Optimised synthesis of florzolotau and its fluorine-18 radiolabelling precursor

Abstract

Diverse neurodegenerative disorders that are neuropathologically characterised by depositions of tau protein aggregates are collectively referred to as tauopathies. This can include diseases such as Alzheimer's disease (AD), frontotemporal lobar degeneration and progressive supranuclear palsy. Tauopathies are classified according to the relative ratio of tau protein isoforms (3R or 4R) that make up their aggregates. Positron emission tomography (PET) enables the visualisation of tau lesions in vivo, but imaging both 3R and 4R deposits with the same imaging agent is an ongoing challenge. An emerging tau PET radiotracer, [¹⁸F]-florzolotau (also known as [¹⁸F]PM-PBB3 or [¹⁸F]APN-1607), reportedly binds to all tau isoforms, making it a clinically useful tool for assessing disease pathology in patients with both 3R and 4R tauopathies. In this work, we report for the first time a complete, convergent synthesis of a radiolabelling precursor of [¹⁸F]-florzolotau and its non-radioactive reference standard from commercially available starting materials. We demonstrate the scalability of our approach to facilitate wider access to this clinically useful imaging agent.