期刊
JOURNAL OF NUCLEAR MEDICINE
卷 61, 期 3, 页码 357-366出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.119.229740
关键词
glutamine; metabolism; glutaminolysis; dynamic PET; kinetic modeling
资金
- David Mahoney Neuroimaging Program of the Dana Foundation
- Paul Calabresi Career Development Award for Clinical Oncology [K12 CA184746]
- National Cancer Institute [P50 CA086438, R01 CA164490, R01 CA172546, R21 CA167803, R01 CA204093]
- Stand Up to Cancer [SU2C-AACRDT0509]
- NIH/NCI Cancer Center support grant [P30 CA008748]
- Bristol-Myers Squibb
F-18-(2S,4R)-4-fluoroglutamine (F-18-FGln) is an investigational PET radiotracer for imaging tumor glutamine flux and metabolism. The aim of this study was to investigate its pharmacokinetic properties in patients with cancer. Methods: Fifty lesions from 41 patients (21 men and 20 women, aged 54 +/- 14 y) were analyzed. Thirty-minute dynamic PET scans were performed concurrently with a rapid intravenous bolus injection of 232 +/- 82 MBq of F-18-FGln, followed by 2 static PET scans at 97 +/- 14 and 190 +/- 12 min after injection. Five patients also underwent a second F-18-FGln study 4-13 wk after initiation of therapy with glutaminase, dual TORC1/2, or programmed death-1 inhibitors. Blood samples were collected to determine plasma and metabolite fractions and to scale the image-derived input function. Regions of interest were manually drawn to calculate SUVs. Pharmacokinetic modeling with both reversible and irreversible 1- and 2-tissue-compartment models was performed to calculate the kinetic rate constants K-1, k(2), k(3), and k(4). The analysis was repeated with truncated 30-min dynamic datasets. Results: Intratumor F-18-FGln uptake patterns demonstrated substantial heterogeneity in different lesion types. In most lesions, the reversible 2-tissue-compartment model was chosen as the most appropriate according to the Akaike information criterion. K-1, a surrogate biomarker for F-18-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman rho = 0.71) and with SUV at 190 min (rho = 0.51). Only K-1 was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). k(3), a surrogate biomarker for glutaminolysis rate, was relatively low in about 50% of lesions. Treatment with glutaminase inhibitor CB-839 substantially reduced the glutaminolysis rates as measured by k(3). Conclusion: F-18-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of F-18-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates.
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