Strategies of positron emission tomography (PET) tracer development for imaging of tau and α-synuclein in neurodegenerative disorders.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by the presence of extracellular amyloid plaques consisting of β-amyloid peptides (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau) protein in the brain. Genetic and animal studies strongly indicate that Aβ, tau and neuroinflammation play important roles in the pathogenesis of AD. Several staging models showed that NFTs correlated well with the disease progression. Positron emission tomography (PET) imaging has become a widely used non-invasive technique to image NFTs for early diagnosis of AD. Despite the remarkable progress made over the past few years, tau PET imaging is still challenging due to the nature of tau pathology and the technical aspects of PET imaging. Tau pathology often coexists with other proteinopathies, such as Aβ plaques and α-synuclein aggregates. Distinguishing tau-specific signals from other overlapping pathologies is difficult, especially in the context of AD, where multiple protein aggregates are present, as well as the spectrum of different tau isoforms (3R and 4R) and conformations. Moreover, tracers should ideally have optimal pharmacokinetic properties to penetrate the blood-brain barrier (BBB) while maintaining specificity, low toxicity, low non-specific binding, rapid uptake and clearance from the brain, and formation of no radiolabeled metabolites in the brain. On the other hand, Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the abnormal accumulations of α-synuclein in neurons. Heterogeneity and the unclear pathogenesis of PD hinder early and accurate diagnosis of the disease for therapeutic development in clinical use. In this review, while referring to existing reviews, we focus on the design strategies and current progress in tau (NFTs) targeting new PET tracers for AD; evolution of non-AD tau targeting PET tracers for applications including progressive supranuclear paralysis (PSP) and corticobasal degeneration (CBD); new PET tracer development for α-synuclein aggregate imaging in PD and giving an outlook for future PET tracer development.