Abstract
PurposeThe glutamine analogue (2S, 4R)-4-[18F]fluoroglutamine ([18F]FGln) was investigated to further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice.Procedures[18F]FGln was synthesized at a high radiochemical purity as analyzed by high-performance liquid chromatography. An orthotopic model was created by injecting luciferase-expressing patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1nu mouse brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1nu/nu mice. Dynamic PET images were acquired after injecting 10–12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1nu/nu and 6 C57BL/6J mice was performed after 9–14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived whole-blood radioactivity and apply the data to multiple pharmacokinetic models.ResultsOrthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n = 12) a tumor-to-muscle (flank) ratio of 1.9 ± 0.7 (range 1.3–3.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake.ConclusionsThe results reinforce that [18F]FGln has preferential uptake in glioma tissue versus that of corresponding healthy tissue and fits well with reversible uptake models.
Highlights
Relatively rare, malignant glioma development in humans often leads to a swift terminal outcome due to the aggressive nature of a large portion of the brain tumors [1, 2]
We describe four pharmacokinetic model evaluations with the thought that future changes to the tracer structure will have a rich source of uptake parameters to quantify in vivo flux changes
The intracranial glioma model was made by injecting female BALB/cOlaHsd-Foxn1nu mice with patient-derived BT3 glioma cells [29] labeled with luciferase into the frontal right hemisphere of the brain at 9 weeks old
Summary
Malignant glioma development in humans often leads to a swift terminal outcome due to the aggressive nature of a large portion of the brain tumors [1, 2]. The complications accompanying intracranial surgery and the high instances of tumor relapse [3] reveal the importance of developing and rigorously testing improved imaging strategies. The compound (2S, 4R)-4[18F]fluoroglutamine ([18F]FGln) has been shown to be suitable for positron emission tomography (PET) imaging intracranial gliomas with the potential to differentiate between actively growing and clinically stable lesions [4]. Cellular import and export of glutamine occurs via many different transport proteins, though the most ubiquitous are classified as generalists and possess the ability to import a variety of similar but different amino acids [9, 10]. The F-18 fluorinated glutamine analogue, [18F]FGln (Fig. 1), has been shown to have comparable uptake kinetics of the natural version when contrasted to [11C]glutamine [11] which has made it a suitable imaging candidate in biological systems
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