček, Zdeněk (referee) ; Řezanka, Pavel (referee)
In recent years, copper radioisotopes have been extensively studied for their suitable coordination and physical properties. Nuclides 61 Cu, 64 Cu and 67 Cu are used in nuclear medicine - in diagnostic as well as in therapeutic applications. The aim of the Thesis is a study of the coordination properties of divalent copper as a stepping stone for the next potential applications. The presented Thesis consists of two thematic parts. The first part deals with the synthesis of cyclam derivatives. Sixteen new macrocyclic ligands with different phosphorus acid coordinating pendant arms (phosphinate, phosphonate, germinal P-C-P) were prepared; an analogous ligand endowed by carboxylic acid pendant arm as well as tetramethylcyclam without coordinating arm were prepared for comparison. The influence of the nature of coordinating acid pendant arms on selectivity and on the rate of copper(II) complexation was studied in detail. The protonation constants of the free ligands and the stability constants of the complexes with selected transition metal ions were determined by potentiometric titrations and by 1 H and 31 P NMR spectroscopy. Kinetic properties - i.e. studies of the formation rate and kinetic inertness of the copper(II) complexes - were performed by UV-Vis spectroscopy. The formation kinetics of the selected...
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Synthesis of unsymmetric DOTA derivatives and study of their complexes
Obuch, Jakub ; Hermann, Petr (advisor) ; Drahoš, Bohuslav (referee)
Lanthanide(III) complexes are compounds with both diagnostic and therapeutic applications. For diagnostic applications, they are used as contrast agents for imaging techniques such as MRI, PET or SPECT. In therapy, complexes of beta or alpha particle- emitting radionuclides are used. If the complexes contain protonable groups, their behaviour is dependent on pH of the solution. Protonation of these groups should occur close to the physiological pH. If the efficiency (relaxivity) of the MRI contrast agent is dependent on protonation state, this method can be used for determination of pH of tissues in vivo. For radiopharmaceuticals, fast complexation of short-lived metal radionuclides is important and protonation might significantly accelerate the complex formation. For therapeutic applications, possibility of labelling at low temperatures when heat-sensitive biovectors (e.g. antibodies) do not decompose. To assess the effect of protonation of amino group in the vicinity of the metal ion, amino-bis(phosphinate) pendant arm was proposed, where the dissociation constant of the amino group below the physiological pH can be expected. Three ligands containing this group and DO3A fragment were prepared and their complexes were studied to assess aforementioned possible uses in medicine. Their structure and...
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Fluorinated macrocycles for 19F MRI
Šmelko, Andrej ; Hermann, Petr (advisor) ; Blahut, Jan (referee)
19 F MRI contrast agents are relatively new, developing field of medical and chemical sciences. In this Theses, based on previous results in this area, new type of Ni2+ complex with possible 19 F MRI applications was synthesized and characterized by relaxometric measurements.
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Large macrocycles and their complexes
Faltejsek, Jan ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Macrocyclic ligands have been used in radiomedicine for a long time. These ligands have been studied mainly in terms of complexation of heavy metal ions and possible use of these com- plexes in diagnostics and radiotherapy. Recent studies have highlighted the potential use of actinium-225 as an alpha-emitting radionuclide. This isotope is suitable for a precise treatment of micrometastases as it emits a cascade of high-energy but short-range alpha radiation. Due to the high linear energy transfer of the emitted particles, the tumor cells at a given location in the patient's body are completely destroyed. This work deals with the preparation and char- acterization of 18-membered polyazamacrocyclic ligands that can be used for complexation of this radioisotope. The prepared substances were characterized by potentiometry, NMR, MS and EA. Thermodynamic data of the complexes of these ligands with "model" heavy metal ions (Ca2+ , Sr2+ and Ba2+ ) were obtained using potentiometry. For cerium(III) complexes with prepared ligands, the pH-dependent kinetics of their formation were studied, and the results of these measurements indicate the possibility of using these ligands in radiomedicine. Keywords: macrocyclic ligands, heavy metal complexes, radiotherapy 1
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Complexes of cyclen-based macrocyclic ligands with a phosphinate pendant arm
Urbanovský, Peter
Lanthanide(III) complexes of DOTA derivatives are utilized in the medical imaging techniques such as magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS), nuclear imaging (PET and SPECT), or optical methods (luminescence). It has been shown that relaxometric parameters of the Gd(III) complexes of DOTA derivatives with a phosphinic acid pendant arm (Gd-DO3APR ) can reach optimal values (e.g. water residence time, τM, being close to ~10 ns). The relaxometric parameters can be further modified through the phosphorus substituents. It is also known that the complexes possess a high thermodynamic stability and they are kinetically inert. The main goal of this Thesis is an investigation of the effect of pendant amino group protonation in substituents bound to the phosphorus atom on properties of the complexes. Thus in this Thesis, DOTA derivatives with the phosphinic acid pendant arm with an amino group and their complexes were prepared and characterized. The complexes are intended as contrast agents for molecular imaging techniques (mainly for MRI and 31 P MRS). The first part of the Thesis introduces two new versatile "phospha-Mannich" protocols performed under mild conditions. Amino-H-phosphinic acids (AHPAs) were synthesized with excess of...
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Macrocyclic ligands for selective complexation of large cations
Šefčík, Martin ; Kotek, Jan (advisor) ; Vojtíšek, Pavel (referee)
4 Abstract Nowadays, macrocyclic complexes of actinides receive an increasing attention for their potential applications in radiotherapy. It requires significant demands on their thermodynamic and kinetic stability which are particularly influenced by an appropriate choice of a ligand. This Thesis focuses on a synthesis and characterization of two ligands that are potentially applicable for complexation of lanthanum as a model of radioactive actinium. Both ligands are based on a fifteen-membered cycle containing pyridine group, 15-pyN3O2. The first ligand, H4L1, contains two phosphonate pendant arms. The second ligand, H2L2, contains two phosphinate pendant arms. Both compounds were prepared and characterized. Keywords Macrocyclic ligands, large cations, phosphonic acids, phosphinic acids, dissociation constants
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