(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models

Abstract

<p>Purpose: The glutamine analogue (2S, 4R)-4-[18F]fluoroglutamine ([18F]FGln) was investigated to</p><p>further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET)</p><p>images of separate orthotopic and subcutaneous glioma xenografts in mice.</p><p>Procedures: [18F]FGln was synthesized at a high radiochemical purity as analyzed by high-performance</p><p>liquid chromatography. An orthotopic model was created by injecting luciferase-expressing</p><p>patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1nu mouse</p><p>brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat</p><p>BT4C glioma cells into the flank and neck regions of Foxn1nu/nu mice. Dynamic PET images were</p><p>acquired after injecting 10–12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min</p><p>after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors)</p><p>were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed</p><p>with CARIMAS software. Blood sampling of 6 Foxn1nu/nu and 6 C57BL/6J mice was performed after 9–</p><p>14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake,</p><p>plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived whole-blood</p><p>radioactivity and apply the data to multiple pharmacokinetic models.</p><p>Results: Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio</p><p>of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n = 12) a tumor-to-muscle</p><p>(flank) ratio of 1.9 ± 0.7 (range 1.3–3.4). Using PET image-derived blood radioactivity corrected by</p><p>population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for</p><p>reversible uptake.</p><p>Conclusions: The results reinforce that [18F]FGln has preferential uptake in glioma tissue versus</p><p>that of corresponding healthy tissue and fits well with reversible uptake models.</p>