Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
AssigneeBristol-Myers Squibb Pharma Company
InventorsRobert Zaczek, Richard E. Olson, Dietmar A. Seiffert, Lorin A. Thompson
Life of this patent
Estimating the term…
Abstract
A method of using radiolabelled and/or radiopharmaceutical small molecule inhibitors of beta-amyloid peptide production for the diagnosis of neurological and other disorders involving APP processing and beta-amyloid production. Radiolabelled small molecule inhibitors identified by the methods of the present invention would be useful in the diagnosis of neurological disorders, such as Alzheimer's disease, which involve elevated levels of Aβ peptides.
Claims46
A method for diagnosing a neurological disease involving APP processing and/or beta-amyloid production within a mammalian body comprising:
- (a) administering a diagnostically effective amount of a radiopharmaceutical secretase inhibitor of APP processing and/or beta-amyloid production;
- wherein the inhibitor is selected from compounds of:
- Formula (I-7), (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide,
- its tritiated formula, (I-7T),
- wherein m is about 2;
- Formula(I-11), (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide,
- its tritiated formula (I-11T),
- wherein m is about 2;
- Formula (I-43) (2S,3R) N1-(1,3-dihydro-1-methyl-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide,
- its tritiated formula (I-43T) Tritiated (2S,3R) N1-[1,3-dihydro-1-methyl-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(n-propyl)-butanediamide,
- wherein m is about 2;
- and
- (b) imaging the area of the patient wherein, the disease is located.
A method of in vivo diagnostic imaging comprising administering to a subject a diagnostically effective amount of a secretase-specific radiolabeled inhibitor of beta-amyloid production;
- which inhibitor is selected from a compounds of:
- Formula (I-7), (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(methylpropyl)-3-(propyl)-butanediamide,
- its tritiated formula(I-7T),
- Formula(I-11), (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide,
- its tritiated formula (I-11T),
- Formula (I-43):
- (2S,3R) N1-[1,3-dihydro-1-methyl-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide.
- its tritiated Formula (I-43T):
- Tritiated (2S,3R) N1-[1,3-dihydro-1-methyl-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(n-propyl)-butanediamide,
- and imaging the area of the patient wherein the disease is located.
A pharmaceutical composition suitable for in vivo diagnostic imaging comprising a secretase-specific radiolabeled inhibitor of beta-amyloid production;
- which inhibitor is selected from a compound of:
- Formula (I-7), (2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide,
- its tritiated Formula (I-7T),
- wherein is about 2;
- Formula (I-11), (2R,3S) N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide,
- its tritiated Formula (I-11T),
- wherein m is about 2;
- Formula (I-43), (2S,3R) N1-[1,3-dihydro-1-methyl-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide,
- its tritiated Formula (I-43T), Tritiated (2S,3R) N1-(1,3-dihydro-1-methyl-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(n-propyl)-butanediamide,
- wherein m is about 2;
- and
- imaging the area of the patient wherein the disease is located.
Dependencies are inferred from the claim text.