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Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging
AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden;Karolinska Univ Hosp, Theme Neurol, Stockholm, Sweden.
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden.
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden.
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 6, p. 1369-1382Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
2019. Vol. 46, no 6, p. 1369-1382
Keywords [en]
Tau PET imaging, Off-target binding, Monoamine oxidase B, Alzheimer's disease, Molecular docking, Binding free energy calculations
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-383497DOI: 10.1007/s00259-019-04305-8ISI: 000466188800022PubMedID: 30919054OAI: oai:DiVA.org:uu-383497DiVA, id: diva2:1316447
Funder
Swedish Foundation for Strategic Research Swedish Research Council, 05817Swedish Research Council, 02695Swedish Research Council, 06086Available from: 2019-05-17 Created: 2019-05-17 Last updated: 2019-05-17Bibliographically approved

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