Purpose: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. Experimental Design: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. Results: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. Conclusions: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

中文翻译：

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用于监测胶质母细胞瘤中丙酮酸激酶 M2 诱导的糖酵解重编程的临床 PET 成像示踪剂 ([18F]DASA-23)


目的：丙酮酸激酶 M2 (PKM2) 催化糖酵解的最后一步，糖酵解是癌症代谢的关键过程。 PKM2 优先由胶质母细胞瘤 (GBM) 细胞表达，在健康大脑中表达量极少。我们描述了一种新型 PET 示踪剂的开发、验证和翻译，用于研究 GBM 中的 PKM2。我们评估了细胞培养物、GBM 小鼠模型、健康人中的 1-((2-氟-6-[18F]氟苯基)磺酰基)-4-((4-甲氧基苯基)磺酰基)哌嗪 ([18F]DASA-23)志愿者和 GBM 患者。实验设计：合成的[18F]DASA-23的摩尔活性为100.47 ± 29.58 GBq/μmol，放射化学纯度> 95%。我们在 GBM 细胞培养物和原位植入小鼠体内的人 GBM 异种移植物中进行了 [18F]DASA-23 的初步测试。接下来，我们在 FDA 的监督下生产了 [18F]DASA-23，并在健康志愿者和神经胶质瘤患者试验队列中对其进行了评估。结果：在小鼠成像研究中，[18F]DASA-23 清楚地描绘了 U87 GBM 与周围健康脑组织的关系，肿瘤与大脑的比率为 3.6 ± 0.5。在人类志愿者中，[18F]DASA-23 穿过完整的血脑屏障并被迅速清除。在 GBM 患者中，[18F]DASA-23 成功勾勒出对比增强 MRI 上可见的肿瘤轮廓。与正常大脑相比，GBM 中 [18F]DASA-23 的摄取显着升高，并且在治疗开始 1 周内识别出代谢无反应者。结论：我们开发并翻译了 [18F]DASA-23 作为一种新的示踪剂，首次在人类受试者中展示了异常表达的 PKM2 的可视化。这些结果需要对 [18F]DASA-23 进行进一步的临床评估，以评估其在影像治疗诱导的异常癌症代谢正常化方面的效用。