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Fluorescent imaging of glutamate: a powerful tool for the comprehension of neurodegenerative diseases

Final Activity Report Summary - GLU_NEUROSENSOR (Fluorescent imaging of glutamate: a powerful tool for the comprehension of neurodegenerative diseases)

L-Glutamate is the most abundant neurotransmitter present in mammalian brain. This amino acid accomplishes essential functions inside the central nervous system (CNS): its movement across the neuronal synapses ensures the regulation of our locomotive and physiological activity and also regulates superior intellectual activity such as affectivity and moods. An alteration of its capacity in sending stimuli between neurons induces great damages of the cerebral structure and consequently neurological disorders. Clinical studies have evidenced that an increase in L-Glutamate concentration is directly linked with the appearance of neurodegenerative diseases such as Parkinson, Alzheimer, Huntington, dementia, amyotrophic lateral sclerosis (ASL).

In this context, the project aims to synthesise fluorescent molecular tools able to make L-Glutamate detectable by fluorescence imaging microscopy in order to visualise its mobility and distribution directly in living cells.

Two strategies have been overcome for the realisation of these fluorescent molecular sensing tools:
- Strategies A: The synthesis of a fluorescent L-Glutamate derivative for determining the mobility and the distribution of this neurotransmitter directly in neurons. This new fluorescent neurotransmiiter has to be internalized in living cells as the natural glutamate is. This is why we had, during the fellowship, to synthesised four fluorescent L-Glutamate derivatives. We marked L-Glutamate in different positions and with three different fluorophores in order to enlarge the probability of success for the cellular up-take. The most promising molecule will now be tested on living neuronal cells in the neurobiologists group we collaborate with.

- Strategies B: The synthesis of a selective luminescent biosensor for L-Glutamate in extracellular space, in other words a selective supramolecular receptor for L-Glutamate that signals the presence of L- Glutamate with a change in luminescence emission of the probe but with no modification of the neurotransmitter. Three tris-bipyridyl Ruthenium complexes with a bipyridine modified in 3,3'-position were synthesised. The 3,3'-modified pyridine possess arms with guanidinium functions able to recognise and detect the glutamate in photoluminescence. Moreover, these ruthenium complexes are able to discriminate L-Glutamate and phosphate anions (abundantly presents in cellular milieu) depending of the detection method, photoluminescence or electrochemiluminescence.

That's important for preventing interferences in detecting L-Glutamate directly in neuronal tissue. These ruthenium complexes could be good candidates for building sensors made by optical fibres that present a face with a deposed polymer doped with our complexes. This kind of sensor could permit our complexes perform remote real-time imaging.