In vitro characterization of a gamma-secretase radiotracer in mammalian brain |
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Authors: | Patel Shil O'Malley Stacey Connolly Brett Liu Wensheng Hargreaves Richard Sur Cyrille Gibson Raymond E |
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Institution: | Department of Imaging Research, Merck and Co. Inc., West Point, Pennsylvania, USA. shailendra_patel@merck.com |
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Abstract: | Inhibition of gamma-secretase is a potential therapeutic target for Alzheimer's disease (AD). The present studies have characterized the in vitro properties of a radiolabeled small molecule gamma-secretase inhibitor, 3H]compound D (Yan et al., 2004, J. Neurosci.24, 2942-2952) in mammalian brain. 3H]Compound D was shown to bind with nanomolar affinity (Kd = 0.32-1.5 nM) to a single population of saturable sites in rat, rhesus and human brain cortex homogenates, the density of binding sites ranging from 4 to 7 nM across the species. Competition studies with a structurally diverse group of gamma-secretase inhibitors with a wide range of binding affinities showed that the binding affinities of these compounds correlated well with their ability to inhibit gamma-secretase in vitro. Autoradiographic studies showed that the specific binding of 3H]compound D was widely distributed throughout adult rat, rhesus and normal human brain. There did not appear to be any difference in distribution of 3H]compound D specific binding sites in AD cortex compared with control human cortex as measured using tissue section autoradiography, nor any correlation between gamma-secretase binding and plaque burden as measured immunohistochemically. 3H]compound D is a useful tool to probe the expression and pharmacology of gamma-secretase in mammalian brain. |
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Keywords: | Alzheimer's disease autoradiography γ-secretase radioligand binding |
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