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Identification and in vitro characterization of C05-01, a PBB3 derivative with improved affinity for alpha-synuclein
Miranda-Azpiazu P, Svedberg M, Higuchi M, Ono M, Jia Z, Sunnemark D, Elmore CS, Schou M et al.. Brain research, 2020-09-18
Topic: Brain proteins, microglia and lab models
The neuropathological hallmark of Parkinsońs disease, multiple system atrophy and dementia with Lewy bodies is the accumulation of α-synuclein. The development of an imaging biomarker for α-synuclein is an unmet need. To date, no selective α-synuclein imaging agent has been identified, though initial studies suggest that the tau tracer [ 11 C]PBB3 displays some degree of binding to α-synuclein. In this study, a series of compounds derived from the PBB3 scaffold were examined using fluorescence imaging and tissue microarrays (TMAs) derived from brain samples with different proteinopathies. One compound, C05-01, was selected based on its higher fluorescence signal associated with Lewy body aggregates compared with other PBB3 analogues. In vitro binding assays using human brain homogenates and recombinant fibrils indicated that C05-01 had higher affinity for α-synuclein (K D /Ki 25 nM for fibrils, Ki 3.5 nM for brain homogenates) as compared with PBB3 (K D 58 nM). In autoradiography (ARG) studies using fresh frozen human tissue and TMAs, [ 3 H]C05-01 displayed specific binding in cases with α-synuclein pathology. C05-01 is the first PBB3 analogue developed as a potential compound targeting α-synuclein. Despite improved affinity for α-synuclein, C05-01 showed specific binding in AD tissue with Amyloid β and tau pathology, as well as relatively high non-specific and off-target binding. Additional efforts are needed to optimize the pharmacological and physicochemical properties of this series of compounds as ligands for α-synuclein. This study also showed that the construction of TMAs from different proteinopathies provides a tool for evaluation of fluorescent or radiolabelled compounds binding to misfolded proteins.
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APA 7th
Miranda-Azpiazu, P., Svedberg, M., Higuchi, M., Ono, M., Jia, Z., Sunnemark, D., et al. (2020). Identification and in vitro characterization of C05-01, a PBB3 derivative with improved affinity for alpha-synuclein. Brain research. https://doi.org/10.1016/j.brainres.2020.147131
Vancouver
Miranda-Azpiazu P, Svedberg M, Higuchi M, Ono M, Jia Z, Sunnemark D, et al. Identification and in vitro characterization of C05-01, a PBB3 derivative with improved affinity for alpha-synuclein. Brain research. 2020. doi:10.1016/j.brainres.2020.147131. PMID: 32956648.
BibTeX
@article{mirandaazpiazu2020-32956648,
author = {Miranda-Azpiazu, P. and Svedberg, M. and Higuchi, M. and Ono, M. and Jia, Z. and Sunnemark, D. and Elmore, C. S. and Schou, M. and others},
title = {{Identification and in vitro characterization of C05-01, a PBB3 derivative with improved affinity for alpha-synuclein}},
journal = {Brain research},
year = {2020},
doi = {10.1016/j.brainres.2020.147131},
pmid = {32956648},
url = {https://doi.org/10.1016/j.brainres.2020.147131}
}
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Key findings
- To date, no selective α-synuclein imaging agent has been identified, though initial studies suggest that the tau tracer [ 11 C]PBB3 displays some degree of binding to α-synuclein.
- One compound, C05-01, was selected based on its higher fluorescence signal associated with Lewy body aggregates compared with other PBB3 analogues.
- In vitro binding assays using human brain homogenates and recombinant fibrils indicated that C05-01 had higher affinity for α-synuclein (K D /Ki 25 nM for fibrils, Ki 3.5 nM for brain homogenates) as compared with PBB3 (K D 58 nM).
- This study also showed that the construction of TMAs from different proteinopathies provides a tool for evaluation of fluorescent or radiolabelled compounds binding to misfolded proteins.
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Study details
- Evidence strengthLow
How this study scored 38/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 22 of the 58 points we could judge it on, which is 38 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Brain research) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2020 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “in vitro”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 32956648) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 22 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 22 of the 58 points we could judge it on is 38 out of 100. |
| Total | 38 / 100 | — |
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