Effect of alpha‐Synuclein on the binding of [18F]MK‐6240 and [18F]AV‐1451
Bibliographic record
Abstract
Abstract Background Binding in alpha‐synuclein containing brain regions have been described for both Flortaucipir ([18F]AV‐1451) and [18F]MK‐6240. Here we assessed whether alpha‐Synuclein constitutes a target for these tau imaging agents. Method We used autoradiographic dot blot to validate specific and evaluate off‐target interactions of [18F]MK‐6240 and [18F]AV‐1451 using sarkosyl‐insoluble extracts from PSP, CBD, PiD, and AD cortical tissue which contain fibrillar forms of tau. Tissue concentrations of alpha‐Synuclein are orders of magnitude lower than NFTs leading us to use recombinant alpha‐Synuclein PFFs to evaluate potential off‐target interactions. Briefly, 1:100 dilutions of each preparation were incubated with 82 fmol of mass in a 30uL total volume. Samples were incubated for 90 minutes at 37°C. Reactions were terminated by pipetting the solution in triplicate onto a glass fiber filter held within a 96‐well dot‐blot aspiration device and the samples were immobilized. Unbound ligand was washed three times with ice cold PBS. The glass fiber filters were transferred to a cassette for exposure to autoradiographic film for 90 minutes and the activity in photostimulated luminescence units per mm2 was calculated using ImageJ software v.1.8.0. Result Disintegrations were corrected for decay and normalized to cerebellar extracts for both ligands. [18F]MK‐6240 demonstrated high specificity, binding in AD extracts and AD extracts subject to trypsin treatment. [18F]AV‐1451 demonstrated similar binding in both native and trypsinized AD extracts, while also showing overlapping binding profiles in human alpha‐synuclein PFFs but not in mouse alpha‐synuclein PFFs. Conclusion [18F]AV‐1451 binds to recombinant human alpha‐Synuclein PFFs as it does to native AD‐tau PHFs. Future experiments should assess patient derived alpha‐Synuclein aggregates as a potential off target binding to [18F]AV‐1451.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".