The development of Gd(III)-based contrast agents for MRI applications has intensified in recent years due to the paramagnetic ion’s long electron spin relaxation time and large effective magnetic moment, µeff. Secondly, the exploitation of the long lived luminescent properties of the Ln(III) ions has lead to the development of luminescent lanthanide probes for sensing, time resolved immunoassay and imaging applications. Herein a series of novel Ln-DO3A based complexes are reported. Modulation of relaxivity, r1, (Gd) and emission intensity (Eu, Tb, Sm and Dy) has been achieved in three ways: Firstly, mono- and bis-methyl Ln-dpp-DO3A based complexes have been prepared, where dpp is a pendant diphenylphosphinamide moiety. These show pH responsive relaxivity (Gd) and luminescence (Eu) with calculated pKa values of 8.65 (± 0.09) and 8.59 (± 0.14). Sensitised emission of Eu(III), Tb(III), Dy(III) and Sm(III) has been observed following excitation of the dpp antenna at λex ~ 270 nm. Relaxivities have been measured as r1 = 7.9 mMˉ¹sˉ¹and r1 = 8.2 mMˉ¹sˉ¹ in acidic media, q = 2 and r1 = 5.4 mMˉ¹sˉ¹ and r1 = 4.4 mMˉ¹sˉ¹ in basic media, q = 1 for the mono- and bis-methyl Gd-dpp-DO3A complexes respectively. The pH responsive behaviour has been attributed to the reversible ligation of the dpp moiety. Secondly, non-covalent attachment of the mono- and bis-methyl Gd-dpp-DO3A-based complexes to Human Serum Albumin (HSA) at pH 7.4 resulted in a 64% (r1 = 11.7 mMˉ¹sˉ ¹) and a 146% (r1 = 16.0 mMˉ¹sˉ¹) enhancement in relaxivity, with binding affinities, K, determined from luminescence studies as K = 22,268 ± 12% Mˉ¹and K = 20,059 ± 14% Mˉ¹ for the mono- and bis-methyl dpp Eu-dpp-DO3A complexes respectively. The negatively charged [Gd-dpp-aDO3A]3ˉ complex was developed in order to improve the observed relaxivity of the HSA bound species: r1 = 16.0 mMˉ¹sˉ¹, K = 17,915 (± 14%) Mˉ¹. Competitive binding studies with the fluorescent probes dansylsarcosine and warfarin showed each of the dpp complex analogues to bind preferentially to HSA site II, only the S-enantiomer of the mono-methyl Gd-dpp-DO3A showed an affinity for site I. Finally, an accumulation and activation strategy following enzyme activity has been demonstrated. Neutral q = 2 Gd(III) ethyl and acetoxymethyl ester Ln-DO3MA based complexes have shown decreased relaxivity in the presence of carbonate due to the inner sphere water molecule displacement by bidentate anion binding. The binding is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in ~ 84% relaxivity enhancement (Gd) as well as Eu luminescence quenching. The high observed relaxivity of the ethyl ester model: r1 = 10.2 mMˉ¹sˉ¹ is attributed to the extremely short observed water exchange lifetime, τm = 7.9 ns.

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This thesis focuses on the development of sensitive, yet kinetically stable, (i.e. non-toxic) contrast agents for Magnetic Resonance Imaging (MRI). MRI is a widely used medical imaging technique in both research and clinical contexts. While currently approved contrast agents have significantly contributed to advancement of clinical diagnosis, there is an increasing need for development of contrast agents with high relaxivity (‘MRI activity’). This demand is approached in the current project by using a tetra-alkynyl cyclen-based ligand to: a. Work towards formation of a gadolinium-based ‘cage’ which would entrap the Gd centre within its cavity in a less coordinatively saturated manner than the current Gd-based MRI contrast agents. b. Synthesize novel oligomeric gadolinium-chelates with improved relaxivity profiles. Two families of oligomeric lanthanide-chelates were synthesized via Huisgen 1,3-dipolar and Diels Alder cycloadditions. The oligomers were produced with A4/B2 hyperbranched polymerisation methodology. The relaxation enhancement properties of the oligomeric Gd(III) and luminescence and where possible Paramagnetic Chemical Exchange Saturation Transfer (ParaCEST) profiles of the oligomeric Eu(III) chelates were studied. The relaxivity studies showed up to a four-fold increase in relaxivity as compared to their corresponding monomer. This is the first example of such significant enhancement in relaxivity of a tetrakis (acetamido)- 1,4,7,10-tetraazacyclododecane (DOTAM)-based gadolinium containing agent. The branched polymers presented in this work, can be modified such that further functional groups can be incorporated with stoichiometric control bearing targeted moieties to image specific biological events. To this end, work was carried towards development of a two different designs for pyridyl-based phosphate-sensing Ln-based complex.

