Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1997-06-18
2001-04-03
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009300, C600S420000
Reexamination Certificate
active
06210655
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to site-specific
13
C-enriched reagents for diagnostic medicine for magnetic resonance imaging. The site-specific
13
C-enriched reagents may be represented by the formula: T-L-R. T is a site-specific targeting group which selectively binds to a disease-related target in an animal or human, R is an inert polymer containing repeating
13
C reporting groups which provide a magnetic resonance imaging signal, and L is a linker group which connects the site-specific targeting group to the inert polymer. The site-specific
13
C-enriched reagents are targeted to and capable of identifying, quantifying, and localizing disease-specific loci, such as blood clots, &bgr;-amyloid plaques of Alzheimer's disease, and tumors through the use of magnetic resonance imaging. The present invention also pertains to a method for employing the site-specific
13
C-enriched reagents in a living mammal.
2. Description of the Background
Many diagnostic and therapeutic medical procedures for visualizing internal organs for the early detection and treatment of many diseases require the administration of contrast enhancing agents to improve the quality of the procedure. Contrast-enhancing agents are used in Magnetic Resonance Imaging (MRI), Computerized Tomography (CT), and X-ray procedures. Computerized Tomography provides a more sophisticated visualization of tissues and organs than does conventional X-ray techniques. Magnetic Resonance Imaging provides a superior soft tissue differentiation than does Computerized Tomography. Magnetic Resonance Imaging procedures generally employ the nuclear magnetic resonance of hydrogen (
1
H) or fluorine (
19
F). The nuclear magnetic resonance sensitivity of
19
F is nearly equivalent to that of
1
H but the biological background of
19
F is negligible. The usefulness of a contrast enhancing agent depends upon the ease of the synthesis of the agent, the site-specificity of the agent, the resistance to in vivo hydrolysis of the agent, and a sufficient amount of signal from the agent along with a high signal-to-noise ratio.
In radioscintigraphy, a radioactive monoclonal antibody is typically injected into a patient for identifying and localizing a tumor, (reviewed in Bischof Delaloye, A. and Delaloye, B.: Tumor imaging with monoclonal antibodies.
Seminars in Nuclear Medicine
25(2):144-164, 1995).
In radioimaging with monoclonal antibodies, a chemically modified (chelate) form of a monoclonal antibody is typically prepared and stored as a relatively stable product. To be used clinically, however, the monoclonal antibody sample must be mixed with a radioactive metal, such as
99m
Tc, then purified to remove excess, unbound radioactive metal, and then administered to a patient within 6 hours, (Eckelman, W. C., Paik, C. H., and Steigman, J.: Three approaches to radiolabeling antibodies with
99m
Tc.
Nuc. Med. Biol
. 16: 171-176, 1989). The entire process is cumbersome and dangerous due to the many manipulations requiring use and disposal of radioactivity. There is some health risk and fear accompanying injection of radioactivity into the patient.
Another example of imaging technology is the diagnosis of Alzheimer's disease, which afflicts over 3 million Americans and is increasing in incidence as the number of senior citizens increases. Currently, diagnosis is made by ruling out other causes for the symptoms of memory loss and dementia. The ability to diagnose Alzheimer's disease could also be critical to the development of an effective therapy. In particular, a therapeutic strategy that would arrest or reverse the buildup in the brain of &bgr;-amyloid plaques, which has been shown to be the cause of nerve cell loss, would require a means for imaging and measuring these deposits. The chemical, Congo red, has been shown to bind to &bgr;-amyloid plaques and a form of Congo red capable of chelating a radioactive metal has been prepared and proposed for use in imaging by radioscintigraphy (
Chem. & Eng. News
, Jun. 17, 1996, pages 33-34). Alternatively, the protein, tissue plasminogen activator, can be used in a radiolabeled form as a diagnostic reagent to image &bgr;-amyloid plaques, U.S. Pat. No. 5,589,154 (Anderson). Still another potential imaging agent is &bgr;-amyloid peptide, which can deposit into the plaque. Although &bgr;-amyloid plaques are within the brain, they are also present in the small and medium-sized arteries serving the brain, and are uniquely associated with Alzheimer's disease, (Vinters, H. V.; Cerebral amyloid angiopathy. A critical review.
