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  [11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

Kuebler, L., Buss, S., Leonov, A., Ryazanov, S., Schmidt, F., Maurer, A., et al. (2021). [11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates. European Journal of Nuclear Medicine and Molecular Imaging, 48(6), 1759-1772. doi:10.1007/s00259-020-05133-x.

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 Creators:
Kuebler, L., Author
Buss, S., Author
Leonov, A.1, Author              
Ryazanov, S.2, Author              
Schmidt, F., Author
Maurer, A., Author
Weckbecker, D., Author
Landau, A. M., Author
Lillethorup, T. P., Author
Bleher, D., Author
Saw, R. S., Author
Pichler, B. J., Author
Griesinger, C.1, Author              
Giese, A., Author
Herfert, C., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Department of NMR-based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: Alpha-synuclein; Parkinson’s disease; PET imaging; Tracer development
 Abstract: Purpose Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases. Methods Specificity and selectivity of [3H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM). Results [3H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (Kd = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (Kd = 19 ± 6.4 nM) as well as amyloid-β1–42 fibrils (Kd = 20 ± 10 nM). [11C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d3)-[11C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein. Conclusion MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties.

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Language(s): eng - English
 Dates: 2020-12-282021-06
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s00259-020-05133-x
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Title: European Journal of Nuclear Medicine and Molecular Imaging
Source Genre: Journal
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Pages: - Volume / Issue: 48 (6) Sequence Number: - Start / End Page: 1759 - 1772 Identifier: -