Molecular imaging of butyrylcholinesterase associated with amyloid-β plaques distinguishes 5XFAD from wild-type mice

Abstract Purpose Diagnosis of Alzheimer’s disease (AD) requires symptoms of dementia and accumulation of amyloid-β (Aβ) and tau in the brain. Molecular imaging of Aβ or tau in AD, though informative, is complicated by the finding that similar changes are found in brains of ~ 30% of cognitively normal older individuals. Butyrylcholinesterase (BChE), normally present in low levels in the cerebral cortex, is found in high levels associated with Aβ plaques in AD. When associated with this pathological structure, the biochemical properties of BChE are altered. The aim of the present study was to determine if [ 18 F]1-Methyl-4-piperidinyl p-fluorobenzoate ([ 18 F]BMP) can image BChE associated with Aβ in 5XFAD mouse model of AD and distinguish it from its wild-type (WT) counterpart. Procedures [ 18 F]BMP was synthesized and evaluated in wild-type (WT), 5XFAD and BChE knock-out (BChE-KO) mouse models for in vivo dynamic PET imaging of BChE. Time-activity curves were generated and [ 18 F]BMP clearance parameters were determined. Brain, liver and urine homogenates were evaluated for [ 18 F]BMP and its metabolites. Ex vivo autoradiography mapped the distribution of [ 18 F]BMP brain retention. Results In vivo PET imaging following injection of [ 18 F]BMP demonstrated significantly greater brain retention of activity in the 5XFAD mouse model compared to WT, while BChE-KO mice mirrored WT levels. Metabolite analysis confirmed [ 18 F]BMP was metabolized in the periphery but survived in sufficient quantity to enter the brain. Ex vivo autoradiography showed [ 18 F]BMP retention in the 5XFAD mouse brain where BChE-associated Aβ plaques were prominent. Conclusions These results demonstrate that PET imaging of BChE-associated Aβ plaques is feasible, offering an avenue to evaluate role(s) of BChE in AD pathogenesis, progression and complement the existing AD biomarker framework.