Pharmacokinetic Assessment of ¹⁸F-(2<i>S,</i>4<i>R</i>)-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. <b>Methods:</b> 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 <i>K</i>₁, <i>k</i>₂, <i>k</i>₃, and <i>k</i>₄ The analysis was repeated with truncated 30-min dynamic datasets. <b>Results</b>: 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. <i>K</i>₁, 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 <i>K</i>₁ was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). <i>k</i>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 <i>k</i>₃<b>Conclusion:</b>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.