Design, Synthesis, and Evaluation of [ 18 F]T-914 as a Novel Positron-Emission Tomography Tracer for Lysine-Specific Demethylase 1.

Autor: Matsuda S; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Hattori Y; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Matsumiya K; Drug Metabolism and Pharmacokinetics Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., McQuade P; Quantitative Translational Science - Imaging, Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States., Yamashita T; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Aida J; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Sandiego CM; Invicro, A Konica Minolta Company, 60 Temple Street, Suite 8A, New Haven, Connecticut 06510, United States., Gouasmat A; Invicro, A Konica Minolta Company, 60 Temple Street, Suite 8A, New Haven, Connecticut 06510, United States., Carroll VM; Invicro, A Konica Minolta Company, 60 Temple Street, Suite 8A, New Haven, Connecticut 06510, United States., Barret O; Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, 92265 Fontenay-aux-Roses, France., Tamagnan G; XingImaging LLC, 760 Temple Street, New Haven, Connecticut 06510, United States., Koike T; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kimura H; Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Sep 09; Vol. 64 (17), pp. 12680-12690. Date of Electronic Publication: 2021 Aug 23.
DOI: 10.1021/acs.jmedchem.1c00653
Abstrakt: Histone methylation is associated with the pathophysiology of neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) catalyzes histone demethylation in a flavin adenine dinucleotide (FAD)-dependent manner. Thus, inhibiting LSD1 enzyme activity could offer a novel way to treat neurodevelopmental disorders. Assessing LSD1 target engagement using positron-emission tomography (PET) imaging could aid in developing therapeutic LSD1 inhibitors. In this study, PET probes based on 4-(2-aminocyclopropyl)benzamide derivatives that bind irreversibly to FAD found in LSD1 were examined. By optimizing the profiles of brain penetrance and brain-penetrant metabolites, T-914 ( 1g ) was identified as a suitable PET tracer candidate. PET studies in nonhuman primates demonstrated that [ 18 F] 1g had heterogeneous brain uptake, which corresponded to known LSD1 expression levels. Moreover, brain uptake of [ 18 F] 1g was reduced by coadministration of unlabeled 1g , demonstrating blockable binding. These data suggest that [ 18 F] 1g warrants further investigation as a potential PET tracer candidate for assessing target engagement of LSD1.
Databáze: MEDLINE
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