Optimization of precursor synthesis, formulation and stability of 1'-[18F]fluoroethyl-β-D-lactose ([18F]FEL) for preclinical studies in detection of pancreatic cancer.
Optimization of precursor synthesis, formulation and stability of 1'-[18F]fluoroethyl-β-D-lactose ([18F]FEL) for preclinical studies in detection of pancreatic cancer.
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优化 1'-[18F]氟乙基-β-D-乳糖 ([18F]FEL) 的前体合成、配方和稳定性，用于检测胰腺癌的临床前研究。
DOI：
10.1016/j.nucmedbio.2014.01.002
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发表时间：
2014-04
影响因子：
3.1
通讯作者：
Alauddin MM
中科院分区：
文献类型：
--
作者：
Paolillo V;De Palatis L;Alauddin MM
1′-[18 F]氟乙基-β-d-乳糖（[18 F]FEL）是一种新型PET显像剂，用于早期检测胰腺癌和肝细胞癌。我们之前报道了使用溴代和甲苯磺酰基前体合成[18 F]FEL，然后使用对硝基前体进行了改进的方法。然而，前体合成中的一些步骤似乎存在产率低的问题。在这里，我们报告了一种合成前体和生产[18 F]FEL的优化方法；我们还描述了 [18 F]FEL 的配方和稳定性。按照文献程序对 d-乳糖 1 进行乙酰化，得到 1',2',3',6',2,3,4,6-d-乳糖八乙酸酯 2a/2b。使用 HBr/乙酸对 2a/2b 进行溴化，生成 1'-溴-2',3',6',2,3,4,6-七-O-乙酰基-α-d-乳糖 3。在甲苯磺酸银和过量乙二醇存在下，进行 3 与乙二醇的偶联，生成 4a。化合物4a与对硝基苯磺酰氯反应生成对硝基苯磺酰衍生物5。使用K[18F]氟化物/kryptofix对5进行放射氟化，得到6，通过HPLC纯化并用甲醇钠水解生成7。化合物2(2a/2b)作为两种异头产物的混合物以83%收率获得。从 2a/2b 混合物中获得化合物 3，作为一种产物，产率为 80%。 3与乙二醇偶合生成4a，产率90%。化合物 5 的产率为 64%，5 的放射性氟化产生 6，产率为 62.5% ± 7.5%（n = 8）。从轰击结束开始，用甲醇钠水解 6，生成 7，产率为 42.0% ± 7.0%（n = 8）。前体化合物 5 的简单 4 步合成已实现，且收率有所提高。已开发出一种新的 [18 F]FEL 配方，使产品在环境温度下保持稳定，用于动物研究。这种改进的[ 18 F]FEL前体合成和稳定制剂应该对放射性示踪剂的常规生产及其临床前和可能的临床应用有用。
1′-[18 F]Fluoroethyl-β-d-lactose ([18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [18 F]FEL; we also describe [18 F]FEL’s formulation and stability. Acetylation of d-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-d-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-d-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n = 8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n = 8) from the end of bombardment. A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of [18 F]FEL should be useful for routine production of the radiotracer and its preclinical and, possibly, clinical applications.
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影响因子：
3.7
作者：
Flores LG;Bertolini S;Yeh HH;Young D;Mukhopadhyay U;Pal A;Ying Y;Volgin A;Shavrin A;Soghomonyan S;Tong W;Bornmann W;Alauddin MM;Logsdon C;Gelovani JG
通讯作者：
Gelovani JG
影响因子：
1.6
作者：
Jacobson, Mark S.;Dankwart, Heather R.;Mahoney, Douglas W.
通讯作者：
Mahoney, Douglas W.
影响因子：
3.1
作者：
Paolillo, Vincenzo;Yeh, Hsin Hsien;Alauddin, Mian M.
通讯作者：
Alauddin, Mian M.
影响因子：
3.5
作者：
CHRISTA, L;FELIN, M;SEVE, AP
通讯作者：
SEVE, AP
影响因子：
1.3
作者：
Walters, Leah R.;Martin, Katherine J.;Mosman, Elton A.
通讯作者：
Mosman, Elton A.