1. Field of the Invention
The present invention relates to new complexes for co-ordinating a transition metal, in particular lanthanides, and their applications in the medical field.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98
The unique electronic properties of the lanthanide ions, such as their long life luminescence and their well-defined emission spectrum, turn these compounds into an ideal tool for usage in the medical field.
Indeed, the use of the lanthanide complexes, enables to distinguish the fluorescence considered as a background noise and the signal targeted. Thus said complexes are often used, in the design of detectors, as spectroscopic and luminescent probes for solving structural and analytical problems and as fluorescence imaging systems.
According to the rules laid down by the “International Union of Pure and Applied Chemistry” (IUPAC), by lanthanide is meant the series of the chemical elements ranging from Cerium (Z=58) to Lutecium (Z=71). By including Lanthane (Z=57), these elements are called lanthonoid. The expression “rare earth” applies to the lanthanoid together with Scandium (Z=21) and Yttrium (Z=39), the latter having similar chemical properties. In practice, the designations as lanthanides, lanthanoid and rare earth are used for describing these elements.
Generally, the lanthanides form their most stable compounds when they are in +3 oxidation state. The electronic structure of the LnIII ions is that of the xenon for the LaIII and then corresponds to the filling of the orbitales 4f14 up to [Xe]4f14 for the LuIII.
Currently, most studies performed with lanthanide complexes have been oriented towards establishing light-emitting probes including long life visible light transmitters, in particular EuIII and TbIII, or transmitters in the near-infrared spectrum, such as the PrIII, ErIII YbIII or the NdIII.
However, as the prohibited transition 4f-4f, so-called Laporte prohibition, prevents the direct excitation of the lanthanides, the latter must be performed using certain adequate organic chromophores.
In the meaning of the invention a “chromophore” is a molecule capable of absorbing the UV/visible light and of transferring to the metallic centre, which, by accepting such energy, becomes “excited” to a state capable of transmitting light (aerial effect). Preferably a “chromophore”, also called “aerial”, corresponds to an atom moiety liable to partake of long enough a sequence with double links matched in an organic molecule. An aromatic cycle carrying delocalisable π electrons will be considered as a chromophore in the sense of the present invention.
Besides, for practical reasons in physiological conditions, the lanthanide ions must be incorporated in highly stable complexes. Indeed, the efficiency of the energy transfer from the ligand on the lanthanide is decisive for the design of highly performing probes.
Moreover, so as to obtain high quantal throughput, non-radiative de-energisation should be prevented, or at least minimised, of the excited state of the lanthanide ion further to an interaction of the metal with the surrounding water molecules.
The incorporation of the chromophores in certain polydentate ligands studied to that end leads to greater stability of the lanthanide chelates in solution, enabling greater protection of the metal from the water molecules.
However, the tendency of the lanthanide ions to adopt a high co-ordination number and their lack of stereochemical selectivity turn the design of these ligands into a major challenge.
A strategy, which has been adopted by different research groups, is based upon a “tripod” structure of a ligand in order to organise three trivalent binding units in ennea-coordinated LnIII complexes.
This approach has led, in some cases, to an efficient protection of the metal from the surrounding water molecules, but synthesis difficulties make it little interesting.
The preparation of the polydentate ligands, enabling the arrangement of four bidentate moieties around a lanthanide ion, has less drawn the attention of the researchers in spite of the excellent luminescence of observed for tetra complex obtained from bidentate chromophore ligands, such as quinolinates or tropolonates.
Recently, octadentate ligands including four divalent chromophores have led to lanthanide complexes with energy emissions in the ultra-violet zone (UV) or in the near-infrared spectrum (NIR) which are very efficient.
However, the structure of these complexes has not been elucidated as yet, and the fact that the part of the structure of the ligand binding the bidentate units together is highly flexible, involves that the protection of the central metal is far from optimum.
USPTO Backgrounds
USPTO Backgrounds