Molecular imaging of nicotinic alpha7 receptors in Alzheimer's disease – MInAlpha7

Alzheimer’s disease (AD) is the most frequent progressive neurodegenerative disease representing the major cause of dementia in elderly subject. With 860000 people affected in France, it is a major public health problem. The diagnosis of AD is currently based on clinical criteria. The certitude diagnosis is assessed by the evidence of post-mortem characteristic brain lesions such as ß-amyloid protein deposits, neurofibrillary tangles and neuronal loss. The exploration of these lesions in vivo using the method of molecular imaging with PET (positon emission tomography) will allow having a sensitive and selective diagnosis tool. This method requires tracers, or radiopharmaceuticals, specific of the molecular target to be explored (abnormal protein, receptor). The deposits of abnormal proteins (ß-amyloid plaques, hyperphophorylated tau) are targets of choice for AD. Radiopharmaceuticals allowing to localise and quantify them are currently proposed. Recent results showed that the density of ß-amyloid plaques determined by PET can be related to the stage of AD, but other showed that this density is unable to predict the cognitive state of patients.
Another approach for obtaining a relevant diagnosis tool for AD is the measurement of changes in biological markers associated to dysfunctions of neurotransmission and neuronal death. The cholinergic neurons are strongly involved in the processes affected during AD and are relevant targets of current treatments. Modifications of cholinergic neurotransmission have been assessed using the PET tracer 11C-nicotine, showing links between the density of nicotinic receptors and attention deficit. The functional exploration of cholinergic neurotransmission appears therefore as a promising approach for the early and selective diagnosis of AD. The nicotinic receptors of alpha7 subtype (alpha7R) play major roles during AD such as: changes in their density, formation of alpha7R- ß-amyloid peptide complexes that are toxic for neurons, reinforcement of neuroinflammation that worsen neuronal lesions. To date, no PET tracer for alpha7R is available.
The objective of this project is to develop 18F-labeled radiopharmaceutical(s) for the diagnosis and therapeutic follow-up of AD using PET molecular imaging of alpha7R.
The specific objectives are: 1) the conception and synthesis of new compounds targeting alpha7R, 2) in vitro evaluation of the pharmacological properties of these compounds (affinity, selectivity), 3) radiolabeling of selected compounds with 18F, 4) evaluation of these 18F-tracers in animal.
This project is based on the recognized expertise of the 2 partners in the field of:
1 Organic chemistry: ICOA (Orléans) is specialized in organic synthesis of compounds aimed at therapeutic use, and thus has all the expertise allowing to product a large panel of new compounds.
2 Radiochemistry, in vitro and in vivo pharmacology, SPECT/PET molecular imaging: the team 3 of Inserm U930 (Tours) has the expertise allowing the development of radiopharmaceuticals aimed at a preclinical and clinical use.
Preliminary results have already been obtained by both partners. On the basis of literature data which described compounds having affinity for alpha7R, we obtained new compounds belonging to 2 chemical families that showed nanomolar affinity for alpha7R. These first results lead to pursue and extend the development of new fluorinated compounds which, in function of their pharmacological properties will be labeled with 18F for further evaluation in animals.