Synthesis and in vitro evaluation of 18F-labelled ACE2 small molecule inhibitors for PET imaging studies

Thesis

This thesis aims to develop ¹⁸F-labelled ACE2 inhibitors as PET tracers for the non-invasive visualisation of ACE2 expression, with potential applications in COVID-19 and other ACE2-related pathologies.

Chapter I provides a general introduction to ACE2, its role in disease, and the rationale for fluorine-18-labelled inhibitors as PET tracers.

Chapter II details the design and synthesis of novel fluorinated analogues of MLN-4760. It starts with the in silico selection of fluorinated MLN-4760 analogues guided by molecular docking, and discusses new synthetic strategies developed to overcome limitations of the existing route. The synthesis of selected analogues is described, and their ACE2 inhibitory activity is evaluated in vitro through IC₅₀ measurements.

Chapter III examines the role of PET in imaging ACE2 expression and reviews existing tracer studies. The radiolabelling of ACE2-targeting analogues is described, including precursor synthesis, fluorine-18 incorporation, and optimisation of labelling conditions.

Chapter IV provides full experimental procedures and characterisation data for the compounds discussed in this thesis.

Authors: Wang, X

• DOI: 10.5287/ora-pzb9gbobj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: MLN-4760; radiochemistry; fluorine-18; ACE2 inhibitors; radiotracers; PET imaging
• Subjects: Chemistry; Chemistry, Organic