Selective imaging probes for differential detection of pathological tau polymorphs in tauopathies

Tauopathies, including Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are characterized by the misfolding and pathological aggregation of the tau protein, leading to neurodegeneration. Although the pathogenesis of these diseases is still a matter for debate, the formation of amyloid inclusions still represents the only histopathological hallmark available. Tau inclusions are not the same in terms of structure and morphology, and different tauopathies are characterized by different polymorphs. Remarkably, the selective detection of these polymorphs is crucial for differential diagnosis, disease monitoring and evaluation of the potential harmfulness of polymorphs, with a significant impact on drug discovery. This review discusses recent advances in the development of imaging probes designed for the selective detection of pathological tau forms associated with specific tauopathies. We explore the application of compounds that can target tau polymorphs characteristic of AD, PiD, PSP and CBD. In particular, we focus on discussing the probes' selectivity and sensitivity in distinguishing between the different tauopathy-associated polymorphs in preclinical settings. The progress and the weaknesses in this field are discussed, to guide the researchers in identifying accurate and potent probes for the selective diagnosis of these different neurodegenerative diseases.