Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Acyclic nitrogen double bonded to acyclic nitrogen – acyclic...
Reexamination Certificate
1997-11-06
2002-07-09
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...
C514S252110, C514S258100, C514S308000, C514S314000, C534S550000, C534S557000, C534S670000, C534S677000, C534S653000, C534S816000, C534S822000, C534S823000, C534S827000, C534S828000, C534S829000, C534S830000, C534S831000, C534S832000, C534S833000, C534S834000, C534S835000, C544S063000, C544S064000, C544S069000, C544S224000, C544S225000, C544S235000, C546S002000, C546S010000, C546S103000, C546S122000, C546S142000, C548S101000, C548S108000, C548S143000, C548S241000, C548S252000, C548S513000, C556S101000, C562S
Reexamination Certificate
active
06417178
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the identification of compounds that are suitable for imaging amyloid deposits in living patients. More specifically, the present invention relates to a method of imaging amyloid deposits in brain in vivo to allow antemortem diagnosis of Alzheimer's Disease. The present invention also relates to therapeutic uses for such compounds.
Alzheimer's Disease (“AD”) is a neurodegenerative illness characterized by memory loss and other cognitive deficits. McKhann et al.,
Neurology
34: 939 (1984). It is the most common cause of dementia in the United States. AD can strike persons as young as 40-50 years of age, yet, because the presence of the disease is difficult to determine without dangerous brain biopsy, the time of onset is unknown. The prevalence of AD increases with age, with estimates of the affected population reaching as high as 40-50% by ages 85-90. Evans et al.,
JAMA
262: 2551 (1989); Katzman,
Neurology
43: 13 (1993).
By definition, AD is definitively diagnosed through examination of brain tissue, usually at autopsy. Khachaturian,
Arch. Neurol.
42: 1097 (1985); McKhann et al.,
Neurology
34: 939 (1984). Neuropathologically, this disease is characterized by the presence of neuritic plaques (NP), neurofibrillary tangles (NFT), and neuronal loss, along with a variety of other findings. Mann,
Mech. Ageing Dev.
31: 213 (1985). Post-mortem slices of brain tissue of victims of Alzheimer's disease exhibit the presence of amyloid in the form of proteinaceous extracellular cores of the neuritic plaques that are characteristic of AD.
The amyloid cores of these neuritic plaques are composed of a protein called the &bgr;-amyloid (A&bgr;) that is arranged in a predominately beta-pleated sheet configuration. Mori et al.,
Journal of Biological Chemistry
267: 17082 (1992); Kirschner et al.,
PNAS
83: 503 (1986). Neuritic plaques are an early and invariant aspect of the disease. Mann et al.,
J. Neurol. Sci.
89: 169; Mann,
Mech. Ageing Dev.
31: 213 (1985); Terry et al.,
J. Neuropathol. Exp. Neurol
46: 262 (1987).
The initial deposition of A&bgr; probably occurs long before clinical symptoms are noticeable. The currently recommended “minimum microscopic criteria” for the diagnosis of AD is based on the number of neuritic plaques found in brain. Khachaturian,
Arch. Neurol.,
supra (1985). Unfortunately, assessment of neuritic plaque counts must be delayed until after death.
Amyloid-containing neuritic plaques are a prominent feature of selective areas of the brain in AD as well as Downs Syndrome and in persons homozygous for the apolipoprotein E4 allele who are very likely to develop AD. Corder et al.,
Science
261: 921 (1993); Divry, P.,
J. Neurol. Psych.
27: 643-657 (1927); Wisniewski et al., in Zimmerman, H. M. (ed.): PROGRESS IN NEUROPATHOLOGY, (Grune and Stratton, N.Y. 1973) pp. 1-26. Brain amyloid is readily demonstrated by staining brain sections with thioflavin S or Congo red. Puchtler et al.,
J. Histochem. Cytochem.
10: 35 (1962). Congo red stained amyloid is characterized by a dichroic appearance, exhibiting a yellow-green polarization color. The dichroic binding is the result of the beta-pleated sheet structure of the amyloid proteins. Glenner, G.
N. Eng. J. Med.
302: 1283 (1980). A detailed discussion of the biochemistry and histochemistry of amyloid can be found in Glenner,
N. Eng. J. Med.,
302: 1333 (1980).
Thus far, diagnosis of AD has been achieved mostly through clinical criteria evaluation, brain biopsies and post mortem tissue studies. Research efforts to develop methods for diagnosing Alzheimer's disease in vivo include (1) genetic testing, (2) immunoassay methods and (3) imaging techniques.
