Metabotropic Glutamate Receptor Subtype 5 Function In Fragile X Syndrome

1552 Background: Fragile X syndrome (FXS), a subtype of autism spectrum disorder (ASD), is caused by (A) epigenetic silencing of the Fragile X Mental Retardation 1 (FMR1) gene leading to the loss or deficit of Fragile X Mental Retardation Protein (FMRP) or (B) mutation in the RNA binding of specific mRNA targets. The lack of FMRP leading to upregulated metabotropic glutamate receptor subtype 5 (mGluR5)signaling in an animal model of FXS has not been confirmed in humans with FXS. However, modification of mGluR5 signaling, a promising new, targeted pharmacologic treatment to restore excitatory/inhibitory balance in the FXS brain, has not been confirmed in humans with FXS. Many clinical trials of pharmacological agents for mGluR5 have been unsuccessful due to the lack of a tool to confirm that the study drug actually engages the desired target (Budimirovic, et al., 2017). We have developed a biomarker to demonstrate engagement of mGluR5 (Wong, et al., 2013) for use in clinical trials of FXS (Brasic, et al., 2019). Objectives: To measure mGluR5 density in relevant brain regions of men with and without fragile X syndrome (FXS) and autism spectrum disorder (ASD) (Fatemi, et al., 2018). Methods: A 24-year-old man with mutation-confirmed FXS, six men with ASD aged 20 + 2.10 years, and three healthy control (HC) men without FXS or ASD aged 27 + 3.61 years underwent structural magnetic resonance imaging (MRI) and positron emission tomography (PET) in a high resolution research tomograph (HRRT) with resolution approaching 2 mm (Rahmim, et al., 2005; Sossi, et al., 2005) for 90 min after the intravenous bolus injection of 185 megabecquerels (MBq) [5 mCi] 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a potent, selective mGluR5 inhibitor (Wong, et al., 2013). The images of the MRI and PET were coregistered for analysis (Wong, et al., 2013). The nondisplaceable binding potential (BPND) (Innis, et al., 2007) of [18F]FPEB, a measurement proportional to the density of unoccupied receptors (Bmax9), was estimated in relevant volumes of interest in the brain utilizing the cerebellum as the reference tissue for graphical analysis (RTGA) (Logan, et al., 1996, 2011). Results: BPNDs for the man with FXS were uniformly lower than the means of the ASD and HC groups (Table). The observation that the sample of men with ASD had significantly higher BPNDs in the cerebellum and postcentral gyrus than the HC men with the multilinear reference tissue, two parameter model (Ichise, et al., 2002) was not confirmed with the RTGA (Logan, et al., 1996, 2011). Conclusions: Although one cannot generalize results from a single man with FXS to the population of individuals with FXS, the current investigation demonstrates that performing sophisticated imaging of mGluR5 in men with FXS is feasible by a team of experts who specialize in FXS. Investigations with an adequate sample size will likely demonstrate that the proposed protocol will provide the tool to establish target engagement for clinical trials of novel agents for mGluR5 in FXS (Brasic, et al., 2019). The proposed protocol will then be key to establish drug occupancy for future clinical trials of novel agents for mGluR5 in FXS.