Neste trabalho, duas estratégias para obtenção de um complexo de rutênio com os tetraazamacrociclos insaturados 2,3,9,10-tetrametil-1,4,8,11-tetraazaciclotetradeca-1,3,8,10-tetraeno (TIM) ou 5,7,712,14,14-hexamethil-1,4,8,11-tetraazaciclotetradeca-4,11-dieno (1,7-CT) foram estudados. [RuCl2(TIM)] e [RuCl2(1,7-CT)] seriam precursores para obtenção de nitrosilo complexos capazes de liberar óxido nítrico fotoquimicamente pela irradiação com luz em comprimentos de onda na região do visível, como na Terapia Fotodinâmica. Essas duas estratégias são a reação utilizando o rutênio como template e a metalação do ligante previamente sintetizado. A estratégia de metalação foi empregada com o ligante 1,7-CT e utilizando o complexo cis-[RuCl2(dmso)] como precursor para obter o cis-[Ru(1,7-CT)Cl2]Cl. Este método foi aplicado com sucesso para sintetizar complexos de rutênio ligantes tetraazamacrocíclicos como cyclam, cyclen, imcyclen. O ligante 1,7-CT foi sintetizado com sucesso. O espectro de infravermelho mostrou bandas em 3130 cm-1, 2910 cm-1, 1663 cm-1, e 1547 cm-1, em acordo com o relatado na literatura, e o espectro de RMN-1H mostrou singletes em 1.45 ppm, 2.04 ppm, 2.77 ppm, e tripletes em 2.92 ppm e 3.39 ppm, como esperado. Tentativas de síntese do complexo de rutênio correspondente não foram bem sucedidas, conforme se depreende pelos espectros de RMN-1H e de infravermelho. A estratégia que aplica o efeito template para a obtenção do complexo foi a que deu os melhores resultados, embora o complexo não tenha sido isolado do meio reacional. Os resultados das análises espectroscópicas obtidos do extrato seco da reação mostram que o complexo [RuCl2(TIM)] foi obtido. Os espectros de absorção no UV-visível foram feitos durante a reação e mostraram que os precursores estavam reagindo, pois novas bandas apareciam em detrimento do desaparecimento das originais, ao longo da reação. Há alguns indícios de que possa ter havido decomposição, pois o espectro de RMN-1H mostrou um pequeno singleto em 2.25 ppm que pode indicar a presença de 2,3-butanodiona como resultado da decomposição. O espectro de RMN-1H também mostrou um quintupleto em 2.09 ppm e um tripleto em 3.13 ppm, conforme esperado para o macrociclo. Os espectros de infravermelho mostraram a presença de bandas em 1690 cm-1, 1429 a 1374 cm-1, 1200 cm-1 e 942 cm-1, consistentes com a presença do TIM no complexo, além da banda em 448 cm-1, consistente com a presença de ligações Ru-N. A comparação entre os espectros de infravermelho do complexo de rutênio com os complexos análogos de níquel e ferro apoia essas atribuições. / ABSTRACT In this work, two strategies to obtain a complex of ruthenium with the unsaturated tetraazamacrocycles 2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene (TIM) or 5,7,712,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (1,7-CT) were studied. [RuCl2(TIM)] and [RuCl2(1,7-CT)] would be precursors to obtain nitrosyl complexes able to deliver nitric oxide photochemically by irradiation with visible light as in photodynamic therapy. These two strategies are the reaction using ruthenium as template and the metallation of the ligand previously synthesized. The metallation strategy was used with the ligand 1,7-CT and the precursos cis-[RuCl2(dmso)4] to obtain cis-[Ru(1,7-CT)Cl2]Cl. This method is successfuly applied to synthesize ruthenium complexes with tetraazamacrocyclic ligands as cyclam, cyclen, imcyclen. The 1,7-CT was successfully synthesized. The infrared spectrum of 1,7-CT showed bands about 3130 cm-1, 2910 cm-1, 1663 cm-1, and 1547 cm-1, in agreement with the data found in the literature, and the 1H-NMR spectrum showed singlets at 1.45 ppm, 2.04 ppm, 2.77 ppm, and triplets at 2.92 ppm and 3.39 ppm, as expected. Attempts to synthesize the corresponding ruthenium complex were unsuccessful as long as 1H NMR and infrared spectroscopy are concerned. The strategy applying the template effect to obtain the complex was the one that gave the more positive results, although the complex was not isolated from the reaction media. Spectral analysis from the dry extract of the reaction drove us to believe that the complex [RuCl2(TIM)] was obtained. The UV-visible absorption spectra taken during the reaction showed that the precursors were properly reacting because new bands were taking place of the originals bands of the precursors during the reaction course. There are some indications that some decomposition may have taken place, as the 1H NMR spectrum showed a small singlet at 2.25 ppm that could indicate the presence of 2,3-butanedione as a result of this decomposition. The 1H NMR spectrum also showed a quintuplet at 2.09 ppm and a triplet at 3.13 ppm, as expected for the macrocycle. The infrared spectrum showed the presence of bands about 1690 cm-1, 1429 to 1374 cm-1, 1200 cm-1 and 942 cm-1, consistent with the presence of TIM in the complex, and the presence of bands about 448 cm-1, consistent with the presence of Ru-N bonds. Comparison of the ruthenium complex infrared spectrum to those of the nickel and iron analogous complexes supports this assumption.

