Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging

Eur J Nucl Med Mol Imaging. 2019 Jun;46(6):1369-1382. doi: 10.1007/s00259-019-04305-8. Epub 2019 Mar 27.

Abstract

Purpose: Several tracers have been designed for tracking the abnormal accumulation of tau pathology in vivo. Recently, concerns have been raised about the sources of off-target binding for these tracers; inconclusive data propose binding for some tracers to monoamine oxidase B (MAO-B).

Methods: Molecular docking and dynamics simulations were used to estimate the affinity and free energy for the binding of several tau tracers (FDDNP, THK523, THK5105, THK5317, THK5351, T807 [aka AV-1451, flortaucipir], T808, PBB3, RO-948, MK-6240, JNJ-311 and PI-2620) to MAO-B. These values were then compared with those for safinamide (MAO-B inhibitor). PET imaging was used with the tau tracer [18F]THK5317 and the MAO-B tracer [11C]DED in five patients with Alzheimer's disease to investigate the MAO-B binding component of this first generation tau tracer in vivo.

Results: The computational modelling studies identified a binding site for all the tau tracers on MAO-B; this was the same site as that for safinamide. The binding affinity and free energy of binding for the tau tracers to MAO-B was substantial and in a similar range to those for safinamide. The most recently developed tau tracers MK-6240, JNJ-311 and PI-2620 appeared, in silico, to have the lowest relative affinity for MAO-B. The in vivo investigations found that the regional distribution of binding for [18F]THK5317 was different from that for [11C]DED, although areas of suspected off-target [18F]THK5317 binding were detected. The binding relationship between [18F]THK5317 and [11C]DED depended on the availability of the MAO-B enzyme.

Conclusions: The developed tau tracers show in silico and in vivo evidence of cross-interaction with MAO-B; the MAO-B component of the tracer binding was dependent on the regional concentration of the enzyme.

Keywords: Alzheimer’s disease; Binding free energy calculations; Molecular docking; Monoamine oxidase B; Off-target binding; Tau PET imaging.

MeSH terms

  • Aged
  • Alanine / analogs & derivatives
  • Alanine / analysis
  • Alzheimer Disease / diagnostic imaging*
  • Benzylamines / analysis
  • Binding Sites
  • Brain / diagnostic imaging
  • Computational Biology
  • Computer Simulation
  • Female
  • Humans
  • Ligands
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Molecular Docking Simulation
  • Monoamine Oxidase / metabolism*
  • Positron-Emission Tomography*
  • Protein Binding
  • Protein Conformation
  • Radiopharmaceuticals / analysis*
  • Retrospective Studies
  • tau Proteins / metabolism

Substances

  • Benzylamines
  • Ligands
  • Radiopharmaceuticals
  • tau Proteins
  • safinamide
  • Monoamine Oxidase
  • Alanine