Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-18
2001-12-11
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C424S009340, C424S009600, C534S747000, C534S822000, C536S026600, C536S029110, C536S029130, C548S362500, C548S364700
Reexamination Certificate
active
06329531
ABSTRACT:
The invention relates to compounds for in-vivo and in-vitro diagnosis of neurodegenerative diseases by means of near infrared radiation (NIR radiation), the use of these compounds as optical diagnostic agents and diagnostic agents that contain these compounds.
Alzheimer's disease (AD) is the most common form of advanced dementia in older humans. The frequency of occurrence of AD increases with the age of the patient and reaches values of 40%-50% in the age group between 85 and 90 years. AD can be diagnosed with certainty only post mortem by the study of the brain of the patient in an autopsy. The brains of Alzheimer patients contain many characteristic amyloid plaques in the neuronal tissue and in the surrounding area of blood vessels that are surrounded by dystrophied neurites and neurofibrillar “tangles.” The brains of Alzheimer patients also show a small number of synapses. In the advanced stage of the disease, a far-reaching degeneration of neuronal structures and a significant decrease in brain volume has been determined (Wiesniewski, H. M., Weigel, J., Alzheimer's Disease Neuropathology. Current Status of Interpretation of Lesion Development. Ann NY Acad Sci 1992, 673: 270-84).
The amyloid plaques consist of, i.a., the amyloid-&bgr;-peptide (A&bgr;), a fragment of the &bgr;-amyloid precursor protein (APP) that consists of 40 to 42 amino acids (Master, C. L.; Simms, G.; Weinman, N. A., et al. Amyloid Plaque Core Protein in Alzheimer Disease and Down Syndrome. Proc Natl Acad Sci USA 1985, 82: 4245-9; Kang, J., Lemaire, H. G., Unterbeck, A. et al. The Precursor of Alzheimer's Disease Amyloid A4 Protein Resembles a Cell-Surface Receptor. Nature 1987, 325: 733-6). The number of plaques does not correlate to the degree of advanced dementia, but it is an early and reliable diagnostic agent for the occurrence of Alzheimer's disease. This results in the hypothesis that the first deposits of A&bgr; take place long before the manifestation of AD and before the first clinical symptoms occur (Hardy, L.; Allsop, D., Amyloid Deposition as the Central Event in the Aetiology of Alzheimer's Disease. Trends Pharmacol Sci 1991, 12: 383-8).
A method that provides for quantitative early detection of the amyloid plaques before the death of the patient, however, had a significant influence on further study of AD and on the development of new active therapy strategies against AD.
At the current time, there is no direct detection of amyloid plaques in the brains of AD patients. The extent of AD is now diagnosed only indirectly based on the brain volume or from metabolic disorders of the brain areas that are affected (MRT and PET). The significant drawback of these methods is, however, only indirect detection of AD, which is often associated with high statistical fluctuation ranges of the results. The detection sensitivity of these methods compared to direct detection of amyloid plaques is therefore considered low.
Several processes for irradiation and imaging diagnoses of biological tissues with long-wave light of the wavelength range of 600 to 1200 nm (near infrared diagnosis) are known. Since biological tissue has a relatively high permeability for long-wave light of this spectral region, another process for graphic tissue visualization is thus available to the diagnostician in addition to modern imaging processes, such as radiography, magnetic resonance tomography or ultrasound diagnosis (Haller, E. B. Time-Resolved Transillumination and Optical Tomography. J Biomed Optics 1996, 1:7-17). The use of NIR radiation for site-dependent recording of blood flow and degree of oxygenation in the brain of infants by the detection of hemoglobin/deoxyhemoglobin absorption is a process that has been known and used for years (Jöbsis, F. F., Noninvasive Infrared Monitoring of Cerebral and Myocardial Oxygen Sufficiency and Circulatory Parameters. Science 1977, 198: 1264-67; Chance, B.; Leigh, J. S., Miyake, H. et al. Comparison of Time-Resolved and Time-Unresolved Measurements of Deoxyglobin in Brain. Proc Natl Acad Sci USA 1988, 85: 4971-75; Benaron, D. A. et al. Optical Time-of-Flight and Absorbance Imaging of Biological Media. Science 1993, 33: 369A).
