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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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Complexes of cyclen-based macrocyclic ligands with a phosphinate pendant arm
Urbanovský, Peter ; Hermann, Petr (advisor) ; Lyčka, Antonín (referee) ; Pinkas, Jiří (referee)
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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Lanthanide complexes of DOTA-"trans"-diamide
Obuch, Jakub ; Hermann, Petr (advisor) ; Kotek, Jan (referee)
Macrocyclic complexes are of great interest due to their utilization in many medic- inal applications, such as MRI contrast agents and radiopharmaceuticals. These com- plexes overcome the toxicity of free heavy metal ions and, thus, enable their use in vivo. In this Thesis, diamide derivative of DOTA (tDODAM) and its lanthanide(III) complexes were prepared and characterised in solution and in the solid state. For cerium(III) com- plex, formation and dissociation kinetics were studied. Structure and dynamics of eu- ropium(III) complex were investigated by multinuclear NMR spectroscopy and various 2D NMR techniques. Similarly to Ln(III)-DOTA complexes, the complexes form square- antiprismatic (SA) and twisted-square-antiprismatic (TSA) isomers and their ratio in solution was determined across the lanthanide series. Structures of 7 lanthanide(III) complexes in the solid state were determined. Thermodynamic data were obtained for Cu(II), Zn(II), Pb(II), Ce(III), Eu(III) and Lu(III) complexes by potentiometric titration. 1
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17O NMR study of LnIIIcomplexes of H4do3apOEt ligand
Svítok, Adam ; Hermann, Petr (advisor) ; Dračínský, Martin (referee)
Macrocyclic complexes of H4dota-like ligands are used in various fields, mainly in medicine. e. g. as MRI contrast agents or luminescent probes. Their applications are greatly influenced by stereochemistry. Stereoisomers of these complexes mostly interconvert with each other in solution. This interconversion can be studied by NMR spectroscopy This work is intended to test 17 O NMR spectroscopy as a tool for monitoring dynamic processes where phosphonate group in the complexes of methylphosphonate derivatives of H4dota is involved. To this end, ligand H4do3apOEt and his LnIII -complexes (Ln ≠ Pm) containing 17 O-labeled phosphonate group were synthesized. Next, 17 O NMR spectra of these complexes were measured and analysed. In an analogy with H4dota complexes, signals of both non-coordinated and coordinated oxygen atoms (except GdIII ) in the complexes could be detected. Fraction of TSA (twisted square-antiprism) and SA (square-antiprism) isomers was determined from the acquired 17 O NMR spectrum for each complex. The determined values were compared with those obtained by analysing 1 H and 31 P NMR spectra of the complexes, which were also measured. The TbIII , DyIII and YbIII complexes (because of high resolution of their 17 O NMR spectra) and CeIII complex (because of anomalous properties of its...
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Coordination Compounds as Contrast Agents for 19F-MRI
Špánek, Jiří ; Kotek, Jan (advisor) ; Vojtíšek, Pavel (referee)
Magnetic Resonance Imaging (MRI) is one of noninvasive imaging and diagnostic methods in today's medicine. The most commonly measured nucleus is H1 of the water molecules present in the human body. There are also methods that use signal saturation transfer between the contrast agent and water molecules via exchangeable H1 nuclei, or use a different nucleus like F19 . Compounds that show a high potential in this area are complexes of paramagnetic ions such as Gd3+ , Eu3+ , Co2+ , Cu2+ and Ni2+ , which can affect relaxation times and chemical shifts of other atoms due to their magnetic properties. This Master's thesis focuses on ligands L1 and L2 which were prepared in the Bachelor thesis. The main focus is on preparation of complexes with selected paramagnetic ions and subsequent study of their properties relevant for a potential use as contrast agents for F19 -MRI and CEST methods. Keywords: F19 -MRI, CEST, macrocyclic ligands, coordination chemistry
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Prion Diseases - a role of transition metal ions
Malová, Zuzana ; Lukeš, Ivan (advisor) ; Moško, Tibor (referee)
Prion diseases are widely spread diseases among mammalians. They are characterized by a change of prion protein structure PrPC (cellular, native state) to PrPSc (scrapie, structure typical for prion diseases). It is a change at secondary structure of protein from α-helical to β-sheet structure, which aggregates in brain. One possibility, why it happens is higher transitional metal ions concentration (Zn(II), Cu(II), Fe(III)) in the brain, which bind to PrPC and affects its structure. Aim of this thesis is a synthesis one of protentional drugs based on 2-aminothiazole and its modification to bind fluorescent or radiochemical markers and in future study of its possible interaction with transition metal ions. Key words: complexes; macrocyclic ligands; copper; prion diseases
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Contrast agents for hereronuclear MRI
Koucký, Filip ; Kotek, Jan (advisor) ; Havlík, Jan (referee)
In this thesis the pH dependency of the coordination modes of lanthanide complexes with macrocyclic ligands based on 1,4,7,10-tetraazacyclododecane skeleton was studied. The cyclen-based ligand structures in this work contained three acetate and one aminoethyl group with a N-alkyl-N-methylphosphonate substituent, DO3AN(R)P, where R is an alkyle substituent on the nitrogen atom of the pendant arm (R = methyl, benzyl). Lanthanide complexes of a previously studied prototype ligand DO3ANP with secondary amino group (R = H) have shown interesting properties in the field of 31 P NMR imaging because of their various coordination properties, which allow in situ pH measurement. These complexes can also be used for monitoring the kinetics of the chemical exchange of the amino group proton in 1 H NMR imaging using the chemical exchange saturation transfer (CEST NMR). In this thesis, two new derivatives DO3ANMeP and DO3ANBnP were prepared in order to better understand the coordination modes changes in this ligand series. Also, their coordination behaviour with selected lanthanide ions was studied (Eu3+ , Gd3+ , Dy3+ , Yb3+ ). Based on a series of NMR and luminescence measurements, it was found out, that in acidic conditions the complexes containing DO3ANP motif bind a water molecule in their coordination...
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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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Coordination properties of TACN ethylphosphonic derivative
Poláková, Zuzana ; Kubíček, Vojtěch (advisor) ; Schulz, Jiří (referee)
Ligand NOTPOEt was synthesized. Protonation constants and stability constants of Cu(II), Zn(II), Ni(II) and Ga(III) complexes were determined by potentiometric titrations. Cu(II) complex was characterized by UV-VIS spectroscopy and formation of Ga(III) complex was studied by NMR spectroscopy. The work was aimed at characterisation of the ligand with respect to potential application in biomedical imaging techniques.
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