Iminophosphoranes as radiolabelling precursors using [11C]CO2-fixation
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».