In near-infrared diagnosis, both the detection of non-absorbed radiation in the form of a transmission visualization and the fluorescence radiation that is emitted after irradiation with near-infrared light can provide tissue-specific data.
The basic problem in the use of near-infrared radiation is the strong scattering of light, so that even in the case of different photophysical properties, this object is poorly distinguished from an object with sharp edges and its surrounding area. The problem grows with increasing removal of the object from the surface and can be seen as a primary limiting factor both in transillumination and in the detection of fluorescence radiation.
The object of the invention is therefore to make available new compounds that overcome the drawbacks of the prior art.
This object is achieved according to the invention in that compounds of general formula I
Fm(—A
1
)(—B
n
)(—W
o
) (I)
in which
F is a dye-signal molecule, which has at least one absorption maximum in the range of 600 to 1200 nm,
A is a biomolecule that binds to &bgr;-amyloid-plaques,
B is a dye that binds to &bgr;-amyloid-plaques,
W is a hydrophilic, low-molecular structural element that binds to &bgr;-amyloid-plaques,
m stands for number 1 or 2, provided that n and o mean 0, or m stands for an integer 3-20,
l and n, independently of one another, stand for number 0, 1 or 2,
o stands for an integer 0, 1, 2, 3 or 4,
provided that the sum of 1, n and o≧1, as well as their physiologically compatible salts, are made available.
It has been found, surprisingly enough, that the compounds according to the invention are stored in or bind to the amyloid plaques or components of the amyloid plaques or are built up there and thus result in a unification and an increase in absorption and fluorescence of the latter in the detecting areas.
The in-vivo detection of &bgr;-amyloid deposits with use of NIR radiation requires dyes as contrast media, which have a high absorption and fluorescence quantum yield in the wavelength range of 600 to 1200 nm and bind selectively to &bgr;-amyloid deposits.
Dyes from the class of polymethines have absorption and fluorescence properties that are characterized by high molar absorption coefficients between 600 and 1200 nm and adequate fluorescence quantum yields. Dyes of this class generally have high photostability.
It has been found, surprisingly enough, that to improve the differentiation between normal and diseased tissue, fluorescence dyes that accumulate in the diseased tissue or selectively bind to pathologically altered tissue components and have a specific absorption and emission behavior are suitable.
In this invention, it has been found, surprisingly enough, that the compounds of general formula I according to the invention bind to the &bgr;-amyloid plaques. The change of the (scattered) irradiated light that is produced by absorption of the dye and/or the fluorescence that is induced by the stimulator radiation is detected and yields the actual tissue-specific data that make possible an assessment on the degree of the pathogenic change.
According to the invention, those dyes are used as signal molecules F that are covalently linked with structures that bind selectively to &bgr;-amyloid plaques or are substituted with such structures.
Compounds of general formula I according to the invention are those in which, for example,
a) 1 and n mean zero, m stands for one and o stands for 1-4, or
b) n and o mean zero, m stands for 3-20 and 1 stands for 1-2, or
c) 1 and o mean zero, m stands for 1-2 and n stands for 1-2, provided that the sum of n and m is less than or equal to 3.
Preferred are compounds of general formula I according to the invention, in which F stands for a cyanine, squarilium, croconium, merocyanine or oxonol dye.
Especially preferred are compounds of general formula I, in which F stands for a cyani
Dyrks Thomas
Licha Kai
Riefke Bjorn
Semmler Wolfhard
Turner Jonathan
Higel Floyd D.
Millen White Zelano & Branigan P.C.
Schering AG
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