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 plaques, the biochemical properties of BChE are altered. The aim of the present study was to determine if the BChE ligand, 18F1-methyl-4-piperidinyl p-fluorobenzoate (18FBMP), can image BChE-associated plaques in the 5XFAD mouse model of AD and distinguish it from its wild-type (WT) counterpart. 18FBMP 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 18FBMP clearance parameters were determined. Brain, liver and urine homogenates were evaluated for 18FBMP and its metabolites. Ex vivo autoradiography mapped the distribution of 18FBMP brain retention. In vivo PET imaging following injection of 18FBMP demonstrated significantly greater brain retention of activity in 5XFAD mice compared to WT, while BChE-KO mice appeared similar to WT levels. Metabolite analysis confirmed 18FBMP was metabolized in the periphery but survived in sufficient quantity to enter the brain. Ex vivo autoradiography showed 18FBMP retention in the 5XFAD brain where BChE-associated plaques were prominent. These results demonstrate that PET imaging of BChE-associated plaques is feasible, offering an avenue to evaluate the role(s) of BChE in AD pathogenesis and progression to complement the existing AD biomarker framework.
Reid et al. (Thu,) studied this question.