دورية
Design, Synthesis, and Evaluation of [18F]T-914 as a Novel Positron-Emission Tomography Tracer for Lysine-Specific Demethylase 1
| العنوان: | Design, Synthesis, and Evaluation of [18F]T-914 as a Novel Positron-Emission Tomography Tracer for Lysine-Specific Demethylase 1 |
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| المؤلفون: | Matsuda, Satoru, Hattori, Yasushi, Matsumiya, Kouta, McQuade, Paul, Yamashita, Tohru, Aida, Jumpei, Sandiego, Christine M., Gouasmat, Alexandra, Carroll, Vincent M., Barret, Olivier, Tamagnan, Gilles, Koike, Tatsuki, Kimura, Haruhide |
| المصدر: | Journal of Medicinal Chemistry; September 2021, Vol. 64 Issue: 17 p12680-12690, 11p |
| مستخلص: | 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 [18F]1ghad heterogeneous brain uptake, which corresponded to known LSD1 expression levels. Moreover, brain uptake of [18F]1gwas reduced by coadministration of unlabeled 1g, demonstrating blockable binding. These data suggest that [18F]1gwarrants further investigation as a potential PET tracer candidate for assessing target engagement of LSD1. |
| قاعدة البيانات: | Supplemental Index |
Find this issue from the American Chemical Society | تدمد: | 00222623 15204804 |
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| DOI: | 10.1021/acs.jmedchem.1c00653 |