Kumar Piyush, Roselt Peter, Reischl Gerald, Cullinane Carlene, Beiki Davood, Ehrlichmann Walter, Binns David, Naimi Ebrahim, Yang Jennifer, Hicks Rodney, Machulla Hans-Juergen, Wiebe Leonard I
Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2. Canada.
Peter McCallum Cancer Institute, Melbourne. Australia.
Curr Radiopharm. 2017;10(2):93-101. doi: 10.2174/1874471010666170313120540.
1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole([18F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [18F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1' β-anomeric bond at C5' will make 1-β-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (β-FAZA), the β-conformer of FAZA, an attractive candidate for clinical hypoxia imaging.
The principle goals were to synthesize β-FAZA and β-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading to β-[18F]FAZA, and to investigate the biodistribution of β-[18F]FAZA in an animal tumor-bearing model using PET imaging.
The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-β-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2AZA). Fluorination of β-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded β-FAZA (21%). The radiolabeling synthon, 1-β-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2TsAZA), on radiofluorination using the 18F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded β-[18F]FAZA. β-[18F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of β-[18F]FAZA was performed in A431 tumor-bearing nude mice.
β-FAZA and β-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [18F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor.
The synthesis of β-FAZA and β-[18F]FAZA are reported. Radiofluorination of β-Ac2TsAZA and the deprotection of β-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of α-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of β-[18F]FAZA in tumor.
1-α-D-(5-脱氧-5-[18F]氟阿糖呋喃糖基)-2-硝基咪唑([18F]FAZA)是一种正电子发射断层显像（PET）放射性示踪剂，在成像局部缺氧方面显示出优异潜力，临床上用于诊断癌症患者的多种实体瘤。然而，[18F]FAZA的放射性氟化反应的放射性化学产率（rRCY）仅为中等水平（约12%）。据推测，C5'位C1'β-异头键的相对稳定性将使FAZA的β-构象体1-β-D-(5-氟-5-脱氧阿糖呋喃糖基)-2-硝基咪唑（β-FAZA）成为临床缺氧成像的一个有吸引力的候选物。
主要目标是合成β-FAZA及其放射性氟化前体β-Ac2TsAZA，建立生成β-[18F]FAZA的放射性氟化化学方法，并使用PET成像研究β-[18F]FAZA在荷瘤动物模型中的生物分布。
将适当保护的呋喃糖与2-硝基咪唑偶联，得到1-β-D-(2,3-二-O-乙酰基阿糖呋喃糖基)-2-硝基咪唑（β-Ac2AZA）。β-Ac2AZA用DAST氟化，随后进行碱性水解，得到β-FAZA（产率21%）。放射性标记合成子1-β-D-(5-O-甲苯磺酰基-2,3-二-O-乙酰基阿糖呋喃糖基)-2-硝基咪唑（β-Ac2TsAZA）在各种反应条件下使用18F/K222络合物进行放射性氟化，随后进行碱催化脱乙酰化，得到β-[18F]FAZA。β-[18F]FAZA在22℃下储存在8%乙醇水溶液中时，放射性化学稳定性至少为8小时。在荷A431肿瘤的裸鼠中进行了基于PET成像的β-[18F]FAZA生物分布初步研究。
β-FAZA和β-Ac2TsAZA的合成产率令人满意。建立了[18F]FAZA的放射化学方法。PET图像显示肿瘤缺氧区域有强烈摄取。
报道了β-FAZA和β-[18F]FAZA的合成。β-Ac2TsAZA的放射性氟化和β-Ac2[18F]FAZA的脱保护操作简便，但与α-[18F]FAZA的相应前体相比，产生的放射性氟化副产物混合物更复杂。PET图像表明β-[18F]FAZA在肿瘤中具有缺氧选择性蓄积。
