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

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...

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Published in:European journal of nuclear medicine and molecular imaging 2021-06, Vol.48 (6), p.1759-1772
Main Authors: Kuebler, Laura, Buss, Sabrina, Leonov, Andrei, Ryazanov, Sergey, Schmidt, Felix, Maurer, Andreas, Weckbecker, Daniel, Landau, Anne M., Lillethorup, Thea P., Bleher, Daniel, Saw, Ran Sing, Pichler, Bernd J., Griesinger, Christian, Giese, Armin, Herfert, Kristina
Format: Article
Language:English
Subjects:
Affinity
Aggregates
alpha-Synuclein - metabolism
Amyloid
Animal models
Animals
Autoradiography
Binding
Brain
Carbon Radioisotopes
Cardiology
Chemical compounds
Dementia disorders
Deuteration
Fibrils
Imaging
Lewy bodies
Lewy Body Disease
Medicine
Medicine & Public Health
Metabolism
Mice
Neurodegenerative Diseases
Neuroimaging
Nuclear Medicine
Oncology
Original
Original Article
Orthopedics
Parkinson's disease
Pharmacokinetics
Pharmacology
Positron emission
Positron emission tomography
Preclinical Imaging
Radiolabelling
Radiology
Radiopharmaceuticals
Rats
Selectivity
Synuclein
Target detection
Tissue Distribution
Tomography
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Summary: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 [ 3 H]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 [ 3 H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils ( K d  = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils ( K d  = 19 ± 6.4 nM) as well as amyloid-β 1–42 fibrils ( K d  = 20 ± 10 nM). [ 11 C]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. (d 3 )-[ 11 C]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.
ISSN:1619-7070
1619-7089
DOI:10.1007/s00259-020-05133-x