Lanthanide elements display many remarkable and exciting properties which explain their widespread use in a number of very important biomedical tools like efficient MRI contrast agents or luminescent probes for highly sensitive assays of bioanalytes amongst other fields of application. In this context, the aim of the present work was to prepare and characterize lanthanide complexes of two ligands that feature a linear or a macrocyclic chelating unit compactly grafted onto a 1,10-phenanthroline derived moiety (phenDTPA and PhenHDO3A). The ditopic nature of the ligands allows the selective incorporation of a d6 metal ion and a lanthanide one in close proximity. The resulting rigid heterobimetallic supramolecular species show useful properties and constitute potential MRI contrast agents or new luminescent compounds depending on the type of the lanthanide and transition metal ions employed: for example, the selfassembly process of gadolinium(III) chelates around an iron(II) ion brings a remarkable increase of their relaxivity, a key parameter for use in MRI. On the other hand, association of a ruthenium and and a near infrared emitting 4f ion like ytterbium(III) gives mixed d-f structures able to harvest visible light and convert it into near infra-red signal. Visible light luminescent pH probes were also obtained with Eu3+ or Tb3+ phenHDO3A complexes.

Cette thèse décrit une stratégie de synthèse de nouvelles générations des nanoparticules (NPs) pour applications biomédicales, visant à une amélioration de leurs performances pour l’imagerie, le diagnostic thérapeutique. Ces NPs présentent plusieurs fonctionnalités leur permettant de réaliser des tâches multiples. Deux types de sondes bimodales ont été développés et étudiés afin d'évaluer leur potentiel comme agents (1) de contraste en IRM et (2) luminescents. Ces objetscombinent les propriétés des complexes de lanthanide (Ln3+) et celles des NPs de silice ou de type coeur-écorce Fe2O3@SiO2 pour une imagerie bimodale. Ces NPs testées sur des cellules vivantes ont permis d’illustrer la preuve du concept aussi bien en IRM avec une augmentation d'intensité des images et un impact significatif sur les relaxivities r1, r2 et r2* qu’en photoluminescence. L’étude du système coeur-écorce a montré que l’influence du contrôle fin de l’écorce autour du noyau d'oxyde de fer a pu être modélisée. / This thesis describes a strategy of synthesis of new generations of nanoparticles (NPs) for biomedical applications, aiming at an improvement of their performances for the imaging, and the therapeutic diagnosis. These NPs present several functionalities enabling them to carry out multiple tasks. Two types of bimodal probes were developed and studied so as to evaluate their potential as contrast agents (1) in MRI and (2) and luminescence. These objects combine the properties of the lanthanide complexes (Ln3+) and those of NPs of silica or core/shell Fe2O3@SiO2 for a bimodal imaging. These NPs tested on living cells were able to illustrate the proof of the concept not only in MRI with an increase of intensity of the images and a significant impact on the relaxivities r1, r 2 and r2* but also in photoluminescence. The study of the core/shell system showed that the influence of the fine control of the shell around the iron oxide core could be modeled.

