Rational design and synthesis of a novel BODIPY-based probe for selective imaging of tau tangles in human iPSC-derived cortical neurons.

Numerous studies have shown a strong correlation between the number of neuro brillary tangles of the tau protein and Alzheimer’s disease progression, making the quantitative detection of tau very promising from a clinical point of view. However, the lack of highly reliable uorescent probes for selective imaging of tau neuro brillary tangles is a major challenge due to sharing similar β–sheet motifs with homologous Amyloid‐β brils. In the current work, we describe the rational design and the in silico evaluation of a small‐size focused library of uorescent probes, consisting of a BODIPY core (electron acceptor) featuring highly conjugated systems (electron donor) with a length in the range 13–19 Å at C3. Among the most promising probes in terms of binding mode, theoretical a nity and polarity, BT1 has been synthesized and tested in vitro onto human induced pluripotent stem cells derived neuronal cell cultures. The probe showed excellent photophysical properties and high selectivity allowing in vitro imaging of hyperphosphorylated tau protein laments with minimal background noise. Our ndings o er new insight into the structure‐activity relationship of this class of tau selective uorophores, paving the way for boosting tau tangle detection in patients possibly through retinal spectral scans.