Specific PET Imaging of xC− Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism

Koglin, Norman; Mueller, André; Berndt, Mathias; Schmitt‐Willich, Heribert; Toschi, Luisella; Stephens, Andrew; Gekeler, Volker; Friebe, Matthias; Dinkelborg, Ludger

doi:10.1158/1078-0432.ccr-11-0687

Cited by 110 publications

(148 citation statements)

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“…Preclinical studies demonstrated a high uptake of 18 F-FSPG in several tumor cell lines occurring specifically via the system x C 2 , a sodium-independent transporter, which has an increased activity in tumors (7). Proof-ofmechanism studies are currently under way describing promising results in humans, which will be important for the further development of 18 F-FSPG as an imaging agent in cancer.…”

Section: Discussionmentioning

confidence: 97%

“…The specificity of uptake was demonstrated recently in cell competition assays and cells with transporter knockdown (6). An excellent tumor visualization was achieved in animal tumor models (7). Biodistribution analysis in rodents showed a rapid blood clearance via the kidneys and low background activity (including in the brain), providing high contrast for tumor imaging (7).…”

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confidence: 99%

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(S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamic Acid: An ¹⁸F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

et al. 2013

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The glutamic acid derivative (S)-4-(3-18 F-Fluoropropyl)-L-glutamic acid ( 18 F-FSPG, alias BAY 94-9392), a new PET tracer for the detection of malignant diseases, displayed promising results in non-small cell lung cancer patients. The aim of this study was to provide dosimetry estimates for 18 F-FSPG based on human whole-body PET/CT measurements. Methods: 18 F-FSPG was prepared by a fully automated 2-step procedure and purified by a solid-phase extraction method. PET/CT scans were obtained for 5 healthy volunteers (mean age, 59 y; age range, 51-64 y; 2 men, 3 women). Human subjects were imaged for up to 240 min using a PET/CT scanner after intravenous injection of 299 6 22.5 MBq of 18 F-FSPG. Image quantification, timeactivity data modeling, estimation of normalized number of disintegrations, and production of dosimetry estimates were performed using the RADAR (RAdiation Dose Assessment Resource) method for internal dosimetry and in general concordance with the methodology and principles as presented in the MIRD 16 document. Results: Because of the renal excretion of the tracer, the absorbed dose was highest in the urinary bladder wall and kidneys, followed by the pancreas and uterus. The individual organ doses (mSv/MBq) were 0.40 6 0.058 for the urinary bladder wall, 0.11 6 0.011 for the kidneys, 0.077 6 0.020 for the pancreas, and 0.030 6 0.0034 for the uterus. The calculated effective dose was 0.032 6 0.0034 mSv/MBq. Absorbed dose to the bladder and the effective dose can be reduced significantly by frequent bladder-voiding intervals. For a 0.75-h voiding interval, the bladder dose was reduced to 0.10 6 0.012 mSv/MBq, and the effective dose was reduced to 0.015 6 0.0010 mSv/MBq. Conclusion: On the basis of the distribution and biokinetic data, the determined radiation dose for 18 F-FSPG was calculated to be 9.5 6 1.0 mSv at a patient dose of 300 MBq, which is of similar magnitude to that of 18 F-FDG (5.7 mSv). The effective dose can be reduced to 4.5 6 0.30 mSv (at 300 MBq), with a bladder-voiding interval of 0.75 h.

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Section: Discussionmentioning

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(S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamic Acid: An ¹⁸F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

et al. 2013

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“…Glutamate, glutamine, and glutamic acid PET radiotracers have been developed (69). Progress has been made with a system X 2 c glutamate derivative PET radiotracer, (4S)-4-(3-18 F-fluoropropyl)-L-glutamate ( 18 F-FSPG), with which primary prostate cancer in 5 of 10 patients and recurrent or metastatic prostate cancer in 7 of 10 FIGURE 3.…”

