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Preparation of 64Cu and its prospective carriers for nuclear medicine.
Kozempel, Ján ; Lešetický, Ladislav (advisor) ; Kotek, Jan (referee) ; John, Jan (referee) ; Příhoda, Jiří (referee)
5 Summary The preparation of 64Cu including it's radiochemical separation and the preparation of its novel radiolabelled tracers intended for the use in nuclear medicine is described in this work. A novel method for the preparation of no carrier added 64Cu, based on the 64Zn(d,2p)64Cu reaction and consecutive dual ion exchange chromatography was developed. The radiochemical product was of high specific activity and with only 61Cu radionuiclidic impurity, which allows it's use for in vitro laboratory experiments or in vivo preclinical tests of labelled tracers. We have focused on the preparation of several 64Cu labelled tracers. Two different types - water soluble polymer carriers and hypoxia selective biacetyl bis- (N4-alkylthiosemicarbazone) complexes of 64Cu were prepared. The water soluble polymer carriers based on the copolymers of NIPAM, GM and HPMA bearing various chelating groups were prepared. The polymeric chain was modified by copolymerization of a monomer with chelating functional group or modified after polymerization. Two standard polyacidic chelators (DOTA, DTPA) as well as three non-common copper chelators (dipicolylamine, thiosemicarbazide, Ag ionophore II) were used. Their potential use in nuclear medicine for local radio- or combined ...
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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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pH-probes for Magnetic Resonance Imaging
Šrolerová, Tereza ; Kotek, Jan (advisor) ; Vojtíšek, Pavel (referee)
Macrocyclic ligands are known for their ability to bind paramagnetic lanthanide metal ions to form kinetically inert and thermodynamically stable complexes that can be used as contrast agents for MRI. This thesis deals with the study of new ligands derived from the known parent ligand H8DOTP - 1,4,7,10-tetraazacyclododecane with four pendant methylenephosphonate groups. The prepared new derivatives contain two different pairs of pendant groups, always in opposite positions of the macrocycle. One of the pairs are methylenephosphonate groups, the other pair are methylenephosphinate groups with different substituents on the phosphorus atom. Specifically, it is a compound with a P-H phosphinate group (H6DO2P2PH ), a phenyl group (H6DO2P2PPh ) and a trifluoroethyl group (H6DO2P2Ptfe ). The thesis describes the synthesis of the target ligands, the preparation of their complexes with paramagnetic ions Eu3+ and Yb3+ and their further study using NMR spectroscopy (pH NMR titration and relaxometric NMR measurements). Keywords: H4DOTA, H8DOTP, MRI, contrast agent, lanthanides, macrocyclic ligands, paramagnetic complexes
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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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Macrocyclic ligands and their complexes with metal ions for utilization in imaging methods
Hrček, Martin ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Currently, a number of methods, both diagnostic and therapeutic, find use in the field of nuclear medicine. The importance of macrocyclic ligands, capable of coordination of ions of employed metal radionuclides, is rising for both mentioned areas. Great potential lies in the area of the so-called theragnostics, i.e., drugs with both diagnostic and therapeutic functions. This thesis makes the first steps towards the concept of a theranostic ligand containing two macrocyclic coordinating centres, each individually optimised for coordinating radioisotopes of one metal ion. The coordination of Ga(III), currently used in diagnostics, is provided in the studied model system by a nine-membered macrocycle with phosphinate pendant arms. The coordination of Lu(III), currently used for radiotherapy, is provided by a twelve-membered macrocycle with phosphinate pendant arms. The results of the NMR measurements in this thesis show that the studied model system behaves in agreement with requirements placed upon the conceived drug. A macrocyclic ligand L1e, optimised for coordination of Lu(III), was prepared with the intended use in the synthesis of the proposed drug. H-phosphinic acids and a derivative of cyclene were also prepared as precursor compounds for a series of bifunctional ligands L1a - L1e. Keywords...
