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]
Summary
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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