Copper(I)-mediated 11C-carboxylation of (hetero)arylstannanes: radiosynthesis of [11C]bexarotene.
Bibliographic record
Abstract
137 Objectives: [11C]CO2 fixation strategies have recently been applied for the synthesis of 11C-carbonylated radiopharmaceuticals. Whereas 11C-carbamates have been translated for human PET studies, the syntheses of 11C-carboxylic acids via [11C]CO2 fixation has proven to be challenging. A novel copper-mediated carboxylation strategy of aryl- and heteroaryl-stannanes is described as a mild (i.e. 1 atm) carboxylation method using CO2 and is transferable for carbon-11 labeled aromatic and heteroaromatic carboxylic acids using [11C]CO2. The methodology was applied to the radiosynthesis of a retinoid X receptor (RXR) agonist, [11C]bexarotene. Methods: Feasibility of the carboxylation reaction was first tested by reactions in a sealed vessel under an atmosphere of CO2. Translation of the method for [11C]CO2 involved varying the reaction temperature, solvent, Cu(I) source, and base, using PhSnBu3 as precursor. The preparation of [11C]benzoic acid was optimized as follows: temperature: 100 °C; time: 5 minutes; solvent: DMF (600 μL); [PhSnBu3] = 0.1 M; [CuTC] = 9.4 mM; and [TMEDA] = 1.3 M. Substrate scope was evaluated using tributyltin compounds substituted by para-substituted benzene derivatives (pMe, pMeO, pCl, and pCF3), followed by compounds substituted with 2-furan, 2-thienyl, and N-heteroarenes (3-pyridyl, 2-pyrazyl, 2-pyrimidyl and 5-pyrimidyl). The new carboxylation method was applied in the fully automated radiosynthesis of [11C]bexarotene using the TracerMaker (Scansys Laboratorieteknik, Denmark) synthesis module. Results: [11C]Benzoic acid was isolated in a decay-corrected RCY of 45% relative to starting [11C]CO2, with molar activity Am = 9.3 GBq/µmol (250 mCi/µmol), and radiochemical purity >99%, in 29 min. Decay-corrected radiochemical yields (RCYs) of ca. 30-70% were obtained with arylstannanes (PhSnBu3 and its corresponding pMe, pMeO and pCF3 substituted derivatives). Formation of 11C-carboxylic acids bearing 3-pyridyl, and 2-pyrazyl groups were successfully generated with RCYs between 32-34%, while yields for the transfer of electron-rich heteroarenes 2-furyl and 2-thienyl were generally lower ( 95% in 41 ± 4 minutes from EOB. Isolated formulations (10% ethanol/90% saline v/v) from scaled up reactions contained up to 5.74 GBq (155 mCi) of activity and high molar activity (Am = 63 GBq/μmol; 1.7 Ci/μmol). Conclusions: We have developed a novel copper-mediated carboxylation methodology for the preparation of (hetero)aryl carboxylic acids from organostannanes using a stoichiometric quantity of CO2 under atmospheric pressure, as well as sub-stoichiometric quantities of [11C]CO2. The successful radiosynthesis, purification, and formulation of [11C]bexarotene, using a fully automated commercial synthesis module, demonstrates feasibility of 11C-carboxylation reactions in radiopharmaceutical production.
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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) | 0.001 | 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 | 0.000 |
| 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".