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内容記述 |
Objectives: [11C/18F]Alkylation of phenol derivatives is a useful method for introduction of 11C or 18F into molecules. However, introduction of 11C or 18F into aromatic amine derivatives has remained a significant challenge [1,2]. Because of its weak nucleophilicity the amino group in these amines is difficult to react with alkylating agents. To solve this problem, we focused on the tBu-P4 base for deprotonation of aromatic amine in situ. tBu-P4 which is known to have low nucleophilicity and basicity comparable to n-butyllithium has been used for a variety of deprotonation reactions. In addition, the large size of the protonated tBu-P4 cation enhances the nucleophilicity of its counter anion. In this study, we developed a simple method for introducing [11C/18F]alkyl motif into aromatic amines in the presence of tBu-P4.Methods: The reaction conditions for the methylation of 2-aminopyridine as a model compound with unlabeled CH3I were optimized at 60 oC for 30 min. Under the optimized conditions, the methylation of various aryl amines was performed. [11C]CH3I, [18F]FEtBr, or [18F]epifluorohydrin (EPIF) [3] was used as an alkylating agent. [11C]Methylation of heteroaryl amine was performed by the reaction of [11C]CH3I with precursor (1 mg) in DMF (150 L) with tBu-P4 at 60 oC for 5 min. [18F]Fluoroalkylation of heteroaryl amine was performed by the reaction of [18F]FEtBr or [18F]EPIF with precursor (1 mg) in DMF (150 L) with tBu-P4 at 60 oC or room temperature for 5 min. Radiochemical conversions (RCCs) were determined by radio-HPLC for these reaction mixtures. Results: The methylation of 2-aminopyridine with unlabeled CH3I in DMF or THF using tBu-P4 gave 2-methylaminopyridine in 21% and 31%, respectively. Compared to other solvents, DMF and THF were found to be suitable for the methylation. At the same time, 2-dimethylaminopyridine was obtained as a byproduct with 30% yield in each solvent. On the other hand, the methylation did not proceed effectively under 1 M NaOH, KOH, Et-P2 (phosphazene base), and NaH in DMF. Based on these conditions, starting from 29.6 GBq of [11C]CO2, [11C]1a–n were synthesized by the reaction of aryl amine with [11C]CH3I and tBu-P4 in DMF under an automated synthesis system developed in house. By purification for the reaction mixture with semi-preparative HPLC, [11C]1a–n were obtained with a synthesis time of 20 ± 5 min and 3–41% radiochemical yield (decay-corrected). To extend application of this method, synthesis of [18F]2–4 with [18F]fluoroalkylating agents was examined. In the synthesis of [18F]2, it was observed that [18F]fluoride was mainly liberated because of degradation of [18F]2. On the other hand, [18F]3 and [18F]4 were also obtained in 20% and 14% RCCs, respectively.Conclusions: We have successively synthesized [11C]1a–n and [18F]2–4 using [11C/18F]alkylagents in the presence of tBu-P4. We are currently optimizing reaction condition to increase the radiochemical yield of [18F]2 and [18F]fluoroethylating efficiency of other aryl amines. |