Stroke
18:311-324, 1987).
Another example of imaging technology is the diagnosis of blood clots. Despite the frequency of pulmonary thromboembolism and its associated morbidity and mortality, diagnosis remains suboptimal. Similarly, noninvasive detection of both deep vein and cerebral thrombosis is currently difficult. Various radiolabeled proteins, such as antifibrin monoclonal antibodies, (Rosebrough, S. F. and Hashmi, M.: Galactose-modified streptavidin-GC4 antifibrin monoclonal antibody conjugates: application for two-step thrombus/embolus imaging.
J. Pharm. Fxp. Ther
. 276(2): 770-775, 1996), fibrin-binding domain fragment of fibronectin (Rosenthall. L. and Leclerc, J.: A new thrombus imaging agent. Human recombinant fibrin binding domain labeled with In-ill.
Clin. Nucl. Med
. 20(5): 398-402, 1995), activated-platelet binding protein fragment (Muto, P., Lastoria, S., Varrella, P., et al.: Detecting deep venous thrombosis with technetium-
99m
-labeled synthetic peptide P280
. J. Nucl. Med
. 36(8): 1384-1391, 1995) and (inactivated) tissue plasminogen activator (De Bruyn, V. H., Bergmann, S. R., Keyt, B. A. and Sobel, B. E.: Visualization of thrombi in pulmonary arteries with radiolabeled, enzymatically inactivated tissue-plasminogen activator.
Circulation
92(5): 1320-1325, 1995) have been utilized for imaging thrombi.
The use of non-targeted, stable isotope-enriched contrast reagents, such as
13
C glucose, has been described previously for imaging and for metabolic studies, (Shulman, R. G., Blamire, A. M., Rothman, D. L. and McCarthy, G. Nuclear magnetic imaging and spectroscopy of human brain function.
Proc. Natl. Acad. Sci. USA
90(8): 3127-3133, 1993; Sonnewald, U., Gribbstad, I. S., Westergaard, N. Nilsen, G., Unsgard, G., Schousboe, A. and Peterson, S. B. Nuclear magnetic resonance spectroscopy: biochemical evaluation of brain function in vivo and in vitro.
Neurotox
. 15(3): 579-590, 1994). Also, the feature of targeted binding to a disease-indicating locus has been described for radioactive isotope-enriched reagents (see references above). Furthermore, tumor-localizing reagents containing metals such as gadolinium, which enhance contrast in proton (
1
H) MRI, have been described, (Young, S. W., Qing, F., Harriman, A., Sessler, J. L., Dow, W. C., Mody, T. D., Hemmi, G. W., Hao, Y. and Miller, R. A. Gadolinium(III) texaphyrin: A tumor selective radiation enhancer that is detectable by MRI.
Proc. Natl. Acad. Sci. USA
93: 6610-6615; Igarashi, N., Igarashi, S., Fujio, N. and Yoshida, A. Magnetic resonance imaging in the early diagnosis of cavernous sinus thrombosis.
Ophthalmologica
209(5): 292-296, 1995; Williams, R. F., Siegle, R. L., Pierce, B. L. and Floyd, L. J. Analogs of synthetic melanin polymers for specific imaging applications.
Invest. Radiology
29: S116-119, 1994; Orang-Khadivi, K., Pierce, B. L., Ollom, C. M., Floyd, L. J., Siegle, R. L. and Williams, R. F. New magnetic resonance imaging techniques for the detection of breast cancer.
Breast Cancer Res. Treat
. 32(1): 119-135, 1994.).
U.S. Pat. No. 4,624,846 (Goldenberg) discloses a method for enhancing the target specificity of antibody localization. The method comprises injecting a second antibody specific to a labeled target-specific antibody to reduce the level of non-targeted circulating specific antibody and thereby increase the localization ratio. Specifically, the method comprises injecting a human subject parenterally wit
Hartley Michael G.
Muccino Richard R.
University of Medicine & Dentistry of NJ
LandOfFree
Site-specific 13C-enriched reagents for diagnostic medicine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Site-specific 13C-enriched reagents for diagnostic medicine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Site-specific 13C-enriched reagents for diagnostic medicine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2527986