The Urgent Need for Molecular Imaging to Confirm Target Engagement for Clinical Trials of Fragile X Syndrome and Other Subtypes of Autism Spectrum Disorder

Brašić, James Robert; Mathur, Anil; Budimirović, Dejan B.

doi:10.5812/ans.91831

Cited by 3 publications

(8 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, this difference in BP ND between the subjects with FXS and control group was significant in areas consistent with known distribution of mGluR5, and which have been functionally implicated in FXS symptomatology. Our results of overall reduced mGlu5 receptor expression in relevant regions of the brain in individuals with FXS replicate recent findings 17 and advance ongoing efforts for a much-needed measure of mGluR5 target engagement for drugs and treatment of symptoms in clinical trials of FXS and related disorders 36 , 37 .…”

Section: Discussionsupporting

confidence: 84%

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

Mody

Petibon

Han

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas. Patients with FXS showed lower [18F]FPEB binding potential (p < 0.01), reflecting reduced mGluR5 availability, than the healthy controls throughout the brain, with significant group differences in insula, anterior cingulate, parahippocampal, inferior temporal and olfactory cortices, regions associated with deficits in inhibition, memory, and visuospatial processes characteristic of the disorder. The results are among the first to provide in vivo evidence of decreased availability of mGluR5 in the brain in individuals with FXS than in healthy controls. The consistent results across the subjects, despite the tremendous challenges with neuroimaging this population, highlight the robustness of the protocol and support for its use in drug occupancy studies; extending our radiotracer development and application efforts from mice to humans.

show abstract

Section: Discussionsupporting

confidence: 84%

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

Mody

Petibon

Han

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…[ 18 F]FPEB 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB), a novel, specific mGluR5 ligand to quantitatively measure the density and distribution of mGluR5s in the brain regions of humans with FXS through PET [21][22][23][24][25][26][27][28][29][30] (Figure 1), constitutes an effective tool to confirm target engagement of mGluR5s of relevance to clinical trials of NAMs for individuals with FXS [31]. Specifically, [ 18 F]FPEB [22,[34][35][36][37] has been shown to demonstrate high uptake and specific binding during the test-retest paradigm for mGluR5 in the anterior cingulate gyrus, putamen, caudate nucleus, and frontal, parietal, and temporal cortices [28,29].…”

Section: Measurement Of Mglur 5 S In the Living Human Brainmentioning

confidence: 99%

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome

et al. 2020

Self Cite

View full text Add to dashboard Cite

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR5 expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR5 density as a proxy of mGluR5 expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR5s. The density and the distribution of mGluR5 were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR5 expression showed that mGluR5 expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.

show abstract

“…Our finding that mGluR5 expression measured by positron emission tomography (PET) with 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB), a potent and safe specific mGluR5 inhibitor (Figure 1 and Figure 2) [58,59], is reduced in all brain regions in men with FXS [2] compared to participants of both sexes with ASD and TD [2,42,[60][61][62], was confirmed utilizing positron emission tomography and magnetic resonance (PET/MR) imaging on an unmedicated cohort of older men with FXS and age-and sex-matched participants with TD suggesting that the current protocol may be a valuable biomarker for mGluR5 expression in clinical trials of novel agents for humans with FXS and other subtypes of ASD [63]. We showed that [ 18 F]FPEB may be a promising tool to obtain quantitative measurements of mGluR5 expression in individuals with FXS for clinical trials and other investigations [2,42,[64][65][66][67]. Since our prior finding of reduced cerebral mGluR5 expression in cortical and subcortical regions of men with FXS has been confirmed [41,63], we sought expand the previous protocol of cerebral mGluR5 expression alone with a more refined measure tool to include simultaneous FRMP levels and cerebral mGluR5 expression for clinical trials of FXS.…”

Section: Introductionmentioning

confidence: 88%

“…The protocols for the study of humans were approved by the Institutional Review Boards of the Institute for Neurodegenerative Disorders (IND) in New Haven, Connecticut [74] and the Johns Hopkins University (JHU) in Baltimore, Maryland [75,76]. Since exposure to radioactivity in PET constitutes greater than minimal risk, this pilot [41,42,64,[71][72][73]. We aimed to determine if (A) FMRP levels are correlated with mGluR 5 expression in men with the FM of FXS [2,41,42] and (B) the measurement of FMRP and PET with ([ 18 F]FPEB) is feasible in men with FXS [2,41,42,60,61].…”

Section: Recruiting Sitesmentioning

confidence: 99%

“…Here, we seek to investigate the relationship between FMRP [68] and mGluR5 expression in unmedicated men with the FM of FXS [15,16]. Development of interventions to ameliorate the specific molecular deficits of individuals with FXS may facilitate the development of treatment plans to address the unique needs of each person [41,42,64,[71][72][73]. We aimed to determine if (A) FMRP levels are correlated with mGluR5 expression in men with the FM of FXS [2,41,42] and (B) the measurement of FMRP and PET with ([ 18 F]FPEB) is feasible in men with FXS [2,41,42,60,61].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study

et al. 2022

Self Cite

View full text Add to dashboard Cite

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials. Unexpectedly marked reductions in mGluR5 expression were observed in cortical and subcortical regions in men with FXS. Reduced mGluR5 expression throughout the living brains of men with FXS provides a clue to examine FMRP and mGluR5 expression in FXS. In order to develop the findings of our previous study and to strengthen the objective tools for future clinical trials of glutamatergic agents in FXS, we sought to assess the possible value of measuring both FMRP levels and mGluR5 expression in men with FXS. We aimed to show the value of measurement of FMRP levels and mGluR5 expression for the diagnosis and treatment of individuals with FXS and related conditions. We administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a specific mGluR5 radioligand for quantitative measurements of the density and the distribution of mGluR5s, to six men with the full mutation (FM) of FXS and to one man with allele size mosaicism for FXS (FXS-M). Utilizing the seven cortical and subcortical regions affected in neurodegenerative disorders as indicator variables, adjusted linear regression of mGluR5 expression and FMRP showed that mGluR5 expression was significantly reduced in the occipital cortex and the thalamus relative to baseline (anterior cingulate cortex) if FMRP levels are held constant (F(7,47) = 6.84, p < 0.001).These findings indicate the usefulness of cerebral mGluR5 expression measured by PET with [18F]FPEB and FMRP values in men with FXS and related conditions for assessments in community facilities within a hundred-mile radius of a production center with a cyclotron. These initial results of this pilot study advance our previous study regarding the measurement of mGluR5 expression by combining both FMRP levels and mGluR5 expression as tools for meaningful clinical trials of glutamatergic agents for men with FXS. We confirm the feasibility of this protocol as a valuable tool to measure FMRP levels and mGluR5 expression in clinical trials of individuals with FXS and related conditions and to provide the foundations to apply precision medicine to tailor treatment plans to the specific needs of individuals with FXS and related conditions.

show abstract

The Urgent Need for Molecular Imaging to Confirm Target Engagement for Clinical Trials of Fragile X Syndrome and Other Subtypes of Autism Spectrum Disorder

Cited by 3 publications

References 13 publications

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome

Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study

Contact Info

Product

Resources

About