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Responsive Contrast Agents for Magnetic Resonance Imaging (MRI)
Krchová, Tereza ; Kotek, Jan (advisor) ; Marek, Radek (referee) ; Platas-Iglesias, Carlos (referee)
ABSTRACT This work is focused on the synthesis of a family of new macrocyclic ligands with exchangeable protons on coordinating groups that could potentially serve (after complexation with suitable paramagnetic lanthanide(III) ions) as responsive contrast agents (CAs) for magnetic resonance imaging (MRI). It is expected that measurement of extracellular pH should bring information for tumorous disease diagnoses and/or for suggesting the most efficient treatment. Therefore, our attention was focused on pH-dependent CAs based on a PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) mechanism capable of reporting pH changes in tissue. The PARACEST-related properties of a series of Ln(III) complexes with the CEST effect caused by amino groups coordinated to the central Ln(III) metal ions were investigated. Such a kind of PARACEST CA is new and has had no precedent in the literature. It was shown that these Ln(III) complexes produce a pH-sensitive PARACEST effect in the pH region relevant for living systems. The study brings proof-of-principle for utilization of complexes with a linear diamine pendant arm, i.e. complexes with two exchanging proton pools, for ratiometric pH determination by MRI independently on the probe concentration. In addition, to ensure a higher kinetic inertness of the...
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Synthesis of beta-cyclodextrin derivatives for medicinal applications
Popr, Martin ; Jindřich, Jindřich (advisor) ; Veselý, Jan (referee)
Synthesis of monosubstituted β-cyclodextrin derivatives for medicinal applications Abstract This thesis is focused on preparation of a set of β-cyclodextrin derivatives with potential use as scaffolds for a construction of novel MRI contrast agents. Firstly, the skeleton of native β-CD was selectively persubstituted at possitions 6 and equipped with azide functions. Per-6-azido-β-CD was then monosubstituted on secondary face of the macrocycle. (E)-cinnamylbromide and propargylbromide were chosen as suitable reagents. The monosubstitution reaction afforded two types of regioisomers, substituted at position 2I -O- or 3I -O-. These regioisomers were sucessfully separated via preparative column chromatography after peracetylation of all free hydroxyl groups. 2I -O-, 3I -O-formylmethyl- and 3I -O- karboxymethyl- analogues were prepared by oxidative transformation of cinnamyl group. Finally the usability of the formylmethyl- derivative for covalent binding with suitable substrate via reductive amination was confirmed. Keywords: cyclodextrins, monosubstitution, cinnamyl, propargyl, formylmethyl, carboxymethyl, reductive amination, MRI, contrast agents
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Responsive Contrast Agents for Magnetic Resonance Imaging (MRI)
Krchová, Tereza
ABSTRACT This work is focused on the synthesis of a family of new macrocyclic ligands with exchangeable protons on coordinating groups that could potentially serve (after complexation with suitable paramagnetic lanthanide(III) ions) as responsive contrast agents (CAs) for magnetic resonance imaging (MRI). It is expected that measurement of extracellular pH should bring information for tumorous disease diagnoses and/or for suggesting the most efficient treatment. Therefore, our attention was focused on pH-dependent CAs based on a PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) mechanism capable of reporting pH changes in tissue. The PARACEST-related properties of a series of Ln(III) complexes with the CEST effect caused by amino groups coordinated to the central Ln(III) metal ions were investigated. Such a kind of PARACEST CA is new and has had no precedent in the literature. It was shown that these Ln(III) complexes produce a pH-sensitive PARACEST effect in the pH region relevant for living systems. The study brings proof-of-principle for utilization of complexes with a linear diamine pendant arm, i.e. complexes with two exchanging proton pools, for ratiometric pH determination by MRI independently on the probe concentration. In addition, to ensure a higher kinetic inertness of the...
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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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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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Responsive Contrast Agents for Magnetic Resonance Imaging (MRI)
Krchová, Tereza
ABSTRACT This work is focused on the synthesis of a family of new macrocyclic ligands with exchangeable protons on coordinating groups that could potentially serve (after complexation with suitable paramagnetic lanthanide(III) ions) as responsive contrast agents (CAs) for magnetic resonance imaging (MRI). It is expected that measurement of extracellular pH should bring information for tumorous disease diagnoses and/or for suggesting the most efficient treatment. Therefore, our attention was focused on pH-dependent CAs based on a PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) mechanism capable of reporting pH changes in tissue. The PARACEST-related properties of a series of Ln(III) complexes with the CEST effect caused by amino groups coordinated to the central Ln(III) metal ions were investigated. Such a kind of PARACEST CA is new and has had no precedent in the literature. It was shown that these Ln(III) complexes produce a pH-sensitive PARACEST effect in the pH region relevant for living systems. The study brings proof-of-principle for utilization of complexes with a linear diamine pendant arm, i.e. complexes with two exchanging proton pools, for ratiometric pH determination by MRI independently on the probe concentration. In addition, to ensure a higher kinetic inertness of the...
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Responsive Contrast Agents for Magnetic Resonance Imaging (MRI)
Krchová, Tereza ; Kotek, Jan (advisor) ; Marek, Radek (referee) ; Platas-Iglesias, Carlos (referee)
ABSTRACT This work is focused on the synthesis of a family of new macrocyclic ligands with exchangeable protons on coordinating groups that could potentially serve (after complexation with suitable paramagnetic lanthanide(III) ions) as responsive contrast agents (CAs) for magnetic resonance imaging (MRI). It is expected that measurement of extracellular pH should bring information for tumorous disease diagnoses and/or for suggesting the most efficient treatment. Therefore, our attention was focused on pH-dependent CAs based on a PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) mechanism capable of reporting pH changes in tissue. The PARACEST-related properties of a series of Ln(III) complexes with the CEST effect caused by amino groups coordinated to the central Ln(III) metal ions were investigated. Such a kind of PARACEST CA is new and has had no precedent in the literature. It was shown that these Ln(III) complexes produce a pH-sensitive PARACEST effect in the pH region relevant for living systems. The study brings proof-of-principle for utilization of complexes with a linear diamine pendant arm, i.e. complexes with two exchanging proton pools, for ratiometric pH determination by MRI independently on the probe concentration. In addition, to ensure a higher kinetic inertness of the...
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Synthesis of beta-cyclodextrin derivatives for medicinal applications
Popr, Martin ; Jindřich, Jindřich (advisor) ; Veselý, Jan (referee)
Synthesis of monosubstituted β-cyclodextrin derivatives for medicinal applications Abstract This thesis is focused on preparation of a set of β-cyclodextrin derivatives with potential use as scaffolds for a construction of novel MRI contrast agents. Firstly, the skeleton of native β-CD was selectively persubstituted at possitions 6 and equipped with azide functions. Per-6-azido-β-CD was then monosubstituted on secondary face of the macrocycle. (E)-cinnamylbromide and propargylbromide were chosen as suitable reagents. The monosubstitution reaction afforded two types of regioisomers, substituted at position 2I -O- or 3I -O-. These regioisomers were sucessfully separated via preparative column chromatography after peracetylation of all free hydroxyl groups. 2I -O-, 3I -O-formylmethyl- and 3I -O- karboxymethyl- analogues were prepared by oxidative transformation of cinnamyl group. Finally the usability of the formylmethyl- derivative for covalent binding with suitable substrate via reductive amination was confirmed. Keywords: cyclodextrins, monosubstitution, cinnamyl, propargyl, formylmethyl, carboxymethyl, reductive amination, MRI, contrast agents
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