Cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives are widely used for various purposes. In a medicine they are applied as ligands for radiometals applied as diagnostic or therapeutic agents against tumours, hypoxic brain tissues etc. In this thesis a new method for asymmetric cyclam derivati- ves preparation was developed. New cyclam derivatives with trifluoroethyl groups were prepared too. Paramagnetic metal complexes with these fluori- nated ligands can be used as contrast agents for 19 F-MRI. Keywords: Cyclam; Non-symmetric protection; Contrast agents; Trifluoroethylamines; Paramagnetic relaxation; 19 F-MRI.

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...

In this doctoral thesis we describe a series of stimuli-responsive polymers which could be used as diagnostic tools or as smart drug delivery systems with simultaneous diagnosis (theranostics). All hereby mentioned polymers are thermoresponsive copolymers of (N-2,2-difluoroethyl)acrylamide exhibiting lower critical solution temperature in aqueous milieu. This means that they are water-soluble at low temperature while when heated above a certain temperature, they self-assemble into nano- or macro- sized assemblies. Because of the high concentration of fluorine atoms, all these polymers could be used as 19 F MRI tracers. We designed multiple different thermoresponsive, thermo- and pH-responsive, thermo-and reactive-oxygen-species-responsive polymers that could find numerous discussed applications in human medicine. We investigated their physico-chemical properties with 1 H and 19 F nuclear magnetic resonance (NMR), size exclusion chromatography (SEC), elemental analysis, dynamic light scattering (DLS), static light scattering (SLS), small angle neutron scattering (SANS), small-angle X-ray scattering (SAXS), and turbidimetry. After the physicochemical optimization of the parameters for the selected applications, their biocompatibility was tested in vitro. Several promising polymers were tested in vivo...

L’objectif ici était de développer une méthode de détection des tumeurs cérébrales via des agents de contraste pour l’IRM du 19F à 7 teslas. Nous évaluons en particulier le potentiel de cette méthode à mettre en évidence l’angiogenèse tumorale à l’aide d’agents de contraste fonctionnalisés avec le peptide RGD et ciblant l’intégrine ανβ3, biomarqueur surexprimé à la surface des néo-vaisseaux irriguant la tumeur. Du fait des basses concentrations locales en agent de contraste, les efforts portent dans un premier temps sur l’optimisation d’une séquence multi échos de spin dédiée à l’imagerie du PFOB (perfluorooctyl bromure), perfluorocarbure biocompatible choisi pour constituer la base de nos agents de contraste. Nous montrons qu’un paramétrage minutieux de cette séquence permet la suppression de la J-modulation et un rehaussement du T2, conduisant à une excellente sensibilité in vitro. La séquence est ensuite testée pour des mesures d’oxygénation dans le foie et la rate chez la souris, après injection d’une émulsion de PFOB. Les résultats indiquent une très bonne précision des mesures après injection d’une seule dose d’émulsion. Notre séquence est également utilisée pour réaliser une étude de biodistribution dynamique, permettant de suivre l’accumulation des nanoparticules d’émulsion dans le foie et la rate juste après injection. Nous montrons par ailleurs qu’il est possible d’évaluer la furtivité d’émulsions contenant différentes quantités de PEG (Poly Ethylène Glycol) en ajustant les données expérimentales sur un modèle pharmacocinétique empirique. La séquence est enfin utilisée pour détecter des nanoparticules d’émulsions fonctionnalisées pour cibler l’intégrine ανβ3 dans un modèle souris U87 de glioblastome. Nous comparons les concentrations en agent de contraste obtenues dans la tumeur avec une émulsion contenant le peptide RGD, et une émulsion contrôle. Les résultats indiquent des concentrations significativement plus élevées avec l’émulsion RGD qu’avec l’émulsion contrôle, supposant un ciblage spécifique d’ανβ3 par les nanoparticules fonctionnalisées. Un dernier chapitre est dédié à une nouvelle méthode de spectroscopie de diffusion en 19F, dont le but est d’éliminer le signal vasculaire provenant des nanoparticules de PFOB circulantes afin d’évaluer le signal ne provenant que des particules liées. / This study aimed at developing a method for detection of brain tumors at 7 teslas thanks to 19F MRI contrast agents. We particularly assessed the potential of this method to highlight tumor angiogenesis with RGD-functionalized contrast agents targeting ανβ3 integrin, a biomarker over-expressed at the surface of new capillary blood vessels. Owing to low local concentrations in contrast agent, the first step consisted in optimizing a multi spin echo sequence dedicated to a well-known biocompatible perfluorocarbon, perfluorooctylbromide (PFOB). We show that careful adjustment of sequence parameters allows cancellation of J-modulation and T2 enhancement, and yields an excellent sensitivity in vitro. Our sequence was then tested for oxygenation measurements in the mouse liver and spleen after injection of a PFOB emulsion. The results demonstrate very good accuracy of the measurements after one single infusion of emulsion. We also perform a dynamic biodistribution study in order to monitor emulsion nanoparticle uptake in the liver and spleen. Moreover, we show that stealth of emulsions grafted with different quantities of polyethylene glycol (PEG) can be assessed by fitting experimental data with a pharmacokinetic empirical model. Our sequence was finally used to visualize ανβ3-targeted nanoparticles in a U87 glioblastoma mouse model. Concentrations found in tumors after injection of an RGD-functionalized emulsion and a control emulsion are compared. Concentrations are found to be significantly higher with the RGD emulsion than with the control emulsion, suggesting specific binding of functionalized nanoparticles with ανβ3 integrin. The last part is dedicated to a new diffusion-weighted 19F NMR spectroscopy sequence. This method aims at suppressing vascular signal coming from circulating PFOB nanoparticles in order to evaluate signal coming from bound nanoparticles only.