Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease

• Autores: Rejc, Luka; Gómez Vallejo, Vanessa; Joya, Ana; Moreno, Oscar; Egimendia, Ander; Castellnou, Pilar; Ríos Anglada, Xabier; Cossío, Unai; Zuriñe, Baz; Passannante, Rossana; Tobalina Larrea, Ignacio; Ramos Cabrer, Pedro; Giralt, Albert; Sastre, Magdalena; Capetillo Zarate, Estibaliz; Koak, Urban; Knez, Damijan; Gobec, Stanislav; Marder, Nora Mariel; Martin, Abraham; Llop, Jordi
• Año de publicación: 2021
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ALZHEIMER DISEASE; AMYLOID BETA; BUTYRYLCHOLINESTERASE; PET; POSITRON EMISSION TOMOGRAPHY
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging. Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples. Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD.
Fil: Rejc, Luka. University Of Ljubljana; Eslovenia
Fil: Gómez Vallejo, Vanessa. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Joya, Ana. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Moreno, Oscar. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Egimendia, Ander. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Castellnou, Pilar. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Ríos Anglada, Xabier. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Cossío, Unai. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Zuriñe, Baz. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Passannante, Rossana. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Tobalina Larrea, Ignacio. Universidad del País Vasco; España
Fil: Ramos Cabrer, Pedro. Centro de Investigacion Cooperativa En Biomateriales.; España
Fil: Giralt, Albert. Universitat Autònoma de Barcelona; España
Fil: Sastre, Magdalena. Imperial College. London Institute Of Medical Sciences.;
Fil: Capetillo Zarate, Estibaliz. Universidad del País Vasco; España
Fil: Koak, Urban. University Of Ljubljana; Eslovenia
Fil: Knez, Damijan. University Of Ljubljana; Eslovenia
Fil: Gobec, Stanislav. University Of Ljubljana; Eslovenia
Fil: Marder, Nora Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Martin, Abraham. No especifíca;
Fil: Llop, Jordi. Centro de Investigacion Cooperativa En Biomateriales.; España