Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
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..
Show others and affiliations
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]

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 [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.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 [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.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.

Place, publisher, year, edition, pages
Springer, 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
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-251698DOI: 10.1007/s00259-019-04305-8ISI: 000466188800022PubMedID: 30919054OAI: oai:DiVA.org:kth-251698DiVA, id: diva2:1316635
Note

QC 20190520

Available from: 2019-05-20 Created: 2019-05-20 Last updated: 2019-05-20Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Ågren, Hans

Search in DiVA

By author/editor
Natarajan Arul, MuruganÅgren, Hans
By organisation
Theoretical Chemistry and Biology
In the same journal
European Journal of Nuclear Medicine and Molecular Imaging
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 12 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf