Reactivity of manganese, technetium and rhenium aquacarbonyl-complexes as potential precursors for radiopharmaceuticals

Technetium is an artificial element and its isotope 99mTc is now used for several years as radio-imaging agent. Much research effort is directed towards enhanced targeting of the imaging agents in order to improve accuracy of the diagnosis and reduce the radiation doses delivered to the patient. Technetium(I) complexes are promising in this field and especially those with the fac-[(CO)3Tc]+ entity. Rhenium which is closely related to technetium, is used as model compound, but has also its own radiopharmaceutical potential with the isotopes 186Re and 188Re. The preparative chemistry of 99mTc has to be performed in water. Therefore, it is of importance to know its actual form in solution and understand its reactivity. Thus the goal of the present work was to investigate the reactivity of fac- [(CO)3Mn(H2O)3]+, fac-[(CO)3Tc(H2O)3]+, fac-[(CO)3Re(H2O)3]+ et fac- [(CO)2(NO)Re(H2O)3]2+ by multinuclear magnetic resonance. The water exchange rates on these complexes have been determined as a function of acidity and for tow of them (Mn and Tc) as a function of temperature. The water exchange rate decreases when going from manganese to technetium and then to rhenium. In the latter case it was found that the replacement of a CO ligand by an NO+ ligand decreases again the lability of the water molecules. For the two rhenium complexes an increase of the water exchange rate with decreasing acidity has been observed. Water molecules on fac-[(CO)3Mn(H2O)3]+, fac-[(CO)3Tc(H2O)3]+, fac- [(CO)3Re(H2O)3]+ complexes are easily substituted. This reaction has been investigated with selected ligands of various types. The complexes show a stronger affinity for soft ligands such as dimethylsulfide than for harder ligands like acetonitrile. Variable pressure experiments for the ligand substitution on fac- [(CO)3Re(H2O)3]+ provided activation volumes. The substitution by the soft ligand was found to be associatively activated whereas the substitution by hard ligands is dissociatively activated. Although activation volumes could not be determined for the substitution reaction on fac-[(CO)3Mn(H2O)3]+ and fac-[(CO)3Tc(H2O)3]+ their similar reactivity suggests that they exhibit the same mechanistic behaviour as fac- [(CO)3Re(H2O)3]+.

Novel chelators for MRI applications

In the last two decades, Magnetic Resonance Imaging (MRI) has evolved into one of the most powerful techniques in diagnostic clinical medicine and biomedical research. MRI is primarily used to produce anatomical images, but may also give information on the physical-chemical state of tissues, flow diffusion and motion. The strong expansion of medical MRI has prompted the development of a new class of pharmacological products, called contrast agents, designed for administration to patients in order either to enhance the contrast between normal and diseased tissue or to indicate organ function or blood flow. Nowadays, around 30 % of all MRI investigations use a contrast medium, which number will certainly further increase with the development of new agents and applications. Since the first clinical application of MRI contrast agents in the eighties, many attempts have been made to ameliorate their efficiency. The aim of this work was to enlarge our knowledge on the physical chemistry of MRI related paramagnetic metal chelates in the perspective of contributing to the development of more efficient, more tissue specific and safer contrast agents. Thermodynamic stability and kinetic inertness of the metal complexes are crucial features for their safe biomedical application. We have carried out detailed kinetic studies on the dissociation of various Gd(III) chelates which have been recently proved to have optimal water exchange rate. The ligands involved both acyclic and macrocyclic molecules. In order to approach the biologically relevant conditions, we studied exchange reactions between these Gd(III) complexes and the endogenously most abundant Zn2+ ion. For the macrocyclic compounds, formation kinetic studies have also been performed for various lanthanides. Lanthanide and transition metal complexes of several novel chelators have been subject of thermodynamic stability studies, using pH-potentiometry, UV-Vis spectrophotometry or 1H NMR. Among the ligands, we find a series of linear, pyridine and phosphonate containing molecules, and diverse macrocyclic, dimeric structures. Their Gd(III) or Mn(II) complexes were characterized with regard to MRI contrast agent application. The rate and mechanism of the water exchange, as well as the rotational dynamics of the molecules have been assessed by variable temperature, variable pressure and multiple field 17O NMR and 1H NMRD measurements. On the Gd(III) complexes of xylene-cored DO3A dimers, we have identified an unexpected aggregation phenomenon. With one of the pyridine and phosphonate containing complexes, we have demonstrated that water exchange rates as high as that on the aqua ion are possible to achieve.

