Research

Development of new carbamate-based imaging probes for cholinesterases

Code:

NC-0009

Range:

01. July 2018 - 31. March 2021

Range:

0,14 FTE

Leader:

Stanislav Gobec

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Cholinesterases (ChEs) are polymorphic serine hydrolases that catalyse the hydrolysis of neurotransmitter acetylcholine (ACh) and other esters. Two ChEs are found in vertebrates: acetylcholinesterase (AChE) and butyrycholinesterase (BChE). Both enzymes are involved not only in physiological processes but also in several pathophysiological processes (e.g. Alzheimer’s disease (AD), tumour formation, Hirschsprung’s disease (HSCR), multiple sclerosis (MS)). ChEs also have non-enzymatic functions in cell adhesion, and cell proliferation and differentiation during early neuronal development. AChE and BChE can thus by used as biomarkers for the detection of AD, HSCR and MS. To date, only few probes and histochemical methods enable ChEs location and activity determination. Accordingly, the development of probes for investigating the roles of ChEs in physiological and pathophysiological processes is required by biologists and neurobiologists.
During previous collaborative research between PI Colletier and PI Gobec, several series of ChE inhibitors were developed (J. Med. Chem. 2014, 57: 8167; Bioorg. Med. Chem. 2015, 23: 4442; Bioorg. Med. Chem. 2016, 25: 633; Sci. Rep. 2016, 6: 39495, Bioorg. Med. Chem. 2017, 25: 633; J. Med. Chem. 2018, 61: 119; Eur. J. Med. Chem. 2018, 156: 598) including potent and selective BChE inhibitors with in vivo activity in mouse model of AD (Sci. Rep. 2016, 6: 39495; J. Med. Chem. 2018, 61: 119; patent application PCT/IB2016/051603). The binding mode of several inhibitors into the active site of BChE was explained by X-ray crystallography, which represents a solid foundation for structure-based optimisation. In this project the collaboration aims at developing new chemical probes for microscopy and molecular imaging of ChEs in vitro and ex vivo to further elucidate their role in physiological and pathophysiological processes. To achieve that, we will take advantage of the complementarity between French and Slovenian groups: the group from Ljubljana has expertise in medicinal and organic chemistry, while the group from Grenoble has expertise in X-ray crystallography that is essential for the project.