Design And Development Of New Ligands For Imaging P2Y12

Abstract

Tackling neurodegenerative diseases represents a critical challenge in modern medicine, with conditions like multiple sclerosis, Alzheimer’s, Huntington’s, and Parkinson’s disease presenting complex pathologies and overlapping symptom profiles. Despite over a century of research, therapeutic interventions remain largely limited to symptom management, highlighting the need for improved diagnostics and interventions.

Chronic neuroinflammation is a shared pathological feature of neurological disorders, contributing to progressive brain tissue loss. Microglia, the CNS’s primary immune cells, regulate inflammatory responses through pro- and anti-inflammatory mechanisms. P2Y12 has emerged as a potential biomarker of the anti-inflammatory state, offering insight into microglial behaviour during disease progression.

Positron Emission Tomography (PET) enables visualisation of biological processes in vivo through biomarker-specific radiotracers. Previous efforts to develop P2Y12 PET tracers repurposed anti-thrombotic ligands labelled with carbon-11, but these lacked the necessary properties for CNS penetration, halting their development.

This thesis addresses these challenges through a comprehensive approach. Computer-aided drug design (CADD) was used to predict optimal binding and physicochemical properties of various known and novel P2Y12 ligands. Rational modifications aimed to improve CNS penetration and tracer viability. In parallel, fluorescent P2Y12 probes were designed and synthesised for use in NanoBRET competitive binding assays, enabling biological evaluation of PET tracer candidates.

By systematically addressing barriers in tracer development, this work supports the creation of CNS-penetrating P2Y12 PET tracers. A successful tracer could offer real-time insight into anti-inflammatory signalling in the CNS, paving the way for earlier diagnosis and more targeted treatment strategies in neurodegenerative diseases.