Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Bioorg Med Chem ; 28(20): 115700, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33069076

RESUMEN

The aggregation of ß-amyloid peptides is associated to neurodegeneration in Alzheimer's disease (AD) patients. Consequently, the inhibition of both oligomerization and fibrillation of ß-amyloid peptides is considered a plausible therapeutic approach for AD. Herein, the synthesis of new naphthalene derivatives and their evaluation as anti-ß-amyloidogenic agents are presented. Molecular dynamic simulations predicted the formation of thermodynamically stable complexes between the compounds, the Aß1-42 peptide and fibrils. In human microglia cells, these compounds inhibited the aggregation of Aß1-42 peptide. The lead compound 8 showed a high affinity to amyloid plaques in mice brain ex vivo assays and an adequate log Poct/PBS value. Compound 8 also improved the cognitive function and decreased hippocampal ß-amyloid burden in the brain of 3xTg-AD female mice. Altogether, our results suggest that 8 could be a novel therapeutic agent for AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Naftalenos/farmacología , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Agregado de Proteínas/efectos de los fármacos , Agregación Patológica de Proteínas/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fragmentos de Péptidos/metabolismo , Agregación Patológica de Proteínas/metabolismo , Relación Estructura-Actividad , Termodinámica
2.
Curr Radiopharm ; 12(1): 58-71, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30605068

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. METHODS: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. RESULTS: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aß-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aß peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aß plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. CONCLUSION: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aß senile plaques.


Asunto(s)
Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacología , Naftalenos/química , Neuroimagen/métodos , Placa Amiloide/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioquímica/métodos , Radiofármacos/síntesis química , Radiofármacos/farmacología , Animales , Simulación por Computador , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Distribución Tisular
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA