Evaluation of an [(18)F]AlF-NOTA Analog of Exendin-4 for Imaging of GLP-1 Receptor in Insulinoma.
Evaluation of an [(18)F]AlF-NOTA Analog of Exendin-4 for Imaging of GLP-1 Receptor in Insulinoma.
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作者：
Kiesewetter DO;Guo N;Guo J;Gao H;Zhu L;Ma Y;Niu G;Chen X
引言：GLP-1受体在葡萄糖稳态中起着重要作用，因此是糖尿病治疗的一个非常重要的靶点。该受体在胰岛素瘤（一种胰腺β细胞肿瘤）中也过表达。我们先前评估了通过与[18 F]FBEM（N-[2-（4-[18 F]氟苯甲酰胺）乙基]马来酰亚胺）缀合制备的两种氟-18-标记的毒蜥外泌肽-4类似物。这两种化合物都表现出良好的肿瘤摄取，但放射性示踪剂的合成是耗时的。为了克服这一挑战，我们开发了NOTA类似物，并使用氟化铝[18F]络合进行放射性标记。方法：将Cys 40-exendin-4与NOTA单N-乙基马来酰亚胺偶联。进行[18F]AlF缀合，并通过制备型HPLC纯化放射性标记的产物。对具有建立的INS-1异种移植物的裸鼠进行动态和静态PET成像扫描。对静态图像中肿瘤和其他主要器官的摄取进行定量（%ID/g），并与阻断研究进行比较。还将PET定量与离体生物分布结果进行了比较。结果如下：HPLC后，放射合成得到[18 F]AlF-NOTA-MAL-cys 40-exendin-4，放射化学产率为23.6 ± 2.4%（未校正，n = 3）;该过程需要约55 min。进样时的比活度范围为19.6 - 31.4 GBq（0.53-0.85 Ci）/µmol。肿瘤摄取在5分钟时达到其最大值（16.09 ± 1.18%ID/g，n = 4），并在研究期间保持几乎恒定。肾脏摄取在整个1小时时间过程中持续增加。exendin-4的预注射引起组织摄取的显著减少，主要例外是肝脏和肾脏，其中摄取不受影响。肿瘤和血浆提取物中放射性成分的HPLC分析显示，注射后60 min主要为母体化合物，而肾脏和尿液提取物仅含有一种极性放射性成分。结论：该放射性示踪剂制备工艺简单，经HPLC纯化后具有较高的比活度。[18 F]AlF-NOTA-MAL-exendin-4显示高肿瘤摄取和高选择性GLP-1组织摄取（INS-1肿瘤、肺、胰腺），但仍遭受高肾脏摄取。
Introduction: The GLP-1 receptor plays an important role in glucose homeostasis and thus is a very important target for diabetes therapy. The receptor is also overexpressed in insulinoma, a tumor of pancreatic beta-cells. We previously evaluated two fluorine-18-labeled analogs of exendin-4 prepared by conjugation with [18F]FBEM (N-[2-(4-[18F]fluorobenzamide)ethyl]maleimide). Both compounds demonstrated good tumor uptake, but the synthesis of the radiotracers was time consuming. To overcome this challenge, we developed a NOTA analog and performed radiolabeling using aluminum [18F]fluoride complexation. Methods: Cys40-exendin-4 was conjugated with NOTA mono N-ethylmaleimide. [18F]AlF conjugation was conducted and the radiolabeled product purified by preparative HPLC. Dynamic and static PET imaging scans were conducted on nude mice with established INS-1 xenografts. Uptake of tumor and other major organs in static images was quantitated (%ID/g) and comparison with blocking studies was made. PET quantification was also compared with ex vivo biodistribution results. Results: The radiosynthesis provided [18F]AlF-NOTA-MAL-cys40-exendin-4 in 23.6 ± 2.4 % radiochemical yield (uncorrected, n = 3) after HPLC; the process required about 55 min. The specific activity at time of injection ranged from 19.6 to 31.4 GBq (0.53-0.85 Ci)/µmol. Tumor uptake had reached its maximum (16.09 ± 1.18% ID/g, n = 4) by 5 min and remained nearly constant for the duration of the study. Kidney uptake continued to increase throughout the entire one hour time course. Pre-injection of exendin-4 caused a marked reduction in tissue uptake with the major exception of liver and kidneys, in which uptake was not affected. HPLC analysis of the radioactive components in extracts of the tumor and plasma showed primarily parent compound at 60 min post-injection, whereas extracts of kidney and urine contained exclusively one polar radioactive component. Conclusion: The radiotracer is prepared in a simple one-step procedure and obtained in high specific activity after HPLC purification. [18F]AlF-NOTA-MAL-exendin-4 shows high tumor uptake and highly selective GLP-1 tissue uptake (INS-1 tumor, lung, pancreas), but still suffers from high kidney uptake.
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影响因子：
9.3
作者：
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[18F] FBEM的自动放射化合物合成：用于肽和蛋白质放射性氟化的硫醇反应性合成。
影响因子：
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