Abstract

PurposeSeveral 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).MethodsMolecular 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.ResultsThe 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.ConclusionsThe 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.

Highlights

  • Materials and methodsAlzheimer’s disease (AD) is characterized by the accumulation of insoluble fibril aggregates of amyloid-beta and tau proteins in the brains of patients

  • When injected in vivo into patients with AD or non-AD tauopathies, they have shown extensive binding in the relevant brain areas and clear discrimination from groups of cognitively normal volunteers [4, 6,7,8,9]. All these tracers showed substantial binding in areas not primarily related to the accumulation of tau pathology in AD [6, 10, 11]

  • For tracers of the THK family and T807, the signal in the basal ganglia has been preliminarily attributed to binding to monoamine oxidase B (MAO-B) [12,13,14]

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Summary

Introduction

Materials and methodsAlzheimer’s disease (AD) is characterized by the accumulation of insoluble fibril aggregates of amyloid-beta and tau proteins in the brains of patients. When injected in vivo into patients with AD or non-AD tauopathies, they have shown extensive binding in the relevant brain areas and clear discrimination from groups of cognitively normal volunteers [4, 6,7,8,9]. All these tracers showed substantial binding in areas not primarily related to the accumulation of tau pathology in AD (e.g. the basal ganglia) [6, 10, 11]. The exact contribution of MAO-B binding to the total off-target signal, and the brain areas that are vulnerable to this off-target signal, remain to be determined for the available tau tracers

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