Received for publication May 21, 2007.
Revised July 17, 2007.
Accepted for publication July 17, 2007.

Ex vivo Occupancy of -Secretase Inhibitors Correlates with Brain A Reduction in Tg2576 Mice

Abstract

Reduction of brain A synthesis by -secretase inhibitors is a promising approach for the treatment of Alzheimer's disease. However, measurement of central pharmocodynamic effects in the AD 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 A reduction by -secretase inhibitors was examined in Tg2576 mice. [3H]-IN973 was used as a -secretase radioligand since it has been shown to bind to -secretase in rats, 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. Gamma-secretase occupancy and brain A reduction were found to be highly correlated in animals dosed with either BMS-299897 or BMS-433796, over a wide range of doses and times post dose, with the exception of the earliest times post dose. This lag in A response to -secretase inhibition is likely related to the delayed clearance of previously produced A. The excellent correlation between brain A and -secretase occupancy suggests that a PET ligand for -secretase could be a valuable biomarker to determine if -secretase inhibitors bind to their target in humans.

Key words: Alzheimer, PET, autoradiography, beta-amyloid precursor protein, occupancy, presenilin

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