Evidence that abnormalities in &bgr; metabolism are necessary and sufficient for the development of AD is based on the discovery of point mutations in the A&bgr; precursor protein in several rare families with an autosomal dominant form of AD. Hardy,
Nature Genetics
1: 233 (1992); Hardy et al.,
Science
256: 184 (1992). These mutations occur near the N- and C-terminal cleavage points necessary for the generation of A&bgr; from its precursor protein. St. George-Hyslop et al.,
Science
235: 885 (1987); Kang et al.,
Nature
325: 733 (1987); Potter WO 92/17152. Genetic analysis of a large number of AD families has demonstrated, however, that AD is genetically heterogeneous. St. George-Hyslop et al.,
Nature
347: 194 (1990). Linkage to chromosome 21 markers is shown in only some families with early-onset AD and in no families with late-onset AD. More recently a gene on chromosome 14 whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein has been identified by Sherrington et al.,
Nature
375: 754-760 (1995). This gene may account for up to 70% of early-onset autosomal dominant AD. Preliminary data suggests that this chromosome 14 mutation causes an increase in the production of A&bgr;. Scheuner et al.,
Soc. Neurosci. Abstr.
21: 1500 (1995). A mutation on a very similar gene has been identified on chromosome 1 in Volga German kindreds with early-onset AD. Levy-Lahad et al.,
Science
269: 973-977 (1995).
Screening for apolipoprotein E genotype has been suggested as an aid in the diagnosis of AD. Scott,
Nature
366: 502 (1993); Roses,
Ann. Neurol.
38: 6-14 (1995). Difficulties arise with this technology, however, because the apolipoprotein E4 allele is only a risk factor for AD, not a disease marker. It is absent in many AD patients and present in many non-demented elderly people. Bird,
Ann. Neurol.
38: 2-4 (1995).
Immunoassay methods have been developed for detecting the presence of neurochemical markers in AD patients and to detect an AD related amyloid protein in cerebral spinal fluid. Warner,
Anal. Chem.
59: 1203A (1987); World Patent No. 92/17152 by Potter; Glenner et al., U.S. Pat. No. 4,666,829. These methods for diagnosing AD have not been proven to detect AD in all patients, particularly at early stages of the disease and are relatively invasive, requiring a spinal tap. Also, attempts have been made to develop monoclonal antibodies as probes for imaging of A&bgr;. Majocha et al.,
J. Nucl. Med.,
33: 2184 (1992); Majocha et al., WO 89/06242 and Majocha et al., U.S. Pat. No. 5,231,000. The major disadvantage of antibody probes is the difficulty in getting these large molecules across the blood-brain barrier. Using antibodies for in vivo diagnosis of AD would require marked abnormalities in the blood-brain barrier in order to gain access into the brain. There is no convincing functional evidence that abnormalities in the blood-brain barrier reliably exist in AD. Kalaria,
Cerebrovascular
&
Brain Metabolism Reviews
4: 226 (1992).
A&bgr; antibodies are also disadvantageous for use in AD diagnostics because they typically stain diffuse deposits of A&bgr; in addition to the neuritic plaques—and the diffuse plaques often predominate. Yamaguchi et al.,
Acta Neuropathol.,
77: 314 (1989). Diffuse plaques may be a separate type of lesion, not necessarily involved in the dementing process of AD. The latter is suggested by findings of diffuse plaques in cognitively normal controls and aged dogs. Moran et al.,
Medicina Clinica
98: 19 (1992); Shimada et al.,
Journal of Veterinary Medical Science
54: 137 (1992); Ishihara et al.,
Brain Res.
548: 196 (1991); Giaccone et al.,
Neurosci. Lett.
114: 178 (1990). Even if diffuse plaques are forerunners of neuritic plaques, the key pathological event in AD may be the process that turns the apparently benign diffuse plaque into the neuritic plaque with its associated halo of degeneration. Therefore, a probe is needed that is specific for the neuritic plaque and NFTs as a more specific marker for AD pathophysiology than antibodies that would also label diffuse plaques.
Recently, radiolabeled A&bgr; peptide has been used to label diffuse, compact and neuritic type plaques in sections of AD brain. Maggio et al., WO 93/04194. However, these peptides share all of the disadv
Klunk William E.
Mathis, Jr. Chester A.
Pettegrew Jay W.
Foley & Lardner
Higel Floyd D.
University of Pittsburgh
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