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

LUKA REJC ; VANESSA GÓMEZ-VALLEJO; ANA JOYA; OSCAR MORENO; ANDER EGIMENDIA; PILAR CASTELLNOU; XABIER RÍOS-ANGLADA; UNAI COSSÍO; ZURIÑE BAZ; ROSSANA PASSANNANTE; IGNACIO TOBALINA-LARREA; PEDRO RAMOS-CABRER; ALBERT GIRALT; MAGDALENA SASTRE; ESTIBALIZ CAPETILLO-ZARATE; URBAN KOAK; DAMIJAN KNEZ; STANISLAV GOBEC; MARIEL MARDER.; ABRAHAM MARTIN; JORDI LLOP

Theranostics

Ivyspring International Publisher

Lugar: Sydney; Año: 2021 vol. 11 p. 6542 - 6559

1838-7640

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, no information on longitudinal increase in BChE activity has so far been provided. 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 wild type (WT) mice. Biodistribution studies were performed in WT animals using dynamic PET-CT imaging. Specific binding was demonstrated by PET imaging blocking studies in 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in 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 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 PET 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 accumulation rate of Aβ plaques in both cerebral cortex and hippocampus of AD animals as 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. This might be attributed to lower binding affinity of inhibitor 4 to BChE, due to Aβ-induced conformational changes.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.