Abstract
18F-(2S,4R)-4-fluoroglutamine (18F-FGln) is an investigational positron emission tomography (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 (21M/20F, aged 54±14 years) were analyzed. 30-min dynamic PET scans were performed concurrent with a rapid intravenous bolus injection of 232±82 MBq of 18F-FGln, followed by two static PET scans at 97±14 min and 190±12 min post-injection. Five patients also underwent a second 18F-FGln study 4-13 weeks after initiation of therapy with either glutaminase, dual TORC1/2, or PD-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 standardized uptake values (SUVs). Pharmacokinetic modeling with both reversible and irreversible one- and two-tissue compartment models was performed to calculate 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 majority of lesions, reversible two-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 with both SUV at 30-min (Spearman’s ϱ=0.71) and with SUV at 190-min (ϱ=0.51). Only K1 was reproducible from truncated 30-min datasets (ICC=0.96). k3, a surrogate biomarker for glutaminolysis rate, was relatively low in ~50% of lesions. Treatment with glutaminase inhibitor CB-839 substantially reduced the glutaminolysis rates as measured by k3. Conclusion: 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.
- Oncology: Brain
- PET
- Radiotracer Tissue Kinetics
- dynamic PET
- glutamine
- glutaminolysis
- kinetic modeling
- metabolism
- Copyright © 2019 by the Society of Nuclear Medicine and Molecular Imaging, Inc.