Alzheimer Disease (AD) is the most common cause of dementia. It is one of the major causes of death globally and the second cause of death among the population over 70, affecting 13 million worldwide, the number expected to increase to more than 100 million by 2050. Currently, there is no effective treatment for AD available on the market, nor is there any reliable option for the early diagnosis of the disease. The diagnosis is therefore mainly based on clinical symptoms, which occur at later stages of the disease, when it is much too late for successful medical intervention. To overcome this growing problem and provide AD patients with better treatment options, there is an urgent need to identify new disease biomarkers to enable longitudinal and non-invasive monitoring of disease progression, enable a targeted approach to design new treatment, diagnostic and theragnostic strategies by shedding light on the pathophysiology of AD and the mechanisms involved in disease progression, and provide with new tools for treatment response evaluation.

In this work, we shed a light on new possibilities of using BChE as AD biomarker and discus pitfalls of detection and evaluation of this enzyme    in vivo    and   ex vivo   in a transgenic mouse model. With this purpose, we have radiolabelled a recently reported potent BChE inhibitor  with the positron emitter carbon-11 ( ¹¹C), and validated its use as   in vivo   PET tracer in two stages. First, biodistribution, metabolism and blood-brain barrier (BBB)-crossing capacity was assessed in WT mice. In parallel, its capability to detect BChE levels in  an AD mouse model was evaluated by  ex vivo  and in vivo PET-CT blocking studies  , using mice with fully developed disease. Second, the potential of this radiotracer for the in vivo longitudinal investigation of BChE expression was evaluated using PET-CT in a mouse model of AD. The results were compared to Aβ deposition in the same mice, investigated using  the validated radiotracer [¹⁸F]florbetaben, to better evaluate the correlation of BChE with AD progression. Finally, the presence of both, BChE and Aβ, was confirmed by ex vivo tissue staining and/or immunohistochemistry (IHC).