Development of [18F]DASA-23 for Imaging Tumor Glycolysis Through Noninvasive Measurement of Pyruvate Kinase M2
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A hallmark of cancer is metabolic reprogramming, which is exploited by cancer cells to ensure rapid growth and survival. Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key step in tumor metabolism and growth. Recently, we reported the radiosynthesis of the first positron emission tomography tracer for visualizing PKM2 in vivo—i.e., [11C]DASA-23. Due to the highly promising imaging results obtained with [11C]DASA-23 in rodent model glioblastoma, we set out to generate an F-18-labeled version of this tracer, with the end goal of clinical translation in mind. Herein, we report the radiosynthesis of 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) and our initial investigation of its binding properties in cancer cells.
We synthesized [18F]DASA-23 via fluorination of 1-((2-fluoro-6-nitrophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine (10) with K[18F]F/K2.2.2 in N,N-dimethylformamide at 110 °C for 20 min. Subsequently, we evaluated uptake of [18F]DASA-23 in HeLa cervical adenocarcinoma cells and in vitro stability in human and mouse serum.
We successfully prepared [18F]DASA-23 in 2.61 ± 1.54 % radiochemical yield (n = 10, non-decay corrected at end of synthesis) with a specific activity of 2.59 ± 0.44 Ci/μmol. Preliminary cell uptake experiments revealed high uptake in HeLa cells, which was effectively blocked by pretreating cells with the structurally distinct PKM2 activator, TEPP-46. [18F]DASA-23 remained intact in human and mouse serum up to 120 min.
Herein, we have identified a F-18-labeled PKM2 specific radiotracer which shows potential for in vivo imaging. The promising cell uptake results reported herein warrant the further evaluation of [18F]DASA-23 for its ability to detect and monitor cancer noninvasively.
Key Words[18F]DASA-23 Pyruvate kinase Tumor glycolysis Fluorine-18 Radiochemistry Positron emission tomography
We would like to thank funding support from the Ben and Catherine Ivy Foundation. We would also like to thank the Radiochemistry Facility at Stanford University for the 18F-18 production and Dr. Bin Shen and Jun Hyung Park for the helpful discussions about this synthesis.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.