title: Ex vivo occupancy of gamma-secretase inhibitors correlates with brain beta-amyloid peptide reduction in Tg2576 mice.
abstract: Reduction of brain beta-amyloid peptide (Abeta) synthesis by gamma-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 gamma-secretase inhibitors in a clinical setting. In this study, the relationship of gamma-secretase site occupancy and brain Abeta40 reduction by gamma-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 gamma-secretase radioligand, since it has been shown to bind to gamma-secretase in rat, rhesus, and human brains with high affinity and specificity. We extended these findings by showing that [3H]IN973 bound to gamma-secretase in Tg2576 brains with an affinity, specificity, and regional localization very similar to the other species. To quantify gamma-secretase occupancy by gamma-secretase inhibitors, an ex vivo binding assay was developed using [3H]IN973 and frozen brain sections from drug-treated mice. Gamma-secretase occupancy and brain Abeta40 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 Abeta40 response to gamma-secretase inhibition is probably related to the delayed clearance of previously produced Abeta40. The excellent correlation between brain Abeta40 and gamma-secretase occupancy suggests that a positron emission tomography ligand for gamma-secretase could be a valuable biomarker to determine whether gamma-secretase inhibitors bind to their target in humans.
authors.affiliation: Research and Development, Neuroscience Drug Discovery, Bristol-Myers Squibb Co., Wallingford, CT 06492, USA. margi.goldstein@bms.com
authors.forename: Margi E
authors.initials: ME
authors.lastname: Goldstein
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Tracey
authors.initials: T
authors.lastname: Fiedler
authors.forename: Jeremy
authors.initials: J
authors.lastname: Toyn
authors.forename: Lawrence
authors.initials: L
authors.lastname: Iben
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Maria
authors.initials: M
authors.lastname: Pierdomenico
authors.forename: Jason
authors.initials: J
authors.lastname: Corsa
authors.forename: C V C
authors.initials: CV
authors.lastname: Prasad
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D011869:Radioligand Assay; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D008024:Ligands; D053829:Amyloid Precursor Protein Secretases