Iminophosphoranes as radiolabelling precursors using [11C]CO2-fixation
Bibliographic record
Abstract
1103 Background: Carbonyl groups are common design elements in synthetic and natural bioactive molecules which have emerged as compelling radiolabeling sites for tracer development.[1][2] Current approaches take advantage of electrophilic activation of in-target produced [11C]CO2 for addition of organometallic or heteroatom-based nucleophiles.[3] However, most of these synthetic strategies rely on the use of harsh conditions or multistep transformations, limiting their use in the synthesis of structurally complex radiopharmaceuticals. To overcome these issues, alternative procedures using direct fixation of [11C]CO2 and one step reactions would be particularly attractive. Objectives: This project aims to develop a [11C]CO2-fixation synthetic methodology to access 11C-isocyanates from iminophosphoranes (IMP) to produce 11C-labeled carbonyl derivatives and radiopharmaceuticals by intermolecular reaction with various nucleophiles. Methods: Determination of the appropriate reaction conditions between IMPs, CO2 and nucleophiles was performed by reacting phenyltriphenylphosphinimine and CO2 with benzylamine or benzyl alcohol under various conditions. A set of IMPs (n = 14) was then used to study the scope of the method by reaction with CO2 and several nucleophiles (n = 19) including amines, alcohols, thiols and Grignards reagents. Optimization of the radiolabelling conditions was realized by reacting phenyltriphenylphosphinimine, no-carrier-added [11C]CO2 (6-9 GBq) and benzylamine in dimethylformamide and in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene at various temperatures and reagents concentrations. Utility of this radiolabelling method was assessed by synthesizing several 11C labelled carbamates, ureas, thiocarbamates and amides. Finally, this procedure was also applied to the synthesis of [11C]CURB, a fatty acid amide hydrolase (FAAH) radioligand. Results: Study of the reaction conditions revealed that an excess of nucleophile was necessary to avoid formation of the symmetrical carbodiimide by-product. Also, using DBU as additive improved reaction rate and yield. This reaction was shown to be compatible with a wide range of nucleophiles (including alcohols, thiols, primary, secondary amines and enolates) and provided corresponding products (carbamates, ureas, amides) in yields ranging from 63% to 94%. Utilization of this methodology for radiolabeling showed that this reaction can be used to synthesize several derivatives including 11C-carbamates, 11C-ureas and 11C-thiocarbamates in variable radiochemical yields (7-99% decay corrected, HPLC yields) in approximately 15 min after end of production. [11C]CURB has also been synthesized in 84% radiochemical yield (decay-corrected, HPLC yield), showing the potential of this methodology in radiopharmaceutical synthesis. Conclusions: Synthesis of 11C-isocyanates and their use in preparation of carbonyl derivatives by reaction of IMPs with [11C]CO2 and nucleophiles has been shown to be a useful method to afford radiolabeled urea, carbamates, thiocarbamates and amides. Structurally diverse compounds were synthesized in one step, in moderate to high radiochemical yields from easily available starting material. In order to confirm the usefulness of this method, fully automated synthesis and purification of several radiopharmaceuticals will be performed. Support: NSERC RGPIN-2017-06167 References: [1] A. A. Wilson, A. Garcia, S. Houle et al., Chem. Eur. J., 2010, 17, 259-264. [2] S. Moriguchi, A. A. Wilson, L. Miller et al., JAMA Psychiatry, 2019, 76, 6, 634-641. [3] B. H. Rotstein, S. H. Liang, M. S. Placzek et al., Chem. Soc. Rev., 2016, 45, 4708-4726.
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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 | 0.001 |
| 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".