Synthesis, Radiosynthesis, in Vitro and in Vivo Evaluation of the GABA<sub>A</sub>-Benzodiazepine Receptor Agonist [<sup>11</sup>C]RO6899880
Bibliographic record
Abstract
The aim of this study is to synthesize and evaluate the GABA A -benzodiazepine receptor agonist radiotracer ( S )-10-chloro-1-(3-(methoxy- 11 C)pyrrolidine-1-carbonyl)-3-phenyl-6,7-dihydro-4 H -pyrido[2,1- a ]isoquinolin-4-one ([ 11 C]RO6899880) using in vitro and in vivo experiments to determine its suitability for human positron emission tomography (PET) neuroimaging studies. RO6899880 and its desmethyl precursor were synthesized over multiple steps in 3% and 2% yields, respectively. Reaction of the precursor with [ 11 C]CH 3 I in DMF with NaOH at 23 °C for 5 min followed by HPLC purification and formulation produced [ 11 C]RO6899880 with a radiochemical yield of 4.1 ± 1.6% (nondecay corrected), radiochemical purity >95% and molar activities of 6.40 ± 0.63 GBq/μmol ( n = 3). Preliminary autoradiography with [ 3 H]RO6899880 was carried out in brain tissues from rat, healthy human, patients with Alzheimer’s disease and chronic traumatic encephalopathy, and aligned with the GABA A antagonist radiotracer [ 3 H]flumazenil. PET imaging in rats revealed modest brain permeability, moderate clearance, and distribution across brain regions with higher uptake in cortical areas. However, polar radiometabolites were found in both plasma and brain homogenates. PET imaging of [ 11 C]RO6899880 in higher species including radiometabolism studies are needed prior to human translation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".