(4S)-4-(3-18F-fluoropropyl)-L-glutamate for imaging of xC transporter activity in hepatocellular carcinoma using PET: preclinical and exploratory clinical studies

J Nucl Med. 2013 Jan;54(1):117-23. doi: 10.2967/jnumed.112.108704. Epub 2012 Dec 11.

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.

Conclusion: (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.

MeSH terms

  • Adult
  • Aged
  • Amino Acid Transport System y+ / metabolism*
  • Biological Transport
  • Carcinoma, Hepatocellular / diagnostic imaging*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glutamates* / adverse effects
  • Glutamates* / metabolism
  • Glutamates* / pharmacokinetics
  • Humans
  • Hyaluronan Receptors / metabolism
  • Liver Neoplasms / diagnostic imaging*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Multimodal Imaging*
  • Neoplasm Grading
  • Positron-Emission Tomography*
  • Radiopharmaceuticals / adverse effects
  • Radiopharmaceuticals / metabolism
  • Radiopharmaceuticals / pharmacokinetics
  • Safety
  • Tomography, X-Ray Computed*

Substances

  • (4S)-4-(3-(18F)fluoropropyl)-L-glutamate
  • Amino Acid Transport System y+
  • Glutamates
  • Hyaluronan Receptors
  • Radiopharmaceuticals
  • SLC7A11 protein, human