Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging.
Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging.
复制标题
将两种新型2-硝基咪唑衍生物作为肿瘤成像的潜在PET放射性物质的合成和评估。
DOI：
10.1016/j.nucmedbio.2010.11.001
复制
发表时间：
2011-05
影响因子：
3.1
通讯作者：
Kung HF
中科院分区：
文献类型：
--
作者：
Zha Z;Zhu L;Liu Y;Du F;Gan H;Qiao J;Kung HF
基于肿瘤缺氧机制，放射性同位素标记的硝基咪唑（azomycin）衍生物已被开发为癌症显像和放射治疗药物。通过在硝基咪唑核上配以不同官能团，合成了新的硝基咪唑衍生物，并对其作为肿瘤显像剂的潜力进行了评价。从市售的2-硝基咪唑、2-氟-n -（2-（2-硝基- 1h -咪唑-1-基）乙基）乙酰胺（NEFA, [19F]7）和2-（2-甲基-5-硝基- 1h -咪唑-1-基）乙基2-氟乙酸酯（NEFT, [19F]8）以及放射性标记前体开始，通过三步合成途径快速合成了溴取代类似物。前体用[18F]F-/18-crown-6/KHCO3在DMSO中于90°C下放射标记10分钟，然后用Oasis HLB滤筒纯化。在EMT-6荷瘤小鼠中进行生物分布研究。注射后30min，测定肿瘤组织和正常组织的摄取（%ID/g）。采用液相色谱-电喷雾电离质谱法（LC/MS）对注射“冷”NEFA （[19F]7）和NEFT （[19F]8）的大鼠尿液和血浆中的代谢物与母体药物进行了区分。制备了两种放射性示踪剂[18F]NEFA （[18F]7）和[18F]NEFT ([18F]8)，平均产率分别为6-7%和9-10%（未校正衰变）。高效液相色谱法测定两种示踪剂的放射化学纯度均为95%。在EMT-6荷瘤小鼠体内的生物分布研究表明，在30min时，[18F]7（0.96, 0.98）和[18F]8（0.61,1.10）的肿瘤与血液和肿瘤与肝脏的比值均高于[18F]FMISO(1)(0.91, 0.59)，后者是一种已被广泛研究的azomycin型缺氧放射线。LC/MS分析表明，氟乙酸是NEFA （[19F]7）和NEFT （[19F]8）的主要体内代谢物。本研究成功制备了两种新的含氟-18标记的2-硝基咪唑衍生物[18F]7和[18F]8，均含有体内可水解基团。进一步的生物学评价是有必要的，以研究它们作为PET放射配体成像肿瘤的潜力。
Nitroimidazole (azomycin) derivatives labeled with radioisotopes have been developed as cancer imaging and radiotherapeutic agents based on the oncological hypoxic mechanism. By attaching nitroimidazole core with different functional groups, we synthesized new nitroimidazole derivatives, and evaluated their potentiality as tumor imaging agents. Starting with commercially available 2-nitroimdazole, 2-fluoro-N-(2-(2-nitro-1H-imidazol-1-yl)ethyl)acetamide (NEFA, [19F]7) and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 2-fluoroacetate (NEFT, [19F]8), as well as radiolabeling precursors - the bromo substituted analogs were quickly synthesized through a three-step synthetic pathway. The precursors were radiolabeled with [18F]F-/18-crown-6/KHCO3 in DMSO at 90 °C for 10 min followed by purification with an Oasis HLB cartridge. Biodistribution studies were carried out in EMT-6 tumor-bearing mice. The uptake (%ID/g) in tumors and normal tissues were measured at 30 min post injection. Liquid chromatography-electrospray ionization mass spectrometry (LC/MS) was used to distinguish metabolites from parent drugs in urine and plasma of rat injected with “cold” NEFA ([19F]7) and NEFT ([19F]8). Two radiotracers, [18F]NEFA ([18F]7) and [18F]NEFT ([18F]8), were prepared with average yields of 6-7% and 9-10% (no decay corrected). Radiochemical purity for both tracers was >95% as determined by HPLC. Biodistribution studies in EMT-6 tumor-bearing mice indicated that the tumor to blood and tumor to liver ratios of both [18F]7 (0.96, 0.98) and [18F]8 (0.61,1.10) at 30 min were higher than those observed for [18F]FMISO (1) (0.91, 0.59), a well-investigated azomycin type hypoxia radiotacer. LC/MS analysis demonstrated that fluoroacetate was the main in vivo metabolite for both NEFA ([19F]7) and NEFT ([19F]8). In this research, two new fluorine-18 labeled 2-nitroimdazole derivatives, [18F]7 and [18F]8, both of which containing in vivo hydrolyzable group, were successfully prepared. Further biological evaluations are warranted to investigate their potential as PET radioligands for imaging tumor.
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影响因子：
8.8
作者：
Chapman, J D;Franko, A J;Sharplin, J
通讯作者：
Sharplin, J
DOI：
10.1016/0360-3016(89)90146-6
发表时间：
1989-11-01
影响因子：
7
作者：
RASEY, JS;KOH, WJ;KROHN, KA
通讯作者：
KROHN, KA
影响因子：
19.7
作者：
YANG, DJ;WALLACE, S;PODOLOFF, DA
通讯作者：
PODOLOFF, DA
DOI：
10.1007/s00259-003-1404-x
发表时间：
2004-04-01
影响因子：
9.1
作者：
Grönroos, T;Bentzen, L;Solin, O
通讯作者：
Solin, O
影响因子：
3.4
作者：
RASEY, JS;GRUNBAUM, Z;KROHN, KA
通讯作者：
KROHN, KA