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In vitro characterization of a γ‐secretase radiotracer in mammalian brain
Author(s) -
Patel Shil,
O'Malley Stacey,
Connolly Brett,
Liu Wensheng,
Hargreaves Richard,
Sur Cyrille,
Gibson Raymond E.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03525.x
Subject(s) - in vitro , human brain , temporal cortex , binding site , gamma secretase , affinities , population , cortex (anatomy) , biology , chemistry , biochemistry , microbiology and biotechnology , biophysics , neuroscience , medicine , environmental health
Inhibition of γ‐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 γ‐secretase inhibitor, [ 3 H]compound D (Yan et al ., 2004, J. Neurosci. 24, 2942–2952) in mammalian brain. [ 3 H]Compound D was shown to bind with nanomolar affinity ( K d = 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 γ‐secretase inhibitors with a wide range of binding affinities showed that the binding affinities of these compounds correlated well with their ability to inhibit γ‐secretase in vitro . Autoradiographic studies showed that the specific binding of [ 3 H]compound D was widely distributed throughout adult rat, rhesus and normal human brain. There did not appear to be any difference in distribution of [ 3 H]compound D specific binding sites in AD cortex compared with control human cortex as measured using tissue section autoradiography, nor any correlation between γ‐secretase binding and plaque burden as measured immunohistochemically. [ 3 H]compound D is a useful tool to probe the expression and pharmacology of γ‐secretase in mammalian brain.