Title: MRI Contrast Agents Based on Saturation Transfer Author: Bc. Tereza Krchová Department: Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague Supervisor: doc. RNDr. Jan Kotek, Ph.D. Supervisor's email: modrej@natur.cuni.cz Abstract: The aim of this thesis was to synthesize macrocyclic ligands (based on the DO3A and DO2A framework) with exchangeable protons on the aminic coordinating groups that could be (after the complexation with suitable paramagnetic metal ions) potential contrast agents based on saturation transfer, so called CEST contrast agents (Chemical Exchange Saturation Transfer). Two ligands H3L1 and H2L2 with one and two aminoethyl groups have been synthesized. The structurally similar ligands H3L1 Me and H3L1 2Me with one exchangeable proton and without it have been also prepared. The protonation constants of the ligands H3L1 and H2L2 have been determined by pH 1 H NMR and potentiometric titrations. The stability constants of metal ion complexes with H3L1 and H2L2 have been also determined by potentiometry. The CEST effect of Eu3+ and Yb3+ complexes with H3L1 , H3L1 Me and H3L1 2Me in solution have been studied. The residence lifetime of the inner-sphere water molecule has been determined for Gd-L1 complex. Keywords: CEST, MRI, aminoethyl, DO3A, DO2A, 17 O...

Aujourd’hui les médecins disposent de nombreuses techniques d’imagerie médicale afin d’établir des diagnostics précis et précoces. Cependant, chacune de ces techniques possède ses propres avantages et inconvénients. C’est pourquoi, l’utilisation de méthodes bi- ou multi-modales paraît intéressante. Parmi celles-ci, la combinaison TEP/IRM permet d’apporter des informations complémentaires. Il est alors nécessaire d’injecter aux patients un traceur adapté à chacune de ces modalités. Ce travail de thèse a donc consisté à synthétiser des plateformes moléculaires « universelles » utilisables pour l’imagerie IRM et TEP selon deux stratégies. La première a consisté en la synthèse d’une molécule composée d’un macrocycle de type DO3A permettant à la fois la chélation d’un atome de gadolinium pour l’IRM mais aussi d’un atome de gallium 68 pour la TEP. L’idée étant, afin d’avoir une sonde bimodale, de réaliser un mélange des deux composés. La seconde stratégie a été de synthétiser une unique molécule pouvant être marquée à la fois par du gadolinium pour l’IRM et par un atome de fluor 18 pour la TEP. Afin de pouvoir cibler un phénomène physiopathologique donné, l’idée de ces plateformes est de pouvoir introduire de manière simple et versatile une biomolécule. La chimie « click » semble être une méthode particulièrement attractive pour pouvoir réaliser cet objectif. Cependant, cette réaction, habituellement catalysée au cuivre est difficilement applicable sur ce genre de plateforme du fait de l’affinité du cuivre pour le macrocycle DO3A. Ce problème a donc été contourné par utilisation de la réaction de chimie « click » catalysée par des complexes de ruthénium afin d’avoir accès aux deux plateformes macrocycliques. / Today physicians can use a wide variety of medical imaging techniques to establish early and accurate diagnosis. Nevertheless, each modality has its own advantages and drawbacks. This is why bi- or multimodality approach seems interesting. Among them, PET/MRI combination seems very promising because it can bring complementary informations. It is therefore necessary to inject to patients tracers specific to each imaging modality. This work described the synthesis of molecular platforms for MRI and PET imaging, according to 2 different strategies. The first one consisted in the synthesis of a DO3A macrocycle allowing the chelation of both gadolinium for MRI and gallium 68 for PET. The aim here is to have a bimodal probe, with a mixture of each compound. The second strategy was the preparation of a single molecule that can be simultaneously labeled by both gadolinium for MRI and fluorine 18 for PET. The final goal is to introduce onto these platforms a biomolecule in a versatile and easy way, to be able to target a specific pathophysiological process. ‘‘Click’’ chemistry seems to be an attractive methodology to achieve this goal. However, this reaction, usually catalyzed with copper is not suitable to DO3A macrocyles due to the copper affinity with those azamacrocycles. This issue has been circumvent by the use of ruthenium catalyzed ‘‘click’’ chemistry. We were then able to access to both macrocycles platforms.

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.