Depuis la proposition en 2006 d’utiliser des nano aimants réalisés par des techniques top-down pour reproduire des « spins artificiels », l’étude des systèmes de spins artificiels a suscité un large intérêt. En effet la possibilité de pouvoir réaliser arbitrairement tous types de réseaux de spins artificiels et de pouvoir imager les configurations magnétiques de ceux-ci dans l’espace direct, offre un large terrain de jeu dans le domaine de la physique statistique. Jusqu’à présent seuls des réseaux de spins d’Ising, multi axes (réseaux kagomé ou carré avec une aimantation planaire) ou plus récemment uni axes (avec une anisotropie perpendiculaire), ont été étudiés. Cependant en physique statistique d’autres modèles de spins sont étudiés et notamment les modèles de Potts à q-états. Au cours de cette thèse nous avons étudié le cas d’un modèle de Potts à 4 états, ayant la particularité de posséder uniquement des interactions dipolaires entre les spins: le modèle de Potts dipolaire. Nous avons tout d’abord réalisé une étude théorique, montrant que sur un réseau carré, en fonction de l’angle entre les spins et ce réseau, le système possède des états fondamentaux très différents : un ordre antiferromagnétique, un ordre respectant les règles de la glace (2 in- 2 out) ou un ordre ferromagnétique. Dans une deuxième partie, nous avons exposé l’étude expérimentale du modèle de Potts dipolaire. Des réseaux formés d’aimants carrés ayant 300 nm de côté ont été réalisés par lithographie électronique, à partir d’une couche épitaxiée de Fer possédant une anisotropie quadratique. A température ambiante, ces plots possèdent une configuration magnétique monodomaine pouvant prendre 4 directions équivalentes, comme recherché pour le modèle de Potts dipolaire à 4 états. Un passage à 350°C (inférieure à la température de Curie) sous champ nul permet d’activer thermiquement la réorientation des spins afin qu’ils se rapprochent de l’état fondamental de l’assemblée de spins. Les configurations magnétiques observées après recuit, à l’aide d’un microscope à force magnétique, montrent l’importance du couplage dipolaire sur les états obtenus, ainsi que l’influence de l’angle entre les spins et l’axe du réseau. Les différentes configurations prédites théoriquement sont bien observées / Since the proposal in 2006 to use nanomagnets patterned by top-down techniques to mimic "artificial spins", the studies of artificial spin systems has attracted wide interest. As a matter of facts, the possibility to design "upon request" arbitrary network and the possibility to determine completely the "spin" configuration with magnetic imaging offer a wide playground for statistical physics. Up to now only Ising spin systems, multi axes with planar magnetization (on square or Kagome lattice) or more recently, single axis with perpendicular anisotropy, have been studied. However, beyond Ising spins, statistical physics and condensed matter physics have shown the interest of other spin models like q-state Potts models. In this thesis, we introduce the dipolar 4-state Potts model. It is shown that on a square lattice, depending on the angle between spins and lattice, the system present very different properties like antiferromagnetic order, spin ice state (2 in-2 out ice rule) and even dipolar ferromagnetism. This model has been realized experimentally. 300 nm square magnets are patterned from a 2 nm thick Fe layer with cubic anisotropy. At room temperature, the magnets present a uniform state with 4 equivalent directions. Upon heating at 350 °C the magnets switch from one direction to another. It is therefore possible to simply drive the system toward its ground state. The magnetic configurations determined by magnetic force microscopy reveals the importance of the dipolar coupling as the different expected ground states (antiferromagnetic, spin ice and ferromagnetic) are indeed observed. It is noticeable that these very different properties are obtained with the same "spins" (magnetic elements) and same lattice

Deux méthodes d'imagerie par résonance magnétique sont proposées pour analyser in vivo le tissu cérébral de la matière blanche. La première méthode permet l'acquisition ultra-rapide de cartes des métabolites cérébraux par une lecture de l'espace réciproque répétée à des intervalles de quelques millisecondes à l'aide d'une nouvelle trajectoire excentrée, combinée à un gradient de retour. Une procédure de correction de phase, pour prévenir la formation d'artéfacts de repliement dans l'image et le spectre, est introduite sur la base de paramètres déterminés à partir du signal des protons de l'eau. Une acquisition des cartes métaboliques tridimensionnelles de la créatine, de la choline, du N-acétylaspartate, du glutamate et du myo-inositol ont été déterminées de manière fiable dans la substance blanche humaine à 3 Tesla avec une matrice de taille 32 × 32 × 16 et une résolution isotropique de 7 mm. La deuxième méthode permet l'acquisition d'un train de 32 images échantillonnées géométriquement le long d'une courbe de recroissance, en employant une série d'échos de gradient excités par un angle de bascule de 5° pour éviter des effets de saturation. Après transformée inverse de Laplace utilisant une régularisation spatiale, on obtient une distribution continue des temps de relaxation spin-réseau, T1. Dans la région de T1 entre 100 ms et 230 ms, on distingue un pic attribué à l'eau hydratant les membranes de la myéline. La fraction apparente de cette composante de l'eau de myéline augmente en fonction de l'intensité du champ magnétique, de 8,3 % à 3 Tesla, à 11,3 % à 4 Tesla, pour atteindre 15,0 % à 7 Tesla / Two magnetic resonance imaging methods are proposed for the in vivo investigation of human brain white matter tissue. The first method allows the ultra-fast acquisition of maps of brain metabolites by repeating the sampling of k-space at intervals of a few milliseconds, with a center-out trajectory combined with flyback gradients. A phase-correction procedure is introduced to prevent the formation of aliasing artifacts in the image and in the spectrum, on the basis of parameters determined from the signal of the ubiquitous water protons. An acquisition of threedimensional metabolite maps of creatine, choline, N-acetylaspartate, glutamate, and myo-inositol were determined reliably in human brain white matter at 3 Tesla with a 32 × 32 × 16 matrix and a 7-mm isotropic resolution. The second method enables the acquisition of a train of 32 images geometrically sampled along an inversion-recovery curve, using a series of gradient echoes excited by a low 5° flip angle to avoid saturation effects. After inverse Laplace transform, using a spatial regularization, a continuous distribution of the spin-lattice relaxation times, T1, is obtained. In the region of T1 between 100 ms and 230 ms, a small component is attributed to water hydrating myelin membranes. The apparent fraction of this myelin water component increases with the strength of the magnetic field, from 8.3% at 3 Tesla, to 11.3% at 4 Tesla, and 15.0% at 7 Tesla