Positron emission tomography (PET) is poised to revolutionize preclinical assessment of high-prevalence neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Although many candidate radiotracers have been developed, the mechanisms that mediate their high affinity binding (i.e., low nM) to the surfaces presented by α-synuclein, tau, or β-amyloid cross-β-sheet aggregates are not fully understood. This is in part because radiotracers tend to be flat heterocycles with limited three-dimensional character, and because their high-density binding partners are composed of shallow channels located along aggregate surfaces. To address this problem, we characterized the interaction of a family of small molecule probes with a library of synthetic binding sites using a thioflavin dye displacement assay. The library was constructed from the PHF6 site of tau protein (Ac-VQ2IV4YK-NH2), which aggregates to form filaments similar to recombinant 3R tau in the presence of heparin. The library was engineered to generate aggregates that shared a common hydrophobic core, but that differed with respect to the hydrophobicity, polarizability, channel width, aromatic side chain availability, and net charge of their external surfaces. Results showed that the peptide library members could be induced to form filamentous aggregates that bound thioflavin dye. Displacement affinity of the probes increased when V4 was substituted with Gly or Phe, whereas affinity for Q2 substitution was highly dependent on probe structure. Within the probe, type and position of substituent significantly affected peptide interactions. Future work will use quantitative structure activity relationship analysis to identify the molecular descriptors that mediate high affinity binding to cross-β-sheet surface sites.

Targeting cross-β-sheet surfaces with small molecule imaging agents

2019 Fall National Meeting

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