title: Development of [18F]DASA-23 for Imaging Tumor Glycolysis Through Noninvasive Measurement of Pyruvate Kinase M2.
abstract: 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.
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 943065, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Beinat
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 943065, USA.
authors.forename: Israt S
authors.initials: IS
authors.lastname: Alam
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 943065, USA.|Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 943065, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: James
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 943065, USA.
authors.forename: Ananth
authors.initials: A
authors.lastname: Srinivasan
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 943065, USA. sgambhir@stanford.edu.|Departments of Bioengineering and Materials Science and Engineering, Bio-X, Stanford University, Stanford, CA, 943065, USA. sgambhir@stanford.edu.
authors.forename: Sanjiv Sam
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020536:Enzyme Activators / Q000494:pharmacology; D006019:Glycolysis; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry*; D011770:Pyruvate Kinase / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D010879:Piperazines; D011770:Pyruvate Kinase
keywords: Fluorine-18; Positron emission tomography; Pyruvate kinase; Radiochemistry; Tumor glycolysis; [18F]DASA-23