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Project

Development of new chemical tools to investigate the role of L-type calcium channels in diseases.

Voltage-gated calcium channels (VGCCs) play a crucial role in maintaining calcium homeostasis, being involved in essential physiological processes, like excitation-contraction coupling, excitation-secretion coupling, and excitation-transcription coupling. Despite their paramount role in all-important human pathologies, the development of tools specifically targeting VGCCs lags compared to other transmembrane proteins. Current examples applicable to fluorescence or PET imaging target solely L-type calcium channels (CaV1), neglecting other VGCC families. In addition, they have a somewhat limited applicability, due to blue-emitting or green-emitting fluorophores or short-lived isotopes such as carbon-11.

This thesis aims to address these limitations by improving chemical probes for CaV1 and broadening the horizons to other VGCC families, namely CaV3. First, we focus on fluorescence imaging devising novel far-red emitting fluorescent ligands for CaV1, which offer inherent advantages, such as avoiding overlap with specimen autofluorescence and lower phototoxicity. Then, we extend the scope of the fluorescent ligands to encompass CaV3, by synthesizing a small library of fluorescent ligands based on the pharmacophore of a selective ligand for CaV3 channels. Finally, intrigued by the potential of PET imaging in drug discovery, diagnosis of disorders, and treatment monitoring, we explore novel PET tracers targeting VGCCs, investigating different radioisotopes and pharmacophores.

While the journey ahead may still be lengthy, the research presented in this thesis represents a significant step forward toward overcoming these challenges and advancing the field of VGCC imaging.

Date:6 Oct 2020 →  Today
Keywords:Fluorescent imaging tool-development, L-type calcium channel (LTCC), Amyotrophic lateral sclerosis (ALS)
Disciplines:Organic chemical synthesis
Project type:PhD project