EPFL2006

Fe N-Heterocyclic Carbene Complexes as Promising Photosensitizers

Yizhu Liu

The photophysics and photochemistry of transition metal complexes (TMCs) has long been a hot field of interdisciplinary research. Rich metal-based redox processes, together with a high variety in electronic configurations and excited-state dynamics, have rendered TMCs excellent candidates for interconversion between light, chemical, and electrical energies in intramolecular, supramolecular, and interfacial arrangements. In specific applications such as photocatalytic organic synthesis, photoelectrochemical cells, and light-driven supramolecular motors, light absorption by a TMC-based photosensitizer and subsequent excited-state energy or electron transfer constitute essential steps. In this context, TMCs based on rare and expensive metals, such as ruthenium and iridium, are frequently employed as photosensitizers, which is obviously not ideal for large-scale implementation. In the search for abundant and environmentally benign solutions, six-coordinate Fe-II complexes ((FeL6)-L-II) have been widely considered as highly desirable alternatives. However, not much success has been achieved due to the extremely short-lived triplet metal-to-ligand charge transfer((MLCT)-M-3) excited state that is deactivated by low-lying metal-centered (MC) states on a 100 fs time scale. A fundamental strategy to design useful Fe-based photosensitizers is thus to destabilize the MC states relative to the 3MLCT state by increasing the ligand field strength, with special focus on making e(g) sigma* orbitals on the Fe center energetically less accessible. Previous efforts to directly transplant successful strategies from (RuL6)-L-II complexes unfortunately met with limited success in this regard, despite their close chemical kinship. In this Account, we summarize recent promising results from our and other groups in utilizing strongly sigma-donating N-heterocyclic carbene (NHC) ligands to make strong-field (FeL6)-L-II complexes with significantly extended 3MLCT lifetimes. Already some of the first homoleptic bis(tridentate) complexes incorporating (CNHCNpyridineCNHC)-N-boolean AND-C-boolean AND)-type ligands gratifyingly resulted in extension of the (MLCT)-M-3 lifetime by more than 2 orders of magnitude compared to the parental Fe(tpy)(2) (tpy = 2,2':6',2 ''-terpyridine) complex. Quantum chemical (QC) studies also revealed that the (MC)-M-3 instead of the (MC)-M-5 state likely dictates the deactivation of the (MLCT)-M-3 state, a behavior distinct from traditional (FeL6)-L-II complexes but rather resembling Ru analogues. A heteroleptic Fe-II NHC complex featuring mesoionic bis(1,2,3-triazol-S-ylidene) (btz) ligands also delivered a 100-fold elongation of the (MLCT)-M-3 lifetime relative to its parental Fe(bpy)(3) (bpy = 2,2'-bipyridine) complex. Again, a Ru-like deactivation mechanism of the (MLCT)-M-3 state was indicated by QC studies. With a COOH functionalized homoleptic complex, a record (MLCT)-M-3 lifetime of 37 ps was recently observed on an Al2O3 nanofilm. As a proof of concept, it was further demonstrated that the significant improvement in the (MLCT)-M-3 lifetime indeed benefits efficient light harvesting with Fe-II NHC complexes. For the first time, close-to-unity electron injection from the lowest-energy (MLCT)-M-3 state to a TiO2 nanofilm was achieved by a stable Fell complex. This is in complete contrast to conventional (FeL6)-L-II-derived photosensitizers that could only make use, of high-energy photons. These exciting results significantly broaden the understanding of the fundamental photophysics and photochemistry of d(6) Fe-II complexes. They also open up new possibilities to develop solar energy-converting materials based on this abundant, inexpensive, and intrinsically nontoxic element.

Amer Chemical Soc2016

Novel chelators for MRI applications

EPFL2006

Fe N-Heterocyclic Carbene Complexes as Promising Photosensitizers

Yizhu Liu

Amer Chemical Soc2016