Made available in DSpace on 2015-05-14T13:21:13Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1246890 bytes, checksum: d8de4e92a3d9c573a9ad39ccb546aa71 (MD5) Previous issue date: 2008-11-13 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Lanthanide macrocyclic complexes, especially containing Gd(III) ions, are largely used as contrast agents in the medical diagnostic technique named Magnetic Resonance Imaging (MRI). Theoretical investigation of these compounds by molecular modeling methods is an emerging research area today. In this work we have performed a conformational study of the following supramolecular compounds: the macrocyclic ligands 1,4,7,10- tetraazacyclododecane (DOTA) and 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (H4DOTA) and the macrocyclic complexes [Gd(DOTA).H2O]- and Gd(PhenHDO3A).H2O, where PhenHDO3A is (rel-10- [(5R,6R)-5,6-dihydro-6-hydroxy-1,10-Phenanthroline-5-yl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid). For this, we have developed and carried out a procedure that involves: (1) the sampling of the conformation space of these compounds through some short molecular dynamics at different temperatures and (2) full geometry optimization in the geometries obtained in the previous stage using semi-empirical AM1 method for the macrocyclic ligands and Sparkle/AM1 model for the macrocyclic lanthanide complexes. Our results revealed that the high flexibility of non-coordinated macrocyclic ligands DOTA and H4DOTA, helped us to test the ability of our methodology to sample different regions of conformation space of these compounds. For the [Gd(DOTA).H2O]- complex, we were capable to find the same conformational isomers which were reported in published works as well as to comprehend relevant details about the mobility of the coordinated water molecule. Furthermore, we also were capable to identify some intermediate local minima related to the dynamics of rotation of the coordinated acetate groups in the studied complexes as well as to the dynamics of ring inversion of the coordinated tetraazadodecane moiety in the Gd(PhenHDO3A).H2O. In conclusion, we possess now an interesting strategy to conduct the search for conformational isomers of these compounds. This knowledge is very important to be applied in the rational design of new molecules to act as contrast agent in MRI. / Complexos macrocíclicos de lantanídeos, em especial com o íon Gd(III), são cada vez mais utilizados como agentes de contrastes na técnica médica de diagnóstico, imagem por ressonância magnética nuclear (MRI). O estudo teórico de novos agentes de contrastes através de modelagem molecular é uma área de pesquisa em grande expansão. No nosso trabalho fizemos um estudo conformacional dos seguintes compostos supramoleculares: os ligantes macrocíclicos 1,4,7,10- tetraazaciclododecano (DOTA) e ácido 1,4,7,10-tetraazaciclododecano- 1,4,7,10-tetraacético (H4DOTA), o complexo macrocíclico [Gd(DOTA)H2O]- e o complexo macrocíclico Gd(PhenHDO3A).H2O, onde PhenHDO3A é (rel-10-[(5R,6R)-5,6-dihidro-6-hidroxi-1,10-fenantrolina-5- il)-1,4,7,10-tetraazaciclododecano-1,4,7-ácido triacético). Para isso, elaboramos e executamos um procedimento que envolve o mapeamento ou amostragem do espaço conformacional desses compostos através de dinâmicas moleculares curtas em diferentes temperaturas para em seguida, essas geometrias serem usadas como pontos de partida para otimização de geometria usando tanto o método semi-empírico AM1 quanto o modelo Sparkle/AM1. Como resultado, podemos citar que a elevada flexibilidade dos ligantes macrocíclicos não coordenados DOTA e H4DOTA, serviu para testar a capacidade da nossa metodologia de visitar regiões distintas do espaço conformacional. Para o complexo [Gd(DOTA)H2O]-, conseguimos encontrar os mesmos isômeros conformacionais que já são reportados em outros estudos, bem como revelar detalhes relativos à mobilidade da molécula de água coordenada. Além disso, conseguimos identificar mínimos locais intermediários que estão relacionados com a dinâmica de rotação dos grupos acetato em ambos os complexos e a dinâmica de inversão do anel tetraazadodecano no complexo Gd(PhenHDO3A).H2O. A relevância desse trabalho está apoiada no fato de que agora temos uma estratégia interessante para realizar a busca de isômeros conformacionais desses compostos, sendo essas informações, muito importantes quando se deseja projetar uma nova molécula para atuar como agente de contraste em MRI.

Ondřej Zemek Organophosphorus derivatives for "click-chemistry" In this diploma thesis two new macrocyclic ligands were synthesized. They have DO3A moiety where metal (lanthanide) ion can be coordinated and terminal acetylenic or azide group connected through the phosphinic acid. Both terminal acetylenic and azide group should serve for connecting to another molecules or partitions by mean of "click chemistry" i.e. [1,3] copperI catalyzed dipolar cycloaddition between azide and acetylene. In this thesis two ligands, its complexes with some lanthanides as well as its precursors were prepared and characterized. Gd3+ complexes will be further used and studied for potential MRI contrast agents applications.

In my master’s thesis I describe basics of magnetic resonance measurement. I focus on methods of DCE-MRI with T1 weighting image. I mention some basic contrast agents which are used in MRI imaging. I describe some of pulse sequences which are used in experimental part of my thesis. There I measure contrast in the sample. The measurement is performed in accordance with an acquisition protocol I have proposed. The experiment part was realized on 1.5 T magnet at Masaryk Oncological Institute in Brno. I improved software which is use to research of MR IR TurboFLASH’s data and made software which is use to evaluation perfuse analysis ours measured sequences. At the end I made a discussion about gained facts.