Proof-of-concept of a novel methylated PET tracer designed to enhance the Photostability of PM-PBB3

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Molecular imaging of tau protein accumulation plays a vital role in elucidating the pathology and enabling early diagnosis of tauopathies, including Alzheimer's disease (AD). [ 18 F]PM-PBB3 is a promising tau positron emission computed tomography (PET) tracer with high selectivity and affinity for tau lesions in both AD and non-AD tauopathies. However, its clinical application is hindered by poor photostability owing to rapid photoisomerization. In this study, we synthesized a novel derivative of PM-PBB3, Me-PM-PBB3, by introducing a methyl group at the γ-position of the former to improve photostability. Compared to PM-PBB3, Me-PM-PBB3 showed a blue-shifted absorption maximum and lower molar extinction coefficient, resulting in a more than 100-fold increase in resistance to photodegradation. Fluorescence staining of AD brain sections demonstrated that Me-PM-PBB3 bound to neurofibrillary tangles. PET imaging using rTg4510 mice, a tauopathy model, revealed that [ 18 F]Me-PM-PBB3 accumulates in the cortex and hippocampus, indicating its effectiveness as a tau PET tracer. However, increased non-specific binding in white matter was also observed, suggesting that structural modifications may affect its in vivo kinetics. Overall, this study presents a novel chemical approach to enhance the photostability of tau PET tracers, and the proof-of-concept was completed using Me-PM-PBB3. • The introduction of methyl groups suppressed photoisomerization of PM-PPB3. • Me-PM-PBB3 bound to neurofibrillary tangles. • [ 18 F]Me-PM-PBB3 accumulated in the cerebral cortex and hippocampus, indicating its effectiveness as a tau PET tracer. • This study presents a new chemical approach to improve the photostability of the tau PET tracer.

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