title: (4S)-4-(3-18F-fluoropropyl)-L-glutamate for imaging of xC transporter activity in hepatocellular carcinoma using PET: preclinical and exploratory clinical studies.
abstract: (4S)-4-(3-(18)F-fluoropropyl)-l-glutamate ((18)F-FSPG, or BAY 94-9392) is a new tracer to assess system x(C)(¯) transporter activity with PET. The aim of this study was to explore the tumor detection rate of (18)F-FSPG, compared with that of (18)F-FDG, in patients with hepatocellular carcinoma (HCC).
  
  
  METHODS
  Preclinically, in vivo HCC models of orthotopically implanted Huh7 and MH3924a cancer cells were studied with (18)F-FSPG in Naval Medical Research Institute nude mice (n = 3) and August-Copenhagen Irish rats (n = 4), respectively. Clinically, 5 patients with HCC who had hyper- or isometabolic lesions on (18)F-FDG PET were enrolled for evaluation of the tracer. Dynamic whole-body PET images with (18)F-FSPG were acquired for up to 120 min after injection of approximately 300 MBq of (18)F-FSPG. Immunohistochemical expression levels of the xCT subunit of the system x(C)(¯) and CD44 of HCC were studied in 4 patients with HCC.
  
  
  RESULTS
  Strong tumor uptake and low background from nontarget tissue allowed excellent tumor visualization in animal models with orthotopically implanted liver tumors. (18)F-FSPG PET procedures were well tolerated in all patients. (18)F-FSPG PET and (18)F-FDG detected lesions in 5 of 5 and 3 of 5 patients, respectively. The maximal standardized uptake values (SUV) were comparable ((18)F-FSPG, 4.7 ± 3.2; (18)F-FDG, 6.1 ± 2.9). The ratios of maximal SUV of the tumor to mean SUV of normal liver were also comparable ((18)F-FSPG, 3.6 ± 2.2; (18)F-FDG, 2.7 ± 1.3), but the mean SUV of normal liver of (18)F-FSPG was significantly lower than that of (18)F-FDG (P < 0.05). Two patients with HCC who showed both xCT and CD44 expression had moderate or intense accumulation of (18)F-FSPG, but the remaining 2 patients with negative CD44 expression showed mild uptake.
  
  
  CONCLUSIONS
  (18)F-FSPG was successfully translated from preclinical evaluation into patients with HCC. (18)F-FSPG may be a promising tumor PET agent with a high cancer detection rate in patients with HCC.
authors.affiliation: Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sora
authors.initials: S
authors.lastname: Baek
authors.forename: Andre
authors.initials: A
authors.lastname: Mueller
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Lim
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Gyungyub
authors.initials: G
authors.lastname: Gong
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kim
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Ryu
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Oh
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Claudia
authors.initials: C
authors.lastname: Bacher-Stier
authors.forename: Lüder
authors.initials: L
authors.lastname: Fels
authors.forename: Norman
authors.initials: N
authors.lastname: Koglin
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Schatz
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
authors.forename: Dae Hyuk
authors.initials: DH
authors.lastname: Moon
mesh_terms: D000328:Adult; D000368:Aged; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D001692:Biological Transport; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D060787:Neoplasm Grading; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D012449:Safety; D014057:Tomography, X-Ray Computed
chemical_list: C569271:(4S)-4-(3-(18F)fluoropropyl)-L-glutamate; D027182:Amino Acid Transport System y+; D005971:Glutamates; D018960:Hyaluronan Receptors; D019275:Radiopharmaceuticals; C118895:SLC7A11 protein, human