A Clinical PET Imaging Tracer ([F-18]DASA-23) to Monitor Pyruvate Kinase M2-Induced Glycolytic Reprogramming in Glioblastoma

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 transla-tion of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[F-18]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl) piperazine ([F-18]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. Experimental Design: [F-18]DASA-23 was synthesized with a molar activity of 100.47 +/- 29.58 GBq/mmol and radiochemical purity>95%. We performed initial testing of [F-18]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [F-18]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. Results: In mouse imaging studies, [F-18]DASA-23 clearly delin- eated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 +/- 0.5. In human volunteers, [F-18]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In patients with GBM, [F-18]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [F-18]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 [F-18]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 [F-18]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.