CONTEXT

Alzheimer’s disease (AD) is a major public health problem for which there is a strong need for tools aimed at improving the early diagnosis and follow-up of currently used and newly developed treatments. For this aim, molecular imaging methods such as Positron Emission Tomography (PET) which monitor in vivo changes of specific brain targets (receptors, transporters, abnormal proteins), are highly relevant. Several findings highlight the particular involvement of alpha-7 nicotinic receptors (Alpha7-R) in AD, such as 1) the changes in their density during the course of the disease; 2) the chronic interactions between them and A-beta leading to neuronal dysfunctions and accumulation of amyloid plaques and phosphorylated tau-containing neurofibrillary tangles; 3) the potential neuroprotective effects provided by their positive allosteric modulators and/or agonists; 4) their regulatory role in microglial activation, a key-actor of neuroinflammation. Considering their multiple roles in AD, in vivo PET exploration of Alpha7-R as well as funding  Alpha7-R agonists would be a major input for improvement of the early diagnosis, follow-up and development of new treatments. To date, no PET tracer of Alpha7-R is available for clinical explorations and no final compound having an Alpha-7 R agonism is available for patients.

TECHNICAL DESCRIPTION

The combination of skills between a multidisciplinary team (Inserm U930) and a chemistry team (ICOA) allows to develop a novel series of alpha 7 compounds, with , at the beginning the main objective to use best ligand to develop a fluor-18-labeled (18F) tracer of Alpha7-R. Following all steps of the typical strategy based on drug design, lead optimization of structures and in vitro screening, optimization of [18F]-labeling methods, evaluation of selected [18F]-tracers using in vivo PET imaging in small animals, and first evaluation of the best [18F]-tracer in healthy human subjects. Thanks to this translational project, a [18F]-tracer of Alpha7-R will be available for PET clinical explorations. In another hand further investigation show clearly the brain penetration of several compounds of our series as well as their potential binding on Alpha7-R and in vitro assays show clearly they agonism activity. This consortium has developped  new selective ligands for Alpha7-R. All the new synthesized compounds were evaluated for their inhibitory effect on the binding of [125I]alpha-bungarotoxin as reference ligand on rat cortex homogenates. It appeared that one original and drugable series of compounds had excellent Ki values as a proof of their efficiency. To date, more than 150 new compounds were synthesized and tested. Among them, 30/94 have a Ki between 10 and 0.1 nM. An international patent application has been filed. Four of these compounds were labeled with [18F], obtained with high purity and specific activity, and first biodistribution studies were performed in rats. For one of these compounds (Ki 10 nM), the brain accumulation reached 0.5-0.8% injected dose/g tissue at 1 h post i.v. injection, with a ratio between the regions rich in Alpha7-R and the cerebellum of 1.3-1.5. In vivo investigations are currently carried on 3 fluorinated compounds having  Ki  beetween 3 and 1 nM.

INDUSTRIAL APPLICATIONS

The challenge is to valuate the original Alpha7-R series in human as to date no such tool is available in imaging or therapy. This will be of major interest in a number of brain disorders of which AD. This project will lead to radiopharmaceutical probe useful at different stages of the disease, thus improving the early diagnosis, follow-up and development treatments, and as well as currative solutions for non radiolabelled compounds.

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