Hannah E. Greenwood, Theranostics, 2022
Cancer cells have unique metabolic demands that are required to support their rapid proliferation and progression. Abnormal tumor glycolysis is routinely used for the clinical diagnosis and staging of cancer using 18F-2-fluoro-2-deoxy-ᴅ-glucose (18F-FDG) positron emission tomography (PET). Despite its clinical utility, FDG uptake in healthy tissues with high glucose demand, such as the brain and at sites of inflammation, can complicate image interpretation.
The metabolic reprograming of tumors is not restricted to catabolic reactions that underpin glycolysis, biosynthesis of DNA, lipids and proteins are additionally affected. Tumor cells frequently upregulate the expression of amino acid transporters on the plasma membrane and a range of radiolabeled amino acid analogs have been developed to image them.
The cystine/glutamate antiporter system, xc-, is a key regulator of the tumor antioxidant response. It is overexpressed in cancer cells and has increased activity.
18F-FSPG ((S)-4-(3-18F-fluoropropyl)-ʟ-glutamate) was first examined as a system xc- specific radiotracer and glutamate analog in preclinical tumor models.
The aim of the present study was to investigate whether changes to the chirality of system xc- substrates may improve tumor visualization when imaged with nanoScan PET/CT and report the initial preclinical evaluation of 18F-FRPG ((R)-4-(3-18Ffluoropropyl)-ʟ-glutamate), a stereoisomer of 18F-FSPG.
Results show that the fast clearance and renal excretion of 18F-FRPG, combined with high tumour uptake and improved metabolic stability compared to 18F-FSPG make it an exciting new tracer for the imaging of system xc-.
Results from nanoScan PET/CT
18F-FRPG and 18F-FSPG uptake was examined in different mouse models:
Orthotopic lung tumor model: 1×106 H460 (human lung carcinoma) cells were administered by a non-invasive intratracheal technique into the lungs of female NSG mice. For imaging, mice were intravenously injected with ~3 MBq of radiotracer, with PET scans acquired for 20 min following a 40 min uptake period. Animals were maintained under anesthesia from the time of radiotracer injection until the completion of imaging. CT images were acquired for anatomical visualization (720 projections; semicircular acquisition; 55 kVp; 600 ms exposure time) using a conventional single mouse imaging bed. All images were reconstructed using Tera-Tomo 3D (Mediso) with 4 iterations, 6 subsets, and 0.4 mm isotropic voxel size. Radiotracer concentration was quantified using VivoQuant software. Tumor volumes of interest were constructed from 2D regions drawn manually using the CT image as reference. Data were expressed as percent injected dose per gram of tissue (% ID/g).
Lung inflammation model: it was induced in female Balb/C mice through intratracheal inhalation of 50 μL lipopolysaccharide (LPS). Imaging was performed 24 h after treatment.
Subcutaneous tumor model: 5×106 A549 and H460 lung carcinoma cells were injected subcutaneously into female Balb/C nu/nu mice. Tumor size was monitored daily, with studies taking place when tumor volume reached ~100 mm3. Approximately 3 MBq of radiotracer was injected via the tail vein. Dynamic PET scans were acquired on a Mediso NanoScan PET/CT system (1-5 coincidence mode; 3D reconstruction; CT attenuation-corrected; scatter corrected) using a four-bed mouse hotel (Mediso). Images were acquired for 60 min following a bolus intravenous injection of ~3 MBq 18F-FRPG or 18F-FSPG through a tail vein cannula. For serial imaging studies using both radiotracers, mice were randomized to first receive either 18F-FSPG or 18F-FRPG. CT images were acquired for anatomical visualization (480 projections; helical acquisition; 55 kVp; 600 ms exposure time).
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