Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging ß-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain.
J Med Chem
; 61(8): 3296-3308, 2018 04 26.
Article
em En
| MEDLINE
| ID: mdl-29356535
ABSTRACT
Alzheimer's disease (AD) is characterized by accumulation of ß-amyloid (Aß) plaques and neurofibrillary tau tangles in the brain. ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aß fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling. Further evaluation in an LC-MS/MS "cold tracer" study in rodents revealed high specific binding to BACE1 in brain. Upon radiolabeling, [18F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
/
Pirazinas
/
Tiazinas
/
Encéfalo
/
Ácido Aspártico Endopeptidases
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Compostos Radiofarmacêuticos
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Secretases da Proteína Precursora do Amiloide
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article