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 18 F-FPEB (3-18 Ffluoro-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 simplified reference tissue model (SRTM), Ichise's original multi-linear reference tissue model (MRTM O ), and Logan noninvasive were tested as reference models with nondisplaceable binding (BP ND ) as outcome parameter. Additionally, test-retest scans were obtained in 6 animals. Results: 18 F-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 BP ND 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 18 F-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.

Kinetic modeling and long‐term test‐retest reproducibility of the mGluR5 PET tracer 18F‐FPEB in human brain

“…In drug addiction research for instance, promising applications include assessing the effects of detoxification and mGluR5-targeted therapy, thereby potentially helping to predict relapse. In rat models, our group recently validated the use of the cerebellum as reference region for 18 F-FPEB allowing reliable and accurate simplified quantification of BP ND (de Laat et al, 2015). In humans Synapse however, such a reference region does not exist (Kå gedal et al, 2013;Patel et al, 2007), challenging the accurate estimation of BP ND using 2TCM (DeLorenzo et al, 2015;Lammertsma et al, 1996).…”

Effects of alcohol exposure on the glutamatergic system: a combined longitudinal 18F‐FPEB and 1H‐MRS study in rats

“…PET images were normalized to a custom‐made rat brain template in Paxinos stereotactic space, allowing the use of a predefined volume‐of‐interest (VOI) map and of statistical parametric mapping (Casteels et al ., ). Non‐displaceable binding (BP ND ) was calculated with the previously validated simplified reference tissue model (SRTM) for 18 F‐FPEB, in rats using the cerebellum as reference region (de Laat et al ., ). To evaluate the value of baseline measurements, we performed a VOI‐based analysis on the nucleus accumbens, hippocampus, prefrontal cortex and striatum using PMOD 3.6 (PMOD Technologies, Zurich, Switzerland).…”

Effects of P‐gp and Bcrp as brain efflux transporters on the uptake of [18F]FPEB in the murine brain

“…However, [ 18 F]FPEB showed metabolic stability in rats. The polar radiometabolites of [ 18 F]FPEB appeared after 60 min, but the proportion did not exceed 5% of the total radioactivity (de Laat et al, ). Therefore, radiometabolism is not a likely issue in the interpretation of the data.…”

“…[ 18 F]FPEB displayed high specificity and affinity for mGluR5 as well as a regional uptake pattern consistent with the known distribution of mGluR5 in rodents, nonhuman primates and human subjects (Hamill et al, ; Patel et al, ; Wang, Tueckmantel, Zhu, Pellegrino, & Brownell, ). In addition, its biological efficacy was validated in preclinical and clinical trials of Parkinson's disease and Alzheimer's disease (Kang & Mozley, ; Laat et al, ; Lohith et al, ). However, the relevance of efflux transporters to the CNS distribution of [ 18 F]FPEB has not yet been reported.…”

“…18 F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([ 18 F]FPEB) is high affinity and selectivity radiotracer for the mGluR5 developed by Hamill et al [ 18 F]FPEB displayed high specificity and affinity for mGluR5 as well as a regional uptake pattern consistent with the known distribution of mGluR5 in rodents, nonhuman primates and human subjects Patel et al, 2005;Wang, Tueckmantel, Zhu, Pellegrino, & Brownell, 2007). In addition, its biological efficacy was validated in preclinical and clinical trials of Parkinson's disease and Alzheimer's disease (Kang & Mozley, 2018;Laat et al, 2015;Lohith et al, 2017).…”