Three New Fully Automated [11C]Carbonylation Chemistry Platforms for Radiopharmaceutical Production via [11C]CO2 and [11C]CO.
Bibliographic record
Abstract
515 Introduction: Relative to 11C-methylation, few 11C-carbonyl-labeled radiopharmaceuticals have been translated for clinical PET research. We report on 3 new fully automated carbonylation systems used to produce: 1) The dopamine D3-preferring agonist radiotracer, [11C]-(+)-PHNO via a multistep automated Grignard reaction from [11C]CO2 to achieve N-11C-propylation; 2) the FAAH and MAO-B ligands, [11C]CURB, and [11C]SL2511.88, with 11C-carbamate and 11C-oxazolidinone scaffolds, respectively via a [11C]CO2-fixation platform; and 3) a novel Palladium-NiXantphos mediated carbonylation reaction using a commercial [11C]CO system for an isotopolog of the Bruton’s tyrosine kinase drug, [11C]PRN442168 labeled at the acrylamide moity, all in sufficient quantities and formulated for routine human use. Methods: 11C-Carbonylation reactions to produce the [11C]-(+)-PHNO, and [11C]CO2 fixation to produce [11C]CURB, and [11C]SL2511.88, were achieved using fully automated synthesis modules controlled by Labview. [11C]PRN442168 is produced using a commercial carbon-11 synthesis module (TracerMaker, Scansys Laboratorieteknik). [11C]-(+)-PHNO. [11C]CO2 is released to a vessel loaded with EtMgBr solution The Grignard reaction is followed by formation of [11C]-propionyl chloride, which is refluxed and then distilled into a cooled secondary vial containing precursor, followed by reduction with LiAlH4. [11C]CURB, and [11C]SL2511.88. The CO2-fixation, using BEMP as fixating agent, followed by dehydration with POCl3 generates the 11C-carbamate, [11C]CURB , and [11C]SL2511.88 is obtained by intramolecular cyclization reaction. [11C]PRN442168. [11C]CO2 is converted to [11C]CO(Molybdenum, 850 °C) and concentrated on silica (5-6 mm3, -196 °C) prior to transferring into a reaction vessel which is pre-charged with iodoethylene, the secondary amine precursor, and palladium-NiXantphos in THF. The mixture is sealed at 1 atm and heated to obtain crude product, prior to HPLC purification. Results: The apparatus for carbonylation via Grignard reaction produced [11C]-(+)-PHNO with uncorrected radiochemical yields (RCY) ranging from 2- 8% (2-7 GBq), molar activities (AM) ranging from 30 - 70 GBq/µmol, and radiochemical purity ≥97% (n>10). The CO2-fixation apparatus produced [11C]CURB and [11C]SL2511.88 with uncorrected RCY ranging from 2-3% (1-2 GBq), AM ranging from 40 - 90 GBq/µmol, and radiochemical purity ≥95% (n>25). The [11C]CO carbonylation produced [11C]PRN442168 with uncorrected RCY ranging from 2-3% (1-2 GBq), with AM from 30 - 40 GBq/µmol and radiochemical purity ≥97 %. Conclusions: We herein describe the application of 3 new fully automated modules for 11C-carbonylation applied to radiopharmaceutical production; [11C]-(+)-PHNO, [11C]CURB, [11C]SL2511.88, and [11C]PRN442168. All of these radiopharmaceuticals are reliably synthesized in yield, purity, and AM which is suitable for routine human PET imaging studies.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".