title: Specific PET imaging of xC- transporter activity using a ¹⁸F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism.
abstract: OBJECTIVE
  (18)F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable ¹⁸F-labeled glutamate analogue for PET imaging of tumors.
  
  
  METHODS
  Derivatives of l-glutamate were investigated in cell competition assays to characterize the responsible transporter. An automated radiosynthesis was established for the most promising candidate. The resulting ¹⁸F-labeled PET tracer was characterized in a panel of in vitro and in vivo tumor models. Tumor specificity was investigated in the turpentine oil-induced inflammation model in rats.
  
  
  RESULTS
  A fluoropropyl substituted glutamate derivative showed strong inhibition in cell uptake assays. The radiosynthesis was established for (4S)-4-(3-[¹⁸F]fluoropropyl)-l-glutamate (BAY 94-9392). Tracer uptake studies and analysis of knockdown cells showed specific transport of BAY 94-9392 via the cystine/glutamate exchanger designated as system x(C)(-). No metabolites were observed in mouse blood and tumor cells. PET imaging with excellent tumor visualization and high tumor to background ratios was achieved in preclinical tumor models. In addition, BAY 94-9392 did not accumulate in inflammatory lesions in contrast to FDG.
  
  
  CONCLUSIONS
  BAY 94-9392 is a new tumor-specific PET tracer which could be useful to examine system x(C)(-) activity in vivo as a possible hallmark of tumor oxidative stress. Both preclinical and clinical studies are in progress for further characterization.
authors.affiliation: Global Drug Discovery, Bayer HealthCare, Berlin, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Koglin
authors.forename: Andre
authors.initials: A
authors.lastname: Mueller
authors.forename: Mathias
authors.initials: M
authors.lastname: Berndt
authors.forename: Heribert
authors.initials: H
authors.lastname: Schmitt-Willich
authors.forename: Luisella
authors.initials: L
authors.lastname: Toschi
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stephens
authors.forename: Volker
authors.initials: V
authors.lastname: Gekeler
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005971:Glutamates / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000378:metabolism*; D051381:Rats; D011923:Rats, Nude; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
chemical_list: C569271:(4S)-4-(3-(18F)fluoropropyl)-L-glutamate; D027182:Amino Acid Transport System y+; D005971:Glutamates; D019275:Radiopharmaceuticals; C118895:SLC7A11 protein, human