Pharmacokinetic assessment of (18)F-(2S,4R)-4-fluoroglutamine in patients with cancer Journal Article
| Authors: | Grkovski, M.; Goel, R.; Krebs, S.; Staton, K. D.; Harding, J. J.; Mellinghoff, I. K.; Humm, J. L.; Dunphy, M. P. S. |
| Article Title: | Pharmacokinetic assessment of (18)F-(2S,4R)-4-fluoroglutamine in patients with cancer |
| Abstract: | 18F-(2S,4R)-4-fluoroglutamine (18F-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 18F-FGln, followed by 2 static PET scans at 97 ± 14 and 190 ± 12 min after injection. Five patients also underwent a second 18F-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 K1, k2, k3, and k4 The analysis was repeated with truncated 30-min dynamic datasets. Results: Intratumor 18F-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. K1, a surrogate biomarker for 18F-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman ρ = 0.71) and with SUV at 190 min (ρ = 0.51). Only K1 was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). k3, 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 k3Conclusion:18F-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of 18F-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates. © 2020 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | metabolism; glutamine; dynamic pet; kinetic modeling; glutaminolysis |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 61 |
| Issue: | 3 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2020-03-01 |
| Start Page: | 357 |
| End Page: | 366 |
| Language: | English |
| DOI: | 10.2967/jnumed.119.229740 |
| PUBMED: | 31601700 |
| PROVIDER: | scopus |
| PMCID: | PMC7067522 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
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