Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Patent
1998-07-22
1999-12-14
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
424 111, 424 165, 424 181, 424 185, 548400, 536102, 5361231, A61K 4900, G01N 3100, G01N 3348
Patent
active
060013311
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a method of imaging amyloid deposits and to labeled compounds useful in imaging amyloid deposits. This invention also relates to a method of delivering a therapeutic agent to amyloid deposits, a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, and a method of determining a compound's ability to inhibit aggregation of amyloid proteins.
BACKGROUND OF THE INVENTION
Amyloidosis is a condition characterized by the accumulation of various insoluble, fibrillar proteins in the tissues of a patient. The fibrillar proteins that comprise the accumulations or deposits are called amyloid proteins. While the particular proteins or peptides found in the deposits vary, the presence of fibrillar morphology and a large amount of .beta.-sheet secondary structure is seen in many types of amyloids. An amyloid deposit is formed by the aggregation of amyloid proteins, followed by the further combination of aggregates and/or amyloid proteins.
The presence of amyloid deposits has been shown in various diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer's disease, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, .beta..sub.2 -microglobulin amyloid in dialysis patients, inclusion body myositis, .beta..sub.2 -amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type II insulinoma.
Thus, a simple, noninvasive method for detecting and quantitating amyloid deposits in a patient has been eagerly sought. Presently, detection of amyloid deposits involves histological analysis of biopsy or autopsy materials. Both methods have major drawbacks. For example, an autopsy can only be used for a postmortem diagnosis.
The direct imaging of amyloid deposits in vivo is difficult, as the deposits have many of the same physical properties (i.e., density and water content) as normal tissues. Attempts to image amyloid deposits using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules has provided some selectivity on the periphery of tissues, but has provided for poor imaging of tissue interiors.
Thus, it would be useful to have a noninvasive technique for imaging and quantitating amyloid deposits in a patient. In addition, it would be useful to have compounds that inhibit the aggregation of amyloid proteins to form amyloid deposits and a method for determining a compound's ability to inhibit amyloid protein aggregation.
SUMMARY OF THE INVENTION
The present invention provides a method of imaging amyloid deposits, the method comprising introducing into a patient a detectable quantity of a labeled compound having the Formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof ##STR1## wherein X and Y are each independently C or N and the X.dbd.Y double bond has the trans configuration; ##STR2## R.sup.1 and R.sup.2 are each independently hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, halogen, amino, di(C.sub.1 -C.sub.6 alkyl)amino, mono(C.sub.1 -C.sub.6 alkyl)amino, nitro, C.sub.1 -C.sub.6 thioalkoxy, or R.sup.1 and R.sup.2 combined form a benzene, cyclopentane, or cyclohexane ring that is fused to the phenyl ring; -C.sub.10 alkenyl, arylalkyl, (heteroaryl)alkyl, (cycloalkyl)alkyl, arylalkenyl, diarylalkyl or --(CH.sub.2).sub.m --A--(CH.sub.2).sub.n --Q; hydroxy, halogen, amino, di(C.sub.1 -C.sub.6 alkyl)amino, nitro, C.sub.1 -C.sub.6 thioalkoxy, aryl, heteroaryl, aryloxy, --CO-aryl, or arylthio; or --NR.sup.4 R.sup.5 represents a 5-, 6- or 7-membered ring containing nitrogen;
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Caprathe Bradley W.
Gilmore John L.
Hays Sheryl J.
Jaen Juan C.
LeVine, III Harry
Ashbrook Charles W.
Dees Jos,e G.
Jones Dameron
Warner-Lambert & Company
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