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Contrast agents for 19F magnetic resonance imaging
Dobrovolná, Tereza ; Kotek, Jan (advisor) ; Vojtíšek, Pavel (referee)
Complexes of transition metal ions with ligands containing fluorine atoms represent an interesting group of 19 F MRI contrast agents that could facilitate the diagnosis of various diseases. The presence of a paramagnetic metal ion in the vicinity of the 19 F nucleus results in shorter relaxation times and the possibility to obtain more NMR spectra in a given time, leading to better resolution. This work deals with the synthesis of the fluorinated macrocyclic ligand H3NOTPtfe , the preparation of its complexes with transition metal ions, their characterization and study by methods suitable for assessing their applicability in 19 F MRI, i.e. relaxometric NMR measurements and electrochemistry. The results show that the chosen concept is promising for 19 F MRI. The prepared complexes are applicable as 19 F MRI contrast agents, some even as redox active 19 F MRI "smart" contrast agents. The best properties were observed for the complex [Co(NOTPtfe )]− . Keywords: heteronuclear MRI, contrast agent, fluorine, PRE effect, spin relaxation, magnetic resonance imaging, paramagnetic complexes
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Coordinatively unsaturated complexes of macrocyclic amides
Mojžíšová, Adéla ; Kotek, Jan (advisor) ; Vojtíšek, Pavel (referee)
Growing number of citizens in developed countries suffers from neurodegenerative diseases. According to World Health Organization (WHO) dementias affect 55,2 million people and their incidence was doubled over last 20 years. Althought the number of cases is increasing, there is still no effective way for their diagnostics or treatment. With development of implantology, there are still common bacterial diseases as a result of formation of bacterial biofilms on unnatural surfaces. The development of synthetic nucleases which could prevent formation of biofilms is therefore one of the scientific aims. The aim of this bachelor thesis is preparation of polyazamacrocycles which contain amino and amidic functional groups. It can be assumed that these compounds will deprotonate amidic groups after coordination of copper(II) ion. These systems are designed to serve as agents for diagnostics of neurodegenerative diseases using positron emission tomography. In addition, as the complexes are coordinatively unsaturated, they can potentially show an artificial nucleases activity and ability to hydrolytically cleave bacterial biofilms.
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Electrochemistry of macrocyclic complexes
Kaďorková, Veronika ; Liška, Alan (advisor) ; Kotek, Jan (referee)
The present thesis summarizes fundamental electrochemical properties of copper(II) complexes derived from three cyclame-like macrocyclic ligands. Target application of the studied complexes is radioimaging in medicine. The complexes were studied by means of DC-polarography and cyclic voltammery on mercury hanging drop electrode in buffered media (0.1M sodium acetate, pH 5) upon mixing of the ligand and copper(II) sulfate stock solutions. All three complexes undergo a single two-electron irreversible reduction process yielding free ligand and copper amalgam. The apparent thermodynamic stability of the investigated complexes (expressed as negative shift of the observed reduction potentials relatively to copper(II) sulfate) correlates to structural motifs employed in the individual ligand molecules. Presence of the bridged moiety as well as the carboxylate group seems to enhance the overall stability whereas the phenolic oxygen atoms in role of donor atoms seem to be less efficient.
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Cyclam-based bifunctional ligands for selective metal ion complexation
Hörnerová, Alžběta ; Kotek, Jan (advisor) ; Havlíček, David (referee)
Recently, the increasing demand for targeting radiopharmaceuticals motiva- tes the research of bifunctional ligands which should be able to coordinate radiometal ion into a stable complex and also contains avalaible functional group for binding to a biological vector. Especially the wide range of copper radionuclides is sparking interest for potencial applications in diagnosis and therapy of tumorous diseases. The ligands of the cyclam family are one of the most suitable for Cu(II) complexation. Relatively small number of unsymmetrically trans-disubstituted derivates has been prepared be- cause of difficult and non-trivial synthesis of these compounds. In this Diploma thesis a new orthogonal protection of cyclam is presented as a possible route of preparation of these compounds. Through this intermediate a ligand with methylenephosphonate and methylene(p-aminobenzyl)phosphinate pendant arms was synthesized, copper complexes of the ligand were prepared and their isomerism and stability/inertness were studied. Keywords: PET, SPECT, radiotherapy, copper, bifunctional ligands, orthogonal pro- tection of cyclam. 1
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Coordinatively unsaturated complexes with potential nucleasic activity
Willimetz, Robert ; Kotek, Jan (advisor) ; Schulz, Jiří (referee)
Biofilms are bacterial colonies attached to the surfaces through matrix of the biopolymer substances they produce. These biofilms can also form on medical implants, where they are responsible for difficult-to-treat chronic infections. One approach to prevent biofilm formation may be using of coordination compounds with nuclease activity. These compounds contain a hydrolytically active metal ion that is able to actively cleave extracellular DNA to prevent matrix and biofilm formation. The aim of this diploma thesis was to prepare a series of Cu(II) complexes of 1,4,7-triazacyclononane derivatives and to observe their potential nuclease activity. One of the complexes was a 1,4,7-triazacyclononane derivative with a thiazole anchor. Prepared complex can be incorporated through this anchor into polymers to a surface with potential ability to prevent biofilm formation.
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