Design and synthesis of high-affinity ligands of AMPA receptors and study of their Fluorine-18 radiolabeling

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data collected in recent years, the use of AMPA potentiators seems to be an interesting approach in the treatment of cognitive deficits (e.g. Alzheimer disease), schizophrenia or depression. Such AMPA signal potentiation could be mediated by positive allosteric modulators (PAMs) of the AMPA receptors, a class of compounds able to produce a fine signal tuning in the presence of the endogenous ligand in the synapse, providing less toxicity than direct agonists.
With this approach, the laboratory of Medicinal Chemistry of Liège university developed many series of AMPA potentiators , among which 1,2,4-benzothiadiazine 1,1-dioxides (BTDs).

In order to better understand the in vivo mapping of AMPA receptors and its evolution in neurological diseases, the present work aims at developing the design and the synthesis of BTDs positive allosteric modulators radiolabeled with a fluorine-18 atom.

Based on previously synthesized series in this field, we investigate the synthesis of a new class of high-affinity AMPA potentiators characterized by the presence of a fluorine atom at selected positions on the structure of the AMPA potentiators.
Thanks to in vitro pharmacological evaluations, we will further determine the best candidates for their fluorine-18 radiolabeling.