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Cross-interaction o...
Cross-interaction of tau PET tracers with monoamine oxidase B : evidence from in silico modelling and in vivo imaging
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- Natarajan Arul, Murugan (författare)
- KTH,Teoretisk kemi och biologi,AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Chiotis, Konstantinos (författare)
- Karolinska Institutet,Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden;Karolinska Univ Hosp, Theme Neurol, Stockholm, Sweden
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- Rodriguez-Vieitez, Elena (författare)
- Karolinska Institutet,Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden
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- Lemoine, Laetitia (författare)
- Karolinska Institutet,Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden
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- Ågren, Hans (författare)
- Uppsala universitet,KTH,Teoretisk kemi och biologi,Uppsala Univ, Dept Phys & Astron, Box 516, SE-75120 Uppsala, Sweden.,Molekyl- och kondenserade materiens fysik,AlbaNova Univ Ctr, KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Nordberg, Agneta (författare)
- Karolinska Institutet,Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Div Clin Geriatr, Stockholm, Sweden;Karolinska Univ Hosp, Theme Aging, Stockholm, Sweden
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(creator_code:org_t)
- 2019-03-27
- 2019
- Engelska.
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 46:6, s. 1369-1382
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Tau PET imaging
- Off-target binding
- Monoamine oxidase B
- Alzheimer's disease
- Molecular docking
- Binding free energy calculations
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