Neste trabalho, duas estratégias para obtenção de um complexo de rutênio com os tetraazamacrociclos insaturados 2,3,9,10-tetrametil-1,4,8,11-tetraazaciclotetradeca-1,3,8,10-tetraeno (TIM) ou 5,7,712,14,14-hexamethil-1,4,8,11-tetraazaciclotetradeca-4,11-dieno (1,7-CT) foram estudados. [RuCl2(TIM)] e [RuCl2(1,7-CT)] seriam precursores para obtenção de nitrosilo complexos capazes de liberar óxido nítrico fotoquimicamente pela irradiação com luz em comprimentos de onda na região do visível, como na Terapia Fotodinâmica. Essas duas estratégias são a reação utilizando o rutênio como template e a metalação do ligante previamente sintetizado. A estratégia de metalação foi empregada com o ligante 1,7-CT e utilizando o complexo cis-[RuCl2(dmso)] como precursor para obter o cis-[Ru(1,7-CT)Cl2]Cl. Este método foi aplicado com sucesso para sintetizar complexos de rutênio ligantes tetraazamacrocíclicos como cyclam, cyclen, imcyclen. O ligante 1,7-CT foi sintetizado com sucesso. O espectro de infravermelho mostrou bandas em 3130 cm-1, 2910 cm-1, 1663 cm-1, e 1547 cm-1, em acordo com o relatado na literatura, e o espectro de RMN-1H mostrou singletes em 1.45 ppm, 2.04 ppm, 2.77 ppm, e tripletes em 2.92 ppm e 3.39 ppm, como esperado. Tentativas de síntese do complexo de rutênio correspondente não foram bem sucedidas, conforme se depreende pelos espectros de RMN-1H e de infravermelho. A estratégia que aplica o efeito template para a obtenção do complexo foi a que deu os melhores resultados, embora o complexo não tenha sido isolado do meio reacional. Os resultados das análises espectroscópicas obtidos do extrato seco da reação mostram que o complexo [RuCl2(TIM)] foi obtido. Os espectros de absorção no UV-visível foram feitos durante a reação e mostraram que os precursores estavam reagindo, pois novas bandas apareciam em detrimento do desaparecimento das originais, ao longo da reação. Há alguns indícios de que possa ter havido decomposição, pois o espectro de RMN-1H mostrou um pequeno singleto em 2.25 ppm que pode indicar a presença de 2,3-butanodiona como resultado da decomposição. O espectro de RMN-1H também mostrou um quintupleto em 2.09 ppm e um tripleto em 3.13 ppm, conforme esperado para o macrociclo. Os espectros de infravermelho mostraram a presença de bandas em 1690 cm-1, 1429 a 1374 cm-1, 1200 cm-1 e 942 cm-1, consistentes com a presença do TIM no complexo, além da banda em 448 cm-1, consistente com a presença de ligações Ru-N. A comparação entre os espectros de infravermelho do complexo de rutênio com os complexos análogos de níquel e ferro apoia essas atribuições. / ABSTRACT In this work, two strategies to obtain a complex of ruthenium with the unsaturated tetraazamacrocycles 2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene (TIM) or 5,7,712,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (1,7-CT) were studied. [RuCl2(TIM)] and [RuCl2(1,7-CT)] would be precursors to obtain nitrosyl complexes able to deliver nitric oxide photochemically by irradiation with visible light as in photodynamic therapy. These two strategies are the reaction using ruthenium as template and the metallation of the ligand previously synthesized. The metallation strategy was used with the ligand 1,7-CT and the precursos cis-[RuCl2(dmso)4] to obtain cis-[Ru(1,7-CT)Cl2]Cl. This method is successfuly applied to synthesize ruthenium complexes with tetraazamacrocyclic ligands as cyclam, cyclen, imcyclen. The 1,7-CT was successfully synthesized. The infrared spectrum of 1,7-CT showed bands about 3130 cm-1, 2910 cm-1, 1663 cm-1, and 1547 cm-1, in agreement with the data found in the literature, and the 1H-NMR spectrum showed singlets at 1.45 ppm, 2.04 ppm, 2.77 ppm, and triplets at 2.92 ppm and 3.39 ppm, as expected. Attempts to synthesize the corresponding ruthenium complex were unsuccessful as long as 1H NMR and infrared spectroscopy are concerned. The strategy applying the template effect to obtain the complex was the one that gave the more positive results, although the complex was not isolated from the reaction media. Spectral analysis from the dry extract of the reaction drove us to believe that the complex [RuCl2(TIM)] was obtained. The UV-visible absorption spectra taken during the reaction showed that the precursors were properly reacting because new bands were taking place of the originals bands of the precursors during the reaction course. There are some indications that some decomposition may have taken place, as the 1H NMR spectrum showed a small singlet at 2.25 ppm that could indicate the presence of 2,3-butanedione as a result of this decomposition. The 1H NMR spectrum also showed a quintuplet at 2.09 ppm and a triplet at 3.13 ppm, as expected for the macrocycle. The infrared spectrum showed the presence of bands about 1690 cm-1, 1429 to 1374 cm-1, 1200 cm-1 and 942 cm-1, consistent with the presence of TIM in the complex, and the presence of bands about 448 cm-1, consistent with the presence of Ru-N bonds. Comparison of the ruthenium complex infrared spectrum to those of the nickel and iron analogous complexes supports this assumption.

Le travail présenté dans ce mémoire de thèse avait pour but de synthétiser de nouveaux composés pour des applications en imagerie médicale. La première partie porte sur la synthèse de ligands hétéroleptiques pour la chélation de deux métaux différents en vue d’une utilisation dans deux types d’imagerie. Pour cela, nous avons d’abord synthétisé des porphyrines. Ces molécules sont connues pour la chélation de nombreux métaux de transition et notamment le cuivre, dont l’isotope cuivre-64 est un radioémetteur β+ utilisable en Tomographie par Émission de Positron (TEP). Ces porphyrines ont été couplées à un dérivé du DOTA, molécule connue pour son application, après métallation avec du gadolinium, en Imagerie par Résonance Magnétique (IRM). Ces composés possèdent des valeurs de relaxivité encourageantes pour une application en IRM. Enfin, des biomolécules ont été modifiées afin de vectoriser nos composés. La seconde partie porte sur la synthèse de composés pour l’imagerie médicale par optique non-linéaire. Nous avons dans un premier temps synthétisé des porphyrines amphiphiles et zwiterrioniques pour la Génération de Second Harmonique (GSH). Leur efficacité a été mesurée et celle-ci est suffisante pour pouvoir envisager l’obtention d’images. Dans un second temps, nous avons travaillé sur la synthèse d’un composé pour une application en imagerie biphotonique et en IRM. Pour cela, nous avons relié un dérivé du DOTA avec un fluorophore de type DPP. Le composé final a été métallé avec du gadolinium et sa relaxivité est supérieure à celle du DOTA(Gd). / The goal of my PhD studies was to synthesize new compounds for possible medical imaging applications. The first part of my thesis focused on the synthesis of heteroleptic ligands to achieve the chelation of two different metals aimed at addressing two types of medical imaging. We first synthesized porphyrins, which are well-known for the chelation of numerous transition metals. We focused on copper, whose copper-64 isotope is a β+ emitter usable in Positron Emission Tomography (PET). These porphyrins have been coupled with a DOTA derivative. This molecule, metallated with gadolinium, is well-known in Magnetic Resonance Imaging (MRI). Our compounds display encouraging relaxivities for MRI applications. At last, these molecular probes have been conjugated to a few biomolecules in order to vectorize our compounds. The second part of this work is related to the synthesis of fluorophores for nonlinear optical imaging. We first synthesized amphiphilic zwitterionic porphyrins for Second Harmonic Generation (SHG). The efficiency of these compounds has been measured and was satisying enough to consider the possibility to perform imaging studies. We also worked on the synthesis of compounds for Two Photon Emission Fluorescence (TPEF) imaging and MRI. We have linked a DOTA derivative with a diketopyrrolopyrrole (DPP). This conjugate has been metallated with gadolinium and its relaxivity has been measured. Interestingly, this value is superior to that of DOTA(Gd).

