RESUMEN
The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aß- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.
Asunto(s)
Encéfalo/diagnóstico por imagen , Compuestos Heterocíclicos con 3 Anillos/química , Proteína Huntingtina/metabolismo , Agregado de Proteínas/fisiología , Piridinas/química , Radiofármacos/química , Enfermedad de Alzheimer , Animales , Biomarcadores/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Femenino , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Tomografía de Emisión de Positrones , Piridinas/síntesis química , Piridinas/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
Asunto(s)
Proteína Huntingtina/análisis , Enfermedad de Huntington/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Agregación Patológica de Proteínas/diagnóstico por imagen , Animales , Modelos Animales de Enfermedad , Perros , Femenino , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Ligandos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Péptidos/genética , Agregación Patológica de Proteínas/genética , Radiofármacos/análisis , Ratas Sprague-DawleyRESUMEN
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
