Design and synthesis of PET-probes targeting AMPA subtype receptors

The AMPA subtype of glutamatergic receptors is the main actor in the fast 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, it also appears that glutamatergic systems are involved in several pathological diseases. For instance, a lack of glutamatergic neurotransmission is observed in cognitive disorders or schizophrenia and an excessive activity is observed in Parkinson or Huntington diseases.

The in vivo study of glutamate receptors mapping and its evolution appears to be an essential step for a better understanding of its implications. However, according to the literature, design of such a probe remains difficult due to the lack of specificity of the probes.

Taking into account the potential in vitro and in vivo activity and specificity of benzothiadizine dioxides (BTDs) acting as AMPA positive allosteric modulators, we are investing the development of new compounds of this class radiolabeled with a fluorine-18 atom. Hence, we are currently developing new series of BTDs characterized by the presence of a fluorine atom and a 7-phenoxy-substituent that are expected to be more active and more specific.
Finally, pharmacological tests to evaluate the best candidates for the radiochemical synthesis and in vivo evaluations are currently in progress.