Le travail présenté dans ce mémoire avait pour but de synthétiser de nouvelles molécules dont l’architecture donne accès à des complexes hétérobimétalliques aux propriétés intéressantes pour l’imagerie médicale multimodale. Dans ce manuscrit plusieurs points principaux ont donc été abordés. La première partie de se travail porte sur la synthèse et la caractérisation des ligands. Nous décrivons dans ce manuscrit la synthèse de cinq nouveaux ligands hétérobismacrocycliques basés sur l’association d’une porphyrine et d’un ou de plusieurs dérivés du cyclène. Ces ligands présentent la particularité d’être solubles en milieux aqueux. Au cours des synthèses, nous avons ciblé les améliorations à apporter à notre travail et élaboré une nouvelle voie de synthèse qui permet d’accéder, en seulement six étapes, à un ligand composé d’une porphyrine, d’un dérivé du cyclène et d’une fonction amine libre qui permettra de greffer le ligand sur un vecteur biologique. La seconde partie de ce manuscrit porte sur l’incorporation de centres métalliques dans les ligands synthétisés ainsi que l’étude de leur efficacité en tant qu’agent de contraste de l’IRM. Nous décrivons la synthèse de cinq complexes de gadolinium (III) et de trois complexes hétérobimétalliques associant du gadolinium (III) et du cuivre (II). En effet, le gadolinium est actuellement utilisé dans les agents de contraste de l’IRM et un des isotopes du cuivre, le cuivre-64, est utilisé en imagerie PET. Nous décrivons un protocole de mesure de la relaxivité des complexes à haut et à bas champs magnétiques. Cinq complexes présentent des valeurs de relaxivité quatre fois supérieures à celles des agents de contraste commerciaux de l’IRM. Le dernier chapitre de ce travail porte sur la synthèse, la caractérisation et les études photophysiques de quatre antennes moléculaires associant des porphyrines et des BODIPY. Nous avons développé deux voies de synthèses originales. La première est basée sur la création de liaisons bore-oxygène en substituant les atomes de fluor portés par l’atome de bore des BODIPY. L’autre voie de synthèse utilise la réaction de cycloaddition dipolaire d’Huisgen. Nous décrivons des études photophysiques qui mettent en évidence des transferts d’énergie du BODIPY vers la porphyrine Nous avons mis en évidence le premier exemple de transfert d’énergie d’une porphyrine vers un BODIPY grâce à un système “blue” BODIPY étendu couplé à des porphyrines par une réaction de chimie “click”. / The goal of my PhD thesis was to synthesize new molecules, which give access to heterobimetallic complexes with interesting properties for multimodal imaging. In this manuscript, several main points have been studied. The first part of this work concerns the synthesis and characterization of ligands. We describe here the synthesis of five new ligands based on the association of one porphyrin and one or several cyclen derivatives. Those ligands are water-soluble. During the synthesis, we have targeted improvements to our work and developed a new synthetic pathway, which allowed us to obtain one ligand incorporating a porphyrin, a cyclen derivative and a free amine function. This function could be activated to further graft the ligand onto a biological vector. The second part of this manuscript describes the chelation of metallic centers into the ligands and the study of their efficiency as MRI contrast agents. We describe the synthesis of five gadolinium (III) complexes and three heterobimetallic complexes associating gadolinium (III) with copper (II). Indeed, gadolinium is currently used in contrast agents for MRI and the radioactive isotope of copper, copper-64 is used in PET imaging. We describe also a procedure to measure the relaxivity of the gadolinium complexes at low and high magnetic fields. Five complexes exhibit relaxivity values five times larger than commercially available MRI contrast agents. The last part of this work is related to the synthesis, characterization and photophysical studies of four molecular antennas incorporating porphyrins and BODIPY. We describe two original synthetic pathways. The first one is based on the formation of boron-oxygen bonds by substitution of the fluorine atoms bound to BODIPY boron atom. The second synthetic pathway involves the Huisgen’s dipolar cycloaddition. We describe photophysical data and give evidences of the energy transfer from BODIPY to porphyrin. We present also the first example of energy transfer from porphyrin to BODIPY in the system obtained by “click” chemistry involving an extended “blue” BODIPY.