title: In vitro characterization of a gamma-secretase radiotracer in mammalian brain.
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.
authors.affiliation: Department of Imaging Research, Merck and Co. Inc., West Point, Pennsylvania, USA. shailendra_patel@merck.com
authors.forename: Shil
authors.initials: S
authors.lastname: Patel
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Malley
authors.forename: Brett
authors.initials: B
authors.lastname: Connolly
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Gibson
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007553:Isotope Labeling; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D011480:Protease Inhibitors / Q000138:chemical synthesis; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011480:Protease Inhibitors; D019275:Radiopharmaceuticals; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human