Design, Synthesis, and Evaluation of [18F]T-914 as a Novel Positron-Emission Tomography Tracer for Lysine-Specific Demethylase 1.
J Med Chem
; 64(17): 12680-12690, 2021 09 09.
Article
en En
| MEDLINE
| ID: mdl-34423983
ABSTRACT
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]1g had heterogeneous brain uptake, which corresponded to known LSD1 expression levels. Moreover, brain uptake of [18F]1g was reduced by coadministration of unlabeled 1g, demonstrating blockable binding. These data suggest that [18F]1g warrants further investigation as a potential PET tracer candidate for assessing target engagement of LSD1.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Sistemas de Liberación de Medicamentos
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Histona Demetilasas
Límite:
Animals
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Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón