Current Progress and Future Directions in Non-Alzheimer's Disease Tau PET Tracers

Abstract

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [¹⁸F]FDDNP, [¹¹C]PBB3, [¹⁸F]flortaucipir, and the [¹⁸F]THK series, for the in vivo detection of tauopathies has marked a significant breakthrough in the fields of neuroscience and radiopharmaceuticals, creating a robust new category of labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other tau PET tracers with improved binding properties have been developed using various chemical scaffolds to target the three-repeat/four-repeat (3R/4R) tau folds in AD. In 2020, [¹⁸F]flortaucipir was approved by the U.S. Food and Drug Administration for PET imaging of tau pathology in adult patients with cognitive deficits undergoing evaluation for AD. Despite remarkable progress in the development of AD tau PET tracers, imaging agents for rare non-AD tauopathies (4R tauopathies [predominantly expressing a 4R tau isoform], involved in progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and globular glial tauopathy, and 3R tauopathies [predominantly expressing a 3R tau isoform], such as Pick's disease) remain substantially underdeveloped. In this review, we discuss recent progress in tau PET tracer development, with particular emphasis on clinically validated tracers for AD and their potential use for non-AD tauopathies. Additionally, we highlight the critical need for further development of tau PET tracers specifically designed for non-AD tauopathies, an area that remains significantly underexplored despite its importance in advancing the understanding and diagnosis of these disorders.

Keywords: 3R pathology; 4R pathology; Tau PET tracers; imaging; neurodegenerative diseases; non-AD tauopathies.