Preclinical evaluation and quantification of 18F-FPEB as a radioligand for PET imaging of the metabotropic glutamate receptor 5

Abstract

The metabotropic glutamate receptor 5 (mGluR5) is a high-interest target for PET imaging because it plays a role in several pathologies, including addiction, schizophrenia, and fragile X syndrome. Methods: We studied the pharmacokinetics of 18F-FPEB (3-18F-fluoro-5-(2-pyridinylethynyl)benzonitrile), a selective PET radioligand for mGluR5, and used it to quantify mGluR5 in rat brain. Quantification was performed using both arterial sampling in combination with compartment models and simplified reference methods. The simpli-fied reference tissue model (SRTM), Ichise's original multi-linear reference tissue model (MRTMO), and Logan noninvasive were tested as reference models with nondisplaceable binding (BPND) as outcome parameter. Additionally, test-retest scans were obtained in 6 animals. Results: 18F-FPEB uptake in rat brain was consistent with its known distribution. No radiometabolites were present in the brain, and binding was specific as shown in blocking experiments, which also confirmed the cerebellum as a viable reference region. A 2-tissue-compartment model was used to determine BPND for the striatum (11.7 ± 1.5), nucleus accumbens (10.6 ± 2.0), hippocampus (9.0 ± 1.2), cortex (7.2 ± 1.0), and thalamus (4.0 ± 0.9). Reference methods were able to estimate these values with small bias (,2%). Test-retest analysis showed high repeatability between scans below 6%, also for shorter scan durations of 30 and 60 min. Conclusion: Because of its favorable reversible kinetics, high specificity, and absence of brain radiometabolites 18F-FPEB proves a highly useful tracer for in vivo visualization of the mGluR5 in rat brain. Moreover, reference tissue models allow noninvasive, rapid scanning with good test-retest.