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In vitro evaluation of [3H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies
Cassis Varlow, Chester A Mathis, Neil Vasdev. Nuclear medicine and biology, 2024-02-19
Topic: Disease mechanisms in lab and animal studies
Alzheimer's disease (AD) and non-AD tauopathies such as chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are characterized by the abnormal aggregation of three-repeat (3R) and/or four-repeat (4R) tau isoforms. Several tau-PET tracers have been applied for human imaging of AD and non-AD tauopathies including [18F]PI-2620. Our objective is to evaluate [3H]PI-2620 and two promising structural derivatives, [3H]PI-2014 and [3H]F-4, using in vitro saturation assays and competitive binding assays against new chemical entities based on this scaffold in human AD tissues for comparison with PSP, CBD and CTE tissues. Thin section autoradiography was employed to assess specific binding and distribution of [3H]PI-2620 and [3H]F-4 in fresh-frozen human post-mortem AD, PSP, CBD and CTE tissues. Immunohistochemistry was performed for phospho-tau (AT8) and 4R-tau (RD4). Homogenate filtration binding assays were performed for saturation analysis and competitive binding studies against [3H]PI-2620. All compounds bound with high affinity in AD tissue. In PSP tissue [3H]PI-2620 demonstrated the highest affinity (5.3 nM) and in CBD tissue [3H]F-4 bound with the highest affinity (9.4 nM). Over 40 fluorinated derivatives based on PI-2620 and F-4 were screened in AD and PSP tissue. Notably, compound 2 was the most potent derivative in PSP tissue (Ki = 7.3 nM). By autoradiography, [3H]PI-2620 and [3H]F-4 demonstrated positive signals similar in intensity in AD, PSP and CTE tissues that were displaced by homologous blockade. Binding of both radiotracers aligned with immunostaining for 4R-tau. This work demonstrates that [3H]PI-2620 and [3H]F-4 show promise for imaging 4R-tau aggregates in non-AD tauopathies. PI-2620 continues to serve as a structural scaffold for PET radiotracers with higher affinity for non-AD tau over AD tau.
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APA 7th
Varlow, C., Mathis, C. A., & Vasdev, N. (2024). In vitro evaluation of [3H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies. Nuclear medicine and biology. https://doi.org/10.1016/j.nucmedbio.2024.108891
Vancouver
Varlow C, Mathis CA, Vasdev N. In vitro evaluation of [3H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies. Nuclear medicine and biology. 2024. doi:10.1016/j.nucmedbio.2024.108891. PMID: 38458074.
BibTeX
@article{varlow2024-38458074,
author = {Varlow, Cassis and Mathis, Chester A and Vasdev, Neil},
title = {{In vitro evaluation of [3H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies}},
journal = {Nuclear medicine and biology},
year = {2024},
doi = {10.1016/j.nucmedbio.2024.108891},
pmid = {38458074},
url = {https://doi.org/10.1016/j.nucmedbio.2024.108891}
}
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Key findings
- In PSP tissue [3H]PI-2620 demonstrated the highest affinity (5.3 nM) and in CBD tissue [3H]F-4 bound with the highest affinity (9.4 nM).
- By autoradiography, [3H]PI-2620 and [3H]F-4 demonstrated positive signals similar in intensity in AD, PSP and CTE tissues that were displaced by homologous blockade.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / 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, multicenter collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Nuclear medicine and biology) |
| 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 | 4 / 5 | 2024 — within 3 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 |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38458074) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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