開發新穎正子影像藥物：3-氟丙基-麩胺酸立體異構物與4-硝基-氟苯丙基合成子的合成研究

Synthesis of Stereoisomers of 4-(3-Fluoropropyl)-L-glutamic acid and 3-[4-nitro-fluorophenyl]propyl Synthon for the Development of Novel PET Imaging Agents

施凱庭(Kai-Ting Shih)

指導教授 ： 忻凌偉

國立臺灣大學/醫學院/藥學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201603222

摘要

為了能夠有選擇性的將18F導入4-硝基苯丙基，本研究以利用新型離去基的親核性氟取代反應為策略，進行氟取代4-硝基苯丙基合成子的開發。2-溴基-4-(3-溴丙基)-1-硝基苯化合物22以及3-(4-硝基-2-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)苯基)丙酸化合物24皆成功的被製備作為未來合成2-以及3-[18F]氟基4-硝基苯取代衍生物之合成子。
(4S)-4-(3-[18F]氟丙基)麩胺酸 ((4S)-4-(3-[18F]Fluoropropyl)- L-glutamate, [18F]FSPG) 是一個具有潛力可評估xc-胱胺酸/麩胺酸反向轉運體的腫瘤正子斷層掃描診斷探針。為了提供高光學純度的[18F]FSPG以及前驅物供臨床試驗使用，本研究對造成外消旋現象的關鍵反應參數進行研究，並且開發再結晶的方法純化關鍵中間體藉以提高光學純度 (ee : 42% → 99%) 。透過最佳化的反應條件或是再結晶的方法可以合成出高光學純度的(2S,4S)-FSPG。除此之外，為了能夠提供FSPG非鏡像異構物作為人體臨床試驗時的品質管制參考，本研究也成功建立(2S,4R)-FSPG的合成方法。

關鍵字

3-氟丙基-麩胺酸 ； 腫瘤正子斷層掃描診斷探針 ； 親核性取代反應 ； 合成子

並列摘要

Nucleophilic aromatic substitution (SNAr) is a common approach to synthesize radiolabeled aryl fluorides. In these reactions, the most widely used leaving groups include trimethylammonium and nitro groups. However, it is a challenge to introduce a fluoride atom into 4-nitrophenylalkane. According to our previous research, it is found that fluorination of 2,4-dinitrophenyl-substituted compound showed low selectivity to yield 2-fluoro-4-nitrophenyl-substituted compound. In this study, novel substituents were used as leaving groups for the selective nucleophilic fluorination. The 2-bromo-4-(3-bromopropyl)-1-nitrobenzene compound 22 and 3-(4-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid compound 24 were successfully prepared as the synthons for the future synthesis of 2-and 3-[18F]fluoro-substituted 4-nitrophenyl-substituted compounds.
(4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (BAY 94-9392, or [18F]FSPG) is a potential tumor-imaging molecular probe to assess system xC- transporter activity using positron emission tomography (PET). Optically pure precursor for the radiosynthesis of [18F]FSPG is crucial to provide high-quality [18F]FSPG for clinical use. To improve the enantiomeric purity of the precursor and reference standard of [18F]FSPG, the key reaction parameters causing the racemization of the intermediates and products were studied. In addition, to recover the desired enantiomer from the intermediates with lower ee, a recrystallization method has been developed to effectively recover the desired enantiomer with high ee (42% → 99%). In conclusion, optically pure precursor and standard of (2S,4S)-FSPG can be obtained either by the optimized reaction conditions, or by recrystallization method. Moreover, to provide the diastereomers of FSPG as references for quality control in human clinical study, the synthesis method for (2S,4R)-FSPG was developed.

並列關鍵字

(3-Fluoropropyl)-glutamate ； tumor-imaging molecular probe ； nucleophilic aromatic substitution ； synthons

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