Pharmacokinetic Assessment of ¹⁸F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer

Abstract

18 F-(2S,4R)-4-fluoroglutamine (18 F-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 18 F-FGln, followed by 2 static PET scans at 97 ± 14 and 190 ± 12 min after injection. Five patients also underwent a second 18 F-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 18 F-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 18 F-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman ρ 5 0.71) and with SUV at 190 min (ρ 5 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: 18 F-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of 18 F-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates.

Kinetic Modeling of 18F-(2S,4R)4-Fluoroglutamine in Mouse Models of Breast Cancer to Estimate Glutamine Pool Size as an Indicator of Tumor Glutamine Metabolism

“…18 F-Gln-PET has been explored as a measure of glutamine metabolism in early clinical trials. 18 F-Gln uptake was seen in a variety of cancers: paraganglioma, breast, colon, lung, pancreas, neuroendocrine, glioma, and thyroid (16)(17)(18)(19)35). Down sloping TACs in these human tumors support reversible kinetics.…”

“…18 F-Glutamate (8-9% of total activity) was seen in the supernatant of mice and rat tumor extracts on HPLC analysis at one hour (20). We note that there has been an alternative compartment model proposed for 18 F-Gln that hypothesize significant metabolism of 18 F-Gln to 18 F-Glutamate (19). Our prior studies in breast cancer mouse models demonstrated that ≥85% of the radioactivity in the supernatant of tumor tissue was in the form of 18 F-Gln and only 9-14% of activity was from metabolites (12).…”

“…The PET radiotracer 18 F-(2S,4R)4-Fluoroglutamine ( 18 F-Gln) has been developed as an in vivo measure of tumor glutamine metabolism (15) and uptake has been seen in a variety of cancers (16)(17)(18)(19). 18 F-Gln utilizes the same cellular transporters as native glutamine but is minimally metabolized (12,17,20).…”

Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer

“…Interestingly, it was shown that CB-839 and Sapanisertib (TAK-228), inhibitor of mTORC1/2, therapies decreased the rate of glutaminolysis. Therefore, 18 F-FGln dynamic PET allows for the study of glutamine flux in patients with cancer, which necessary in order to evaluate specific cancer types with glutamine addiction, as well as responses to targeted therapies with inhibitors of the glutaminolysis pathway [67].…”

Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design

“…F-Gln uptake has been shown to be enhanced in glutamine-avid tumors. 13 Total-body dynamic PET imaging 14 will enable fully quantitative analysis of glucose utilization (for 18 F-FDG) and glutamine transport and conversion to glutamate (for 18 F-Gln) for all lesions.…”