Tau PET probes for Alzheimer's disease detection and their structural characterization

There are two hallmarks for the Alzheimer's disease that are currently used to identify the disease- the presence of the proteins Amyloid-β and Tau. Amyloid PET has been studied for a long time and many effective probes have been introduced, some approved by the FDA, including [¹⁸F]-florbetaben (Neuraceq), [¹⁸F]-florbetapir (Amyvid), [¹⁸F]-flutemetamol (Vizamyl). However, it was found that imaging of NFTs could give more accurate results as the accumulation of Tau could directly be correlated with neurodegeneration, which isn't the case for Amyloid-β. Amyloid PET is thereby a diagnostic tool, which can rather be used for confirming the absence of Alzheimer's Disease. Tau PET, which was found to be a potentially useful diagnostic tool was explored further as it can directly be associated with the extent of spread of the disease. This led to the discovery of many probes for Tau PET. The initial ones were non-selective for Tau over Aβ. Further exploration suggested two generations of Tau probes, both with higher selectivity for Tau over Aβ. A second generation was introduced to overcome the shortcomings of the first generation which are examined in this review. Much research on effective Tau PET probes has led to an FDA-approved Tau probe, ¹⁸F-flortaucipir. This systematic review discusses the characteristics and effectiveness of the first-generation probes, second-generation probes and other newer probes. It discusses the structural changes made in the probes over time that led to the enhancement of their properties as a Tau probe, that is, increased affinity and selectivity for Tau. It also discusses the shortcomings of probes developed so far and the ideal characteristics for Tau probes.