Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1999-05-26
2002-10-08
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C534S015000, C424S009100, C424S009360, C424S001650, C424S009300
Reexamination Certificate
active
06461588
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the novel use of metal ion chelates of bile acid conjugates with molecules having chelating activity as contrast agents in the diagnostic technique known as “magnetic resonance imaging” (M.R.I.), in particular as blood pool agents.
Complexes formed of chelating agents and suitable metals are already used as contrast agents in the following diagnostic techniques: X-ray imaging, nuclear magnetic resonance imaging (M.R.I.) and scintigraphy.
In particular, medical diagnosis using magnetic resonance imaging (M.R.I.), a recognizedly powerful diagnostic technique in clinical practice (Stark, D. D., Bradley, W. G., Jr., Eds. “Magnetic Resonance Imaging” The C. V. Mosby Company, St. Louis, Mo. (USA), 1988), mainly employs paramagnetic pharmaceutical compositions, preferably containing chelated complexes of bi-trivalent paramagnetic metal ions with polyaminopolycarboxylic ligands and/or their derivatives or analogues.
The images basically coming from the NMR signal of water protons are the result of a complex interaction between different parameters, such as proton density and T
1
and T
2
relaxation times. A contrast enhancement can be obtained through the administration of exogenous chemical substances which significantly change the resonance properties of nearby water protons (see Lauffer, R. B. Chem. Rev. 1987, 87, 901).
The paramagnetic contrast agents used for N.M.R imaging act modifying the relaxation times of the water protons present in the tissues in which said contrast agent is concentrated, and they can therefore increase the contrast between different tissues, or between healthy and diseased tissues.
Gadolinium paramagnetic complexes, due to their high capability of reducing relaxation times of the protons of nearby water molecules through dipolar interaction, have been the object of studies, publications and patents.
Some of them are at present in clinical use as M.R.I. contrast agents:
Gd-DTPA, N-methylglucamine salt of the gadolinium complex with diethylenetriaminopentaacetic acid, MAGNEVIST®; Gd-DOTA, N-methylglucamine salt of the gadolinium complex with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAREM®; Gd-HPDO3A, gadolinium complex with [10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, PROHANCE®; Gd-DTPA-BMA, gadolinium complex with diethylenetriaminopentaacetic acid bis(methylamide), OMNISCAN®.
The contrast agents listed above and commercially available are intended for a general use. In fact, after administration, the said M.R.I. contrast agents diffuse in blood and in the extracellular areas of various parts of the body before being excreted. They are therefore similar, in this respect, to the iodinated compounds used for X-ray medical diagnosis.
At present the medical profession is in need of contrast agents that are aimed at specific organs or for imaging of the blood system, which cannot be well defined by means of the usual products already commercially available. The first approach to obtain the latter consisted in covalently linking the contrast agent to macromolecules, such as proteins, or in inglobating it inside stable molecular aggregates such as liposomes, or still in using the so-called superparamagnetic particles.
For example, the gadolinium complex with diethylenetriaminopentaacetic acid (Gd-DTPA) was linked to human albumin (HSA), polylysine or dextran (Oksendal A. N. et al., J. Magn. Reson. Imaging, 157, 1993; Rocklage S. M., “Contrast Agents, Magn. Res. Imaging, Mosby Year Book, 372-437, 1992) in order to minimize or even suppress the diffusion from blood into the extracellular fluid thus providing a higher retention of the agent in the blood system. Such an approach, although attaining the desired effect, suffers from disagreeable side effects as the agent itself is excreted with difficulty.
A different strategy is the use of superparamagnetic particles coated with polyethylene glycols or hydrocarbons in order to reduce the hepatic uptake by endothelial reticulum or by other systems (Tilcock C., Biochim. Biophys. Acta, 77, 1993; Bogdanoy A. A. et al., Radiology, 701,1993), thus prolonging the permanence of said agents in blood. In this case also the above mentioned side effects occur, as well as problems due to the high production cost.
The demand for an efficient blood pool agent, having low toxicity and reasonably economic costs, is therefore still unmet.
The present invention relates to the novel use as blood pool agents of specifically selected compounds, already previously described by the Applicant in international patent application WO-A-95/32741, resulting from the conjugation of a bile acid with a chelating agent, which are capable of chelating the ions of paramagnetic bi-trivalent metals, as well as novel compounds, the process for the preparation thereof and the use thereof as blood pool agents.
Said compounds have shown a good hepatobiliary excretion (see Rings P. L. et al., Acta Radiologica, 38, 125, 1997) which makes them promising contrast agents for visualizing the hepatobiliary system.
It has now surprisingly been found that a specific class of said compounds remains in the vascular system for a sufficiently long time so as to be valuable for use as contrast agents for the imaging of the vascular system, particularly of coronaries.
This effect can be clearly evidenced carrying out in vivo tests in animals (such as rabbit, monkey). The permanence in the vascular system can in fact be immediately visualized when plotting the proton relaxation values (1/T
1
) of blood samples of the animal, taken at appropriate time intervals after administration of the contrast agent.
As Gd(III) complexes are among the preferred paramagnetic species, high 1/T
1
values are evidence of high concentrations of the contrast agent in blood.
The difference between a conventional extracellular contrast agent and a blood pool agent, is well clarified in the paper by Lauffer et al., Radiology, 529,1998 in which T
1
profiles in blood as a function of time elapsed after the administration of the contrast agent are reported.
In particular, the complexes of the present invention, when administered for example to the rabbit at a dosage compatible with a reasonable safety index, are capable of inducing changes in relaxation rates (measured in &Dgr;1/T
1
) in blood higher than 5 s
−1
10 minutes after administration, thus being promising for use as contrast agents for the imaging of the vascular system.
It has been found that this type of effect cannot be solely related to the presence of bile acids, but it depends on the chemical structure of said complexes. It seems, in fact, that the chelating unit should be preferably linked to the steroidal skeleton through a bond at the 3,7 or 12 positions of the bile acid.
It has, in fact, been proved that any linkage between the chelating unit and the bile acid involving the carboxylic group at the 24 position would yield complexes having unsatisfactory permanence in the vascular system.
REFERENCES:
patent: 6010681 (2000-01-01), Margerum et al.
patent: 9532741 (1995-12-01), None
Anelli Pier Lucio
Brocchetta Marino
De Haen Christoph
Gazzotti Ornella
Lattuada Luciano
Bracco Imaging S.p.A.
Jones Dameron L.
Nixon & Vanderhye P.C.
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