RUBEN MARIO (FR)
KRUK DANUTA (PL)
RAJADURAI CHANDRASEKAR (IN)
RUBEN MARIO (FR)
KRUK DANUTA (PL)
RAJADURAI CHANDRASEKAR ET AL: "Spin Transition in a Chainlike Supramolecular Iron(II) Complex", INORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 45, no. 25, 2006, pages 10019 - 10021, XP002472201, ISSN: 0020-1669
RAJADURAI C. ET AL.: "Above room temperature spin transition in a metallo-supramolecular coordination oligomer/polymer", CHEMICAL COMMUNICATIONS, vol. 25, May 2007 (2007-05-01), pages 2636 - 2638, XP002478130
THOMPSON ET AL: "Structural studies of thermal- and light- induced transitions in iron(II) spin-crossover complexes", COMPTES RENDUS - CHIMIE, ELSEVIER, PARIS, FR, vol. 8, no. 9-10, September 2005 (2005-09-01), pages 1365 - 1373, XP005096099, ISSN: 1631-0748
Claims :
The use of a spin crossover complex with the general formula [M x+ (L y ) H W ]AN) 2 where
M is a positively charged metal ion,
L is a heteroaromatic ligand containing at least one nitrogen atom in its ring system,
AN is a negatively charged inorganic anion, w means zero or one or two x means two or three, y means two or three, and z means two, three or four as a contrast agent in magnetic resonance imaging of human or animal bodies .
2. The use according to claim 1 with a complex with the general formula [M x+ (L y ) Hj AN) z with Fe 2+ or Fe 3+ or Co 2+ for the metal ion
3. The use according to one of the claims 1 or 2 with a complex with the general formula [M x+ (L y ) H w ] AN) z with BF 4 " or Cl " or SO 4 2" or ClO 4 " for the inorganic anion AN.
4. The use according one of the claims 1, 2 or 3 with L = (4'- (4 ' ' ' -pyridyl) -1, 2 ' : 6' 1' ' -bispyrazolylpyridine) and y = 2. |
The use of the spin crossover complex [M^ + (La)H w ]AN) 2 as a magnetic resonance imaging contrast agent
The invention relates to the use of the spin crossover complex [M x+ (L y ) H w ] AN) z as a contrast agent in magnetic resonance imaging (MRI) according to claim 1.
A very active field of application of nuclear relaxation enhancement is the development and use of magnetic materials as contrast agents in magnetic resonance imaging. The magnetic species enhance the proton relaxation rates due to a random variation of the electron spin - nuclear spin interactions (the dipole-dipole interaction and the magnetic hyperfine interaction between the nuclear and electron magnetic moments) , which open new pathways for longitudinal as well as transverse relaxation.
A well known category of contrast agents is paramagnetic solutions of transition metal complexes (very popular are Gd and Mn based contrast agents) . In this case the origin of the nuclear relaxation enhancement is found in the value of the electronic magnetic moment (about 650 times that of the proton) . The efficiency of contrast agents is investigated involving a concept of relaxivity, referring to the nuclear relaxation enhancement normalized to 1 mM concentration of the magnetic species. At not too high concentration of the paramagnetic species, the enhancement is proportional to that concentration. Measurements of the relaxation enhancement or relaxivity over a broad range of magnetic fields are referred to as relaxometry, and the resulting curve is denoted as a nuclear magnetic relaxation dispersion (NMRD) profile. On the experimental side, the NMRD profiles are usually measured by the field-cycling technique, where the magnetic field is rapidly switched between different values. The measured relaxivity values for Gd and Mn based contrast agents are usually in the range of 20-50 l/mM*s (D. Kruk, T. Nilsson, J. Kowalewski, Phys . Chem. Chem. Phys., 3, 4907-4917, (2001), D. Kruk, J. Kowalewski, J " . Biol. Inorg. Chem., 8 (5), 512-518, (2003) ) .
The publication Chandrasekar Rajadurai, Frank Schramm, Susan Brink, Olaf Fuhr, Robert Kruk, Mohammed Ghafari, Mario Ruben, "Spin Transition in a Chainlike Supramolecular Iron (II) Complex", Inorg. Chem. (communication) , (2006), 45, 10019-10021 teaches the synthesis, structure and characterization of the spin transfer complex [Fe 11 - (L) 2 H] (ClO 4 ) 3 . MeOH [L = 4 ' - (4 ' ' ' -pyridyl) -1, 2 ' : 6' 1' ' -bis- (pyrazolyl) pyridine] (complex 1) . The publication also describes the reversible, thermally driven spin transition at 286 K with a hysteresis loop of ca. 2 K of complex 1.
The publication of Chandrasekar Rajadurai, Olaf Fuhr, Robert Kruk, Mohammed Ghafari, Horst Hahn and Mario Ruben, "Above room temperature spin transition in a metallo-supramolecular coordination oli- gomer/polymer", Chem. Commun. , 2007, 2636-2638 gives more information about the spin transition and other physical properties of the complex 1.
It is an object of the present invention to propose agents which can be used as a contrast agent in magnetic resonance imaging. In particular it is an object of the invention to propose an advantageous use of the above mentioned spin crossover complexes.
According to the invention the use of a spin crossover complex is proposed as a contrast agent in magnetic resonance imaging of human or animal bodies having the general formula [M x+ (L y ) Hj AN) z where
M is a positively charged metal ion,
L is a heteroaromatic ligand containing at least one nitrogen atom in the ring system,
AN is a negatively charged inorganic anion, w means zero, one or two x means two or three, y means two or three, and z means two, three or four
Complexes with the general formula [M x+ (L y ) H w ] AN) z with Fe or Fe or Co 2+ for the metal ion M x+ are preferred. Especially preferred are complexes having the general formula [M x+ (L y ) H w ] AN) z with BF 4 " or Cl " or
SO. 2- or ClO 4 " for the inorganic anion AN and/or with L = (4'-(4'''- pyridyl) -1, 2' : 6' 1' ' -bispyrazolylpyridine) and y = 2.
Most useful are complexes with the following structure:
[Fe 11 CL 2 )H] (C1O 4 ) 3 (L = (4'-(4'"-pyridyl)-l,2':6'l"-bispyrazolylpyridine) (I)
The complexes according to the invention are applied in the usual way as contrast agents, e.g. orally or intravenously. Of course, not poisonous anions are used.
In the following the invention is explained in more detail:
The above mentioned Iron (II) containing spin crossover complex [Fe 11 (L 2 ) HJ (ClO 4 ) 3 'MeOH (I) (w = 1) was used to test the NMRD relaxation profile of the compound with different magnetic field. In this experiment, the NMRD relaxation profiles of the compound have been collected for the discussed material.
The diagram according to the figure was obtained.
One can conclude from this experiment that:
1. The proton relaxation is very efficient (taking into account comparable distances between the electron spin and proton spin in this case and in the case of the mentioned paramagnetic contrast agents)
2. One observes very significant difference between the proton relaxation rates in a guide narrow temperature range. This effect is due to the thermally driven spin transition of Fe. There is a mixture of HS (high spin) and LS (low spin) states of Fe at 300K. The relaxation enhancement is caused by the presence of the magnetic moment associated with HS Fe. Upon heating the HS fraction has further increased leading to a more efficient proton relaxation. The relaxation enhancement is very sensitive for the fraction of HS Fe.
3. We found better relaxation rates at higher temperatures (see figure, open squares) , which are useful to discriminate warmer regions of the human or animal bodies, such as tumor tissue.