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NEUROPHARMACOLOGY

Ex Vivo Occupancy of -Secretase Inhibitors Correlates with Brain -Amyloid Peptide Reduction in Tg2576 Mice

Research and Development, Neuroscience Drug Discovery, Bristol-Myers Squibb Co., Wallingford, Connecticut

Reduction of brain -amyloid peptide (A) synthesis by -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 -secretase inhibitors in a clinical setting. In this study, the relationship of -secretase site occupancy and brain A40 reduction by -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 -secretase radioligand, since it has been shown to bind to -secretase in rat, rhesus, and human brains with high affinity and specificity. We extended these findings by showing that [³H]IN973 bound to -secretase in Tg2576 brains with an affinity, specificity, and regional localization very similar to the other species. To quantify -secretase occupancy by -secretase inhibitors, an ex vivo binding assay was developed using [³H]IN973 and frozen brain sections from drug-treated mice. -Secretase occupancy and brain A40 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 A40 response to -secretase inhibition is probably related to the delayed clearance of previously produced A40. The excellent correlation between brain A40 and -secretase occupancy suggests that a positron emission tomography ligand for -secretase could be a valuable biomarker to determine whether -secretase inhibitors bind to their target in humans.

Address correspondence to: Dr. Margi Goldstein, Bristol-Myers Squibb Co., Neuroscience Drug Discovery, 5 Research Pkwy., Wallingford, CT 06492. E-mail: margi.goldstein{at}bms.com