Abstract
Reduction of brain β-amyloid peptide (Aβ) synthesis by γ-secretase inhibitors is a promising approach for the treatment of Alzheimer's disease. However, measurement of central pharmacodynamic effects in the Alzheimer's disease patient will be a challenge. Determination of drug occupancy may facilitate the analysis of efficacy of γ-secretase inhibitors in a clinical setting. In this study, the relationship of γ-secretase site occupancy and brain Aβ40 reduction by γ-secretase inhibitors was examined in Tg2576 mice. [3H](2R,3S)-2-Isobutyl-N1-((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-propylsuccinamide (IN973) was used as a γ-secretase radioligand, since it has been shown to bind to γ-secretase in rat, rhesus, and human brains with high affinity and specificity. We extended these findings by showing that [3H]IN973 bound to γ-secretase in Tg2576 brains with an affinity, specificity, and regional localization very similar to the other species. To quantify γ-secretase occupancy by γ-secretase inhibitors, an ex vivo binding assay was developed using [3H]IN973 and frozen brain sections from drug-treated mice. γ-Secretase occupancy and brain Aβ40 reduction were found to be highly correlated in animals dosed with either 2-[(1R)-1-[[4-chlorophenyl)-sulfonyl](2,5-difluorophenyl)amino] ethyl]-5-fluoro-benzenepropanoic acid (BMS-299897) or (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) over a wide range of doses and times postdose, with the exception of the earliest times postdose. This lag in Aβ40 response to γ-secretase inhibition is probably related to the delayed clearance of previously produced Aβ40. The excellent correlation between brain Aβ40 and γ-secretase occupancy suggests that a positron emission tomography ligand for γ-secretase could be a valuable biomarker to determine whether γ-secretase inhibitors bind to their target in humans.
Footnotes
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A portion of this work was previously presented at the Society for Neuroscience 2005; 12–16 Nov 2005; Washington, DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.125492.
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ABBREVIATIONS: AD, Alzheimer's disease; Aβ, β-amyloid peptide; APP, β-amyloid precursor protein; PS, presenilin; CSF, cerebrospinal fluid; IN973, (2R,3S)-2-isobutyl-N1-((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-propylsuccinamide; BMS-299897, 2-[(1R)-1-[[(4-chlorophenyl)-sulfonyl](2,5-difluorophenyl)amino]ethyl]-5-fluoro-benzenepropanoic acid; BMS-433796, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide; PET, positron emission tomography; CHAPS, [(3-cholamidopropyl)dimethylammonio]propanesulfonate; CHAPSO, 3-([3-cholamidopropyl])dimethylammonio])-2-hydroxy-1-propanesulfonate.
- Received May 14, 2007.
- Accepted July 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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