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

• Published in: European journal of nuclear medicine and molecular imaging Vol. 46; no. 6; pp. 1369 - 1382
• Main Authors: Murugan, N. Arul, Chiotis, Konstantinos, Rodriguez-Vieitez, Elena, Lemoine, Laetitia, Ågren, Hans, Nordberg, Agneta
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2019; Springer Nature B.V
• Subjects: Affinity; Alzheimer's disease; Amine oxidase (flavin-containing); Binding energy; Binding free energy calculations; Binding sites; Cardiology; Computer applications; Computer simulation; Enzymes; Fluorine isotopes; Free energy; Imaging; In vivo methods and tests; Medical imaging; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Molecular docking; Monoamine oxidase B; Nuclear Medicine; Off-target binding; Oncology; Original; Original Article; Orthopedics; Oxidase; Positron emission; Radiology; Tau PET imaging; Tau protein; Tomography; Tracers; Off-target binding; Monoamine oxidase B; Binding free energy calculations; Alzheimer’s disease; Tau PET imaging; Molecular docking
• ISSN: 1619-7070; 1619-7089; 1619-7089
• DOI: 10.1007/s00259-019-04305-8

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 [
18
F]THK5317 and the MAO-B tracer [
11
C]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 [
18
F]THK5317 was different from that for [
11
C]DED, although areas of suspected off-target [
18
F]THK5317 binding were detected. The binding relationship between [
18
F]THK5317 and [
11
C]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.