Section: Emerging Amino Acid-based Pet Radiotracersmentioning

confidence: 99%

Evaluation of Prostate Cancer with Radiolabeled Amino Acid Analogs

2016

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Conventional imaging of prostate cancer has limitations related to the frequently indolent biology of the disease. PET is a functional imaging method that can exploit various aspects of tumor biology to enable greater detection of prostate cancer than can be provided by morphologic imaging alone. Radiotracers that are in use or under investigation for targeting salient features of prostate cancer include those directed to glucose, choline, acetate, prostate-specific membrane antigen, bombesin, and amino acids. The tumor imaging features of this last class of radiotracers mirror the upregulation of transmembrane amino acid transport that is necessary in carcinomas because of increased amino acid use for energy requirements and protein synthesis. Natural and synthetic amino acids radiolabeled for PET imaging have been investigated in prostate cancer patients. Early work with naturally occurring amino acid-derived radiotracers, such as L-11 C-methionine and L-1-11 C-5-hydroxytryptophan, demonstrated promising results, including greater sensitivity than 18 F-FDG for intraprostatic and extraprostatic cancer detection. However, limitations with naturally occurring amino acid-derived compounds, including metabolism of the radiotracer itself, led to the development of synthetic amino acid radiotracers, which are not metabolized and therefore more accurately reflect transmembrane amino acid transport. Of the synthetic amino acid-derived PET radiotracers, anti-1-amino-3-18 F-fluorocyclobutane-1-carboxylic acid ( 18 F-FACBC or 18 F-fluciclovine) has undergone the most promising translation to human use, including the availability of simplified radiosynthesis. Several studies have indicated advantageous biodistribution in the abdomen and pelvis with little renal excretion and bladder activity-characteristics beneficial for prostate cancer imaging. Studies have demonstrated improved lesion detection and diagnostic performance of 18 F-fluciclovine in comparison with conventional imaging, especially for recurrent prostate cancer, although issues with nonspecific uptake limit the potential role of 18 F-fluciclovine in the diagnosis of primary prostate cancer. Although work is ongoing, recently published intrapatient comparisons of 18 F-fluciclovine with 11 C-choline reported higher overall diagnostic performance of the former, especially for the detection of disease relapse. This review is aimed at providing a detailed overview of amino acid-derived PET compounds that have been studied for use in prostate cancer imaging.

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“…18 F-FSPG was radiolabeled as described previously (9). The specific activity of 18 F-FSPG formulated for intravenous administration was 74.4 6 59.6 GBq/mmol (range, 35.0-235.6 GBq/mmol), and the radiochemical purity was 91.6% 6 1.5% (range, 90.1%-94.4%).…”

Section: Radiopharmaceutical Preparationmentioning

confidence: 99%

Exploratory Clinical Investigation of (4S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamate PET of Inflammatory and Infectious Lesions

et al. 2015

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Specific PET Imaging of xC− Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism

Cited by 110 publications

References 44 publications

(S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamic Acid: An ¹⁸F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

(S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamic Acid: An ¹⁸F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

Evaluation of Prostate Cancer with Radiolabeled Amino Acid Analogs

Exploratory Clinical Investigation of (4S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamate PET of Inflammatory and Infectious Lesions

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Specific PET Imaging of xC− Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism

Cited by 110 publications

References 44 publications

(S)-4-(3-18F-Fluoropropyl)-l-Glutamic Acid: An 18F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

(S)-4-(3-18F-Fluoropropyl)-l-Glutamic Acid: An 18F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

Evaluation of Prostate Cancer with Radiolabeled Amino Acid Analogs

Exploratory Clinical Investigation of (4S)-4-(3-18F-Fluoropropyl)-l-Glutamate PET of Inflammatory and Infectious Lesions

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(S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamic Acid: An ¹⁸F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

(S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamic Acid: An ¹⁸F-Labeled Tumor-Specific Probe for PET/CT Imaging—Dosimetry

Exploratory Clinical Investigation of (4S)-4-(3-¹⁸F-Fluoropropyl)-l-Glutamate PET of Inflammatory and Infectious Lesions