Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-08-10
2004-11-16
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009300, C424S009320, C424S009323, C424S009360, C424S009364, C424S009365
Reexamination Certificate
active
06818203
ABSTRACT:
DESCRIPTION
The invention relates to the use of perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration of <10
−3
mol/l, a hydrodynamic micelle diameter (2 Rh)>1 nm and a proton relaxivity in plasma (R
1
)>10 l/mmol·s as contrast media in MR-imaging both for visualization of plaque, lymph nodes, infarcted and necrotic tissue and for independent visualization of necrotic tissue and tumor tissue. It has been shown that perfluoroalkyl-containing metal complexes with the above-mentioned properties are extremely well suited for the independent visualization of plaque, tumors and necroses with the aid of MR-imaging and simultaneously can also cover the diagnostically important area of infarction and necrosis imaging.
Arteriosclerosis is the most important and most frequent pathological alteration of arteries with hardening, thickening, loss of elasticity and lumen constriction. It represents the most frequent cause of death in Western industrialized countries. Vascular wall alterations are produced by lipid retention, connective tissue reproduction and calcification with irregular dispersion for wall instability, vascular stenosis and for storage of clots. Causes of disease are numerous exogenic and endogenic noxae or diseases, e.g., hypertonia, hyperlipidemia, hyperfibrinogenemia, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammations, hypoxia, mental stress, age and family stress. The latter result in the disruption of the integrity of the vascular inside wall, in the disruption of growth control of smooth muscle cells of the vascular wall and in impairing the degradation of aged cell components. Treatment of arteriosclerosis itself is not possible; the target of medical efforts is prevention by reducing risk factors, e.g., using lipid reducing agents.
The diagnosis of arteriosclerosis in clinical practice is currently carried out mainly by angiography as a gold standard. The limitation in all processes that are based on the measurement of the reduction of the vascular lumen is, however, the early stage of the disease, which is characterized by a thickening of the vascular wall in the case of a normal vascular lumen (Glagov, S., Zarins, C. K. Quantitating Atherosclerosis. In: Bond, M. G.; Insull, W.; Glagov, S.; Chandler, A. B.; Cornhill, J. F. (eds.). Clinical Diagnosis of Atherosclerosis. Quantitative Methods of Evaluation. New York: Springer-Verlag, 1983, 11-35). Another method for diagnostic assessment of vascular wall and vascular lumen is the intravascular or percutaneous ultrasound.
Magnetic nuclear spin resonance tomography (MRT) is a modem, non-invasive radiological process, which makes possible the visualization of physiological and pathophysiological structures with a very good space and time resolution. The use of specific contrast media with selective concentration in certain tissues and organs can increase the diagnostic value considerably in this case. Contrast medium preparations with selective concentration in arteriosclerotic plaque were able to detect location and degree of the disease at an early time and thus to make possible a targeted therapy and prophylaxis, and therefore the search for suitable contrast media began early.
Thus, hematoporphyrin derivatives are claimed in U.S. Pat. No. 4,577,636 as contrast media for the detection of atherosclerotic plaque. As methods, scintigraphy, radiography, fluorescence and, for paramagnetic metalloporphyrins, even NMR-spectrometry, are mentioned. As paramagnetic ions, Gd, Cr, Co, Ni, Ag and Eu are cited.
The disadvantage to these compounds is that the porphyrins are stored in the skin and cause discolorations that can last up to several weeks. Moreover, they result in a photosensitization. In addition, the danger exists that in a long retention time in vivo, the metalloporphyrin loses the metal.
In Application WO 95/09856, metalloporphyrins (deuteroporphyrins) are claimed for diagnosis and therapy of plaque. As a diagnostic method, MRI is mentioned. These porphyrins also cause discolorations of the skin. in Application WO 95/09013, conjugates that consist of specifically binding polypeptides and metal complexes are claimed. These compounds are also to bind to plaque and thus make possible their diagnosis and therapy. As diagnostic methods, scintigraphy, computer tomography, and MRI are mentioned. While scintigraphy is confirmed by experiment, data is lacking for MRI.
Labeled phycocyanines are claimed as contrast media for the imaging of plaque in U.S. Pat. No. 5,807,536. As diagnostic methods, radiography, computer tomography, scintigraphy, SPECT and MRI are mentioned here. Scintigraphy is confirmed by experiment.
Numerous contrast media for infarction and necrosis imaging are known from the literature. Tests were carried out early on to improve the localization of infarctions and necroses by use of contrast media in noninvasive processes such as scintigraphy or nuclear spin tomography. The literature devotes a great deal of space to attempts to use porphyrins for necrosis imaging. The results that are achieved paint a contradictory picture, however. Winkelman and Hoyes thus describe in Nature, 200, 903 (1967) that manganese-5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin (TPPS) selectively accumulates in the necrotic portion of a tumor.
Lyon et al. (Magn. Res. Med. 4, 24 (1987)) observed, however, that manganese-TPPS is dispersed into the body, specifically into the kidney, liver, tumor and only in a small portion to the muscles. It is advantageous in this case that the concentration in the tumor reach its maximum only on the fourth day and also only after the authors have increased the dose from 0.12 mmol/kg to 0.2 mmol/kg. The authors therefore also speak of a non-specific uptake of TPPS in the tumor. Bockhurst et al. in turn report in Acta Neurochir 60, 347 (1994, Suppl.) that MnTPPS binds selectively to tumor cells.
Foster et al. (J. Nucl. Med. 26, 756 (1985)) in turn found that
111
In-5,10,15,20-tetrakis-(4-N-methyl-pyridinium)-porphyrin (TMPyP) does not accumulate in the necrotic portion, but rather in the living edge areas. It follows from the above that a porphyrin-tissue interaction exists, is obvious but not necessary.
In Circulation Vol. 90, No. 4, part 2, page 1468, Abstract No. 2512 (1994), Ni et al. report that they can visualize infarction areas with a manganese-tetraphenyl-porphyrin (Mn-TPP) and a gadolinium-mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219, both substances were used for infarction and necrosis imaging. The authors Marchal and Ni write (see Example 3) that for the compound Gd-MP, the metal content of the infarcted kidney was as high as that of the non-infarcted organ, but that for the myocardium in the infarcted tissue (Example 1), it was nine times as high. It was surprising that the ratio of the signal intensities during MRI for infarcted tissue in comparison to healthy tissue was comparatively high in both cases, at 2.10 or 2.19. Other metalloporphyrins were described in Application DE 19835082 (Schering AG).
Porphyrins tend to be stored in the skin, which results in photosensitization. The sensitization can last for days, and indeed even weeks. This is an undesirable side effect when using porphyrins as diagnostic agents. In addition, the therapeutic index for porphyrins is only very small, since, e.g., for Mn-TPPS, an action starts only at a dose of 0.2 mmol/kg, but the LD
50
is already approximately 0.5 mmol/kg.
Contrast media for necrosis and infarction imaging not derived from the porphyrin skeleton have been described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX).
In DE 19744003, oligomeric compounds, which consist of a nucleus and are bonded to the 1-3 metal complexes, are claimed.
In Application 19744004, lipophilic metal complexes for necrosis and infarction imaging are claimed. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins, and peptides.
In EPIX
Mareski Peter
Misselwitz Bernd
Niedballa Ulrich
Platzek Johannes
Raduechel Bernd
Hartley Michael G.
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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