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Synthesis of chelators for use in diagnostic imaging
Kretschmer, Jan ; Polášek, Miloslav (advisor) ; Kubíček, Vojtěch (referee) ; Hrubý, Martin (referee)
Metals play a crucial role in medicine as a part of therapeutic or diagnostic preparations. However, in the majority of cases, their properties cannot be utilized entirely in free ionic form. Organic molecules capable of chelation are used to open the full potential of the metal. The molecules are called chelators and are the core theme of this thesis. The most important function of these molecules is the chelation and coordination of the metal, but chelators can provide other important functionalities. This work, therefore, focuses on the design, synthesis, and application of such polyfunctional chelators and is divided into two parts: DO3A-Hyp This part of the thesis deals with chelators that can be used as amino acids to incorporate lanthanides into peptides. The developed chelators provide a short and rigid connection of the metal to the peptide chain. Tripeptides containing two units of such chelators with a central amino acid bearing a CF3 group were synthesized to demonstrate the capability of DO3A-Hyp building blocks. Two paramagnetic metals were combined within this tripeptide, and it was shown that such a rigid and locked system could be used for combining their magnetic susceptibility tensors. These magnetic susceptibility tensors were used for manipulation of the 19 F NMR shift of the CF3...
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Trivalent and tetravalent metal complexes for radiodiagnostics
Hacaperková, Eliška ; Kubíček, Vojtěch (advisor) ; Drahoš, Bohuslav (referee) ; Polášek, Miloslav (referee)
Fluorine-18 is the most utilized nucleus for positron emission tomography (PET). In 2009, incorporation of fluorine-18 to the coordination sphere of Al(III) was introduced as a new alternative for commonly employed compounds with F-C bond. Such a radiotracer consists of two parts: a metal complex with a fluoride and a peptide or a small/part of biomolecule. Shortly after that, first clinical studies showed a promising potential of such com- pounds for clinical use. Despite a great number of papers dealing with this issue, the research is mostly application-driven and focused on the peptide part of the molecule responsible for specific accumulation within the organism. Studies oriented on a sta- bility of metal-ligand-fluorine ternary system are rather rare and only very little is known about such a three-component system from a chemical point of view in gen- eral. However, stability of F-Al bond strongly dependents on the chemical structure of other ligands in the coordination sphere. Pendant arms of a hexadentate ligand (usually used for Al(III) complexation, e.g., H3NOTA) can compete with fluoride and cause its release which leads to unspecific radioactivity accumulation. Lower ligand denticity should increase the F-Al bond stability, but can decrease the stability of the whole complex at the...
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Pyridine-N-oxide analogue of DOTA as a building block for MRI contrast agents
Polášek, Miloslav ; Hermann, Petr (advisor) ; Geraldes, Carlos F. G. C. (referee) ; Botta, Mauro (referee) ; Marek, Radek (referee)
Conclusions In my PhD project I synthesized two new polydentate macrocyclic ligands, the monofunctional DO3A-pyNO and the bifunctional DO3A-pyNO-C. Both compounds are based on the design of DOTA, with one of the acetate pendant arms being replaced with a pyridine-Noxide arm. This structural modification has a tremendous influence on chemical properties of the lanthanide(III) complexes of these compounds. The water exchange rate in the gadolinium(III) complexes is significantly accelerated in comparison with the complexes of DOTA. In fact, the values are almost optimal for use of the Gd(III) complexes as contrast agents for magnetic resonance imaging. Besides, the complexes exist exclusively in the form of square antiprismatic isomers. I investigated the complexes by various physico-chemical techniques in solution and in solid state, in order to elucidate the relationship between their structure and properties. On the basis of these results I found an explanation to the unexpectedly fast water exchange rate observed on the squareantiprismatic isomers. I established a synthetic protocol that can be used for the attachment of the bifunctional ligand DO3A-pyNO-C to any amine-bearing molecule. I prepared a series of conjugates with polyamidoamine dendrimes and a conjugate with per-6-amino--cyclodextrine and...
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Complexes of macrocyclic ligands with phosphonate and phosphinate penant arms for molecular imaging
Pazderová, Lucia ; Kubíček, Vojtěch (advisor) ; Pinkas, Jiří (referee) ; Polášek, Miloslav (referee)
In an effort to increase the thermodynamic stability and the kinetic inertness of the complexes, the five new azamacrobicyclic ligands derived from TACN, cyclen, and cyclam have been prepared. The ligands were decorated with phosphinate or phosphonate pendant arms to maintain fast complexation. Since the ascending importance of targeted diagnostic and therapy, the bone-targeted non-bridged cyclam derivative with phosphinate-bis(phosphonate) pendant arm (H5TE1PBP) has also been synthesized. The ligands were studied with respect to their application. The bridged TACN (H2bpbtacn) and cyclen (H4bpbcen) ligands show high macrocyclic basicity (logK1 = 12.25 and 12.70, respectively). The thermodynamic stability of H2bpbtacn with Cu(II) ion is more than ten orders of magnitude lower than that of the NOTA ligand. The stability constants of H4bpbcen with Cu(II) and Zn(II) ions are comparable to those given for the DOTA. The stability of Ln(III)-bpbcen complexes is 7-10 orders of magnitude lower compared to DOTA complexes. For both ligands, the lower thermodynamic stability of the complexes is attributed to the high rigidity of the ligand structure. The bridged cyclam derivatives with phosphonate (H4TE2P), bis(phosphinate) (H4TE2bpin), or phosphinate (H2TE2PH) pendants are characterized by high stability of...
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Pyridine-N-oxide analogue of DOTA as a building block for MRI contrast agents
Polášek, Miloslav ; Hermann, Petr (advisor) ; Geraldes, Carlos F. G. C. (referee) ; Botta, Mauro (referee) ; Marek, Radek (referee)
Conclusions In my PhD project I synthesized two new polydentate macrocyclic ligands, the monofunctional DO3A-pyNO and the bifunctional DO3A-pyNO-C. Both compounds are based on the design of DOTA, with one of the acetate pendant arms being replaced with a pyridine-Noxide arm. This structural modification has a tremendous influence on chemical properties of the lanthanide(III) complexes of these compounds. The water exchange rate in the gadolinium(III) complexes is significantly accelerated in comparison with the complexes of DOTA. In fact, the values are almost optimal for use of the Gd(III) complexes as contrast agents for magnetic resonance imaging. Besides, the complexes exist exclusively in the form of square antiprismatic isomers. I investigated the complexes by various physico-chemical techniques in solution and in solid state, in order to elucidate the relationship between their structure and properties. On the basis of these results I found an explanation to the unexpectedly fast water exchange rate observed on the squareantiprismatic isomers. I established a synthetic protocol that can be used for the attachment of the bifunctional ligand DO3A-pyNO-C to any amine-bearing molecule. I prepared a series of conjugates with polyamidoamine dendrimes and a conjugate with per-6-amino--cyclodextrine and...
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