Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 N. Stonewall Avenue, Oklahoma City, OK 73117, USA.
Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 N. Stonewall Avenue, Oklahoma City, OK 73117, USA.
Nucl Med Biol. 2018 Apr;59:9-15. doi: 10.1016/j.nucmedbio.2017.12.006. Epub 2017 Dec 27.
Positron emission tomography (PET) of myocardial infarction (MI) by infarct avid imaging has the potential to reduce the time to diagnosis and improve diagnostic accuracy. The objective of this work was to synthesize F-labeled glucaric acid (FGA) for PET imaging of isoproterenol-induced cardiomyopathy in a rat model.
We synthesized F-FGA by controlled oxidation of F-fluorodeoxy glucose (FDG), mediated by 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in presence of NaBr and NaOCl in highly-buffered reaction conditions. After ascertaining preferential uptake of F-FGA in necrotic as compared to normal H9c2 myoblasts, the biodistribution and circulation kinetics of F-FGA was assessed in mice. Moreover, the potential of F-FGA to image myocardial damage was investigated in a rat model of isoproterenol-induced cardiomyopathy. Isoproterenol-induced myocardial injury was verified at necropsy by tissue staining and plasma cardiac troponin levels.
Synthesis of radiochemically pure F-FGA was accomplished by a 5 min, one step oxidation of F-FDG. Reaction yield was quantitative and no side-products were detected. Biodistribution studies showed rapid elimination from the body (k = 0.83 h); the major organ of F-FGA accumulation was kidney. In the rat model, isoproterenol-treatment resulted in significant increase in cardiac troponin. PET images showed that the hearts of isoproterenol-treated rats accumulated significant amounts of F-FGA, whereas healthy hearts showed negligible uptake of F-FGA. Target-to-nontarget contrast for F-FGA accumulation became significantly more pronounced in 4 h images as compared to images acquired 1 h post-injection.
F-FGA can be easily and quantitatively synthesized from ubiquitously available F-FDG as a precursor. The resultant F-FGA has a potential to serve as an infarct-avid agent for PET imaging of MI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: F-FGA/PET will complement existing perfusion imaging protocols in therapeutic decision making, determination of revascularization candidacy and success, differentiation of ischemia from necrosis in MI, discrimination of myocarditis from infarction, and surveillance of heart transplant rejection.
正电子发射断层扫描（PET）通过梗死亲和成像对心肌梗死（MI）进行成像，有可能缩短诊断时间并提高诊断准确性。这项工作的目的是合成 F 标记的葡萄糖酸（FGA），用于在异丙肾上腺素诱导的大鼠心肌病模型中进行 PET 成像。
我们通过在高度缓冲的反应条件下，使用 4-乙酰氨基-2,2,6,6-四甲基哌啶 1-氧自由基（TEMPO）介导，用 NaBr 和 NaOCl 对 F-氟脱氧葡萄糖（FDG）进行受控氧化，合成了 F-FGA。在确定 F-FGA 在坏死组织中比正常 H9c2 成肌细胞摄取更多之后，评估了 F-FGA 在小鼠中的生物分布和循环动力学。此外，还研究了 F-FGA 在异丙肾上腺素诱导的心肌病大鼠模型中对心肌损伤成像的潜力。通过组织染色和血浆心肌肌钙蛋白水平，在尸检时证实了异丙肾上腺素诱导的心肌损伤。
通过 F-FDG 的 5 分钟一步氧化反应，完成了放射化学纯 F-FGA 的合成。反应产率是定量的，没有检测到副产物。生物分布研究表明，F-FGA 从体内迅速消除（k=0.83h）；F-FGA 积累的主要器官是肾脏。在大鼠模型中，异丙肾上腺素处理导致心肌肌钙蛋白显著增加。PET 图像显示，异丙肾上腺素处理过的大鼠心脏积累了大量的 F-FGA，而健康心脏几乎没有摄取 F-FGA。与注射后 1 小时获得的图像相比，4 小时图像中 F-FGA 积累的靶标与非靶标对比度变得更加明显。
F-FGA 可以从普遍存在的 F-FDG 轻松且定量地合成，作为前体。所得的 F-FGA 有可能成为 MI 的 PET 成像中梗死亲和剂。知识的进步和对患者护理的影响：F-FGA/PET 将补充现有的灌注成像方案，用于治疗决策、确定血运重建的候选资格和成功、区分 MI 中的缺血与坏死、鉴别心肌炎与梗死以及监测心脏移植排斥反应。
