Structure-based optimization and binding assays for discovery of tau PET radiotracers: synthesis and in vivo evaluation of [ <sup>11</sup> C]Z-3272
Bibliographic record
Abstract
Human tau protein has six isoforms, differing in the number of microtubule-binding repeats. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primarily 4-repeat (4R)-tauopathies, and Alzheimer’s disease (AD) and chronic traumatic encephalopathy are mixed 3R/4R-tau. Here, a promising lead compound for positron emission tomography (PET) imaging of non-AD tauopathies (Z5873993272; methyl-1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylate; Z-3272) was identified as a potential 4R-tau binding ligand through computational structure-based optimization from the 2D structure of known 4R-tau ligands, followed by iterative competition binding assays. Homologous binding assays in post-mortem AD, PSP, and CBD brain with [ 3 H]Z-3272 provided K d (nmol/L) values ( n = 3) of AD = 1.2 ± 0.1, PSP = 2.7 ± 0.9, and CBD = 1.7 ± 0.1. [ 11 C]Z-3272 was synthesized by 11 C-methylation, by reaction of [ 11 C]CH 3 I with 1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylic acid with NaHCO 3 in DMF at 70 °C for 3 min. The crude product was purified by semi-preparative HPLC and formulated in saline, with an overall synthesis time of 35 min from end of bombardment. [ 11 C]Z-3272 was isolated with a non-decay corrected radiochemical yield of 4 ± 1% ( n = 4), high radiochemical purity (>95%), and high molar activity (149 ± 55.5 GBq/μmol). PET imaging following bolus injection of [ 11 C]Z-3272 in rats showed high initial brain radioactivity (>2.3 standardized uptake values (SUV)) with moderate washout (∼0.7 SUV at 60 min); however, ex vivo studies revealed the rapid formation of troublesome brain penetrant radiometabolites. Medicinal chemistry optimization is underway to improve binding affinity, selectivity, and metabolic stability.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".