Reshef Ayelet, Shirvan Anat, Waterhouse Rikki N, Grimberg Hagit, Levin Galit, Cohen Avi, Ulysse Luckner G, Friedman Gad, Antoni Gunnar, Ziv Ilan
NST NeuroSurvival Technologies Ltd., Petach Tikva, Israel.
J Nucl Med. 2008 Sep;49(9):1520-8. doi: 10.2967/jnumed.107.043919. Epub 2008 Aug 14.
Clinical molecular imaging of apoptosis is a highly desirable yet unmet challenge. Here we provide the first report on (18)F-labeled 5-fluoropentyl-2-methyl-malonic acid ((18)F-ML-10), a small-molecule, (18)F-labeled PET tracer for the imaging of apoptosis in vivo; this report includes descriptions of the synthesis, radiolabeling, and biodistribution of this novel apoptosis marker. We also describe the use of (18)F-ML-10 for small-animal PET of neurovascular cell death in experimental cerebral stroke in mice.
(18)F-ML-10 was synthesized by nucleophilic substitution from the respective mesylate precursor, and its biodistribution was assessed in healthy rats. Permanent occlusion of the middle cerebral artery (MCA) was induced in mice, and small-animal PET was performed 24 h later.
Efficient radiolabeling of ML-10 with (18)F was achieved. Biodistribution studies with (18)F-ML-10 revealed rapid clearance from blood (half-life of 23 min), a lack of binding to healthy tissues, and rapid elimination through the kidneys. No significant tracer metabolism in vivo was observed. Clear images of distinct regions of increased uptake, selectively in the ischemic MCA territory, were obtained in the in vivo small-animal PET studies. Uptake measurements ex vivo revealed 2-fold-higher uptake in the affected hemisphere and 6- to 10-fold-higher uptake in the region of interest of the infarct. The cerebral uptake of (18)F-ML-10 was well correlated with histologic evidence of cell death. The tracer was retained in the stroke area but was cleared from blood and from intact brain areas.
(18)F-ML-10 is useful for noninvasive PET of neurovascular histopathology in ischemic cerebral stroke in vivo. Such an assessment may assist in characterization of the extent of stroke-related cerebral damage and in the monitoring of disease course and effect of treatment.
细胞凋亡的临床分子成像极具吸引力，但仍是一项尚未解决的挑战。在此，我们首次报道了（18）F标记的5-氟戊基-2-甲基丙二酸（（18）F-ML-10），一种用于体内细胞凋亡成像的小分子（18）F标记PET示踪剂；本报告包括对这种新型细胞凋亡标志物的合成、放射性标记和生物分布的描述。我们还描述了（18）F-ML-10在小鼠实验性脑卒中小动物PET成像中用于神经血管细胞死亡检测的应用。
（18）F-ML-10由相应的甲磺酸酯前体通过亲核取代合成，并在健康大鼠中评估其生物分布。在小鼠中诱导大脑中动脉（MCA）永久性闭塞，24小时后进行小动物PET成像。
实现了（18）F对ML-10的高效放射性标记。（18）F-ML-10的生物分布研究显示其从血液中快速清除（半衰期为23分钟），不与健康组织结合，并通过肾脏快速排泄。体内未观察到明显的示踪剂代谢。在体内小动物PET研究中，获得了清晰的图像，显示在缺血性MCA区域有明显的摄取增加区域。离体摄取测量显示，受影响半球的摄取量高出2倍，梗死灶感兴趣区域的摄取量高出6至10倍。（18）F-ML-10在大脑中的摄取与细胞死亡的组织学证据密切相关。该示踪剂保留在中风区域，但从血液和完整脑区清除。
（18）F-ML-10可用于体内缺血性脑卒中小动物神经血管组织病理学的无创PET成像。这种评估可能有助于确定与中风相关的脑损伤程度，并监测疾病进程和治疗效果。
