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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 ([ 18 F]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 [ 18 F]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.

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick’s disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.

Background [ 13 N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [ 13 N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [ 13 N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time. Due to its short half-life of 10 min, FDA and USP regulations allow [ 13 N]ammonia to be tested in quality control (QC) sub-batches with limited quality control testing performed on the sub-batches for patient use. The current EP and the original USP method for the determination of the radiochemical purity and identity of [ 13 N]ammonia depended on an HPLC method using a conductivity detector and a solvent free of other salts. This HPLC method created issues in a modern cGMP high volume PET manufacturing facility where the HPLC is used with salt containing mobile phase buffers for quality control analysis of other PET radiopharmaceuticals. Flushing of the HPLC system of residual salt buffers which may interfere with the [ 13 N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [ 13 N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC. Results We have developed and validated a streamlined automated synthesis for [ 13 N]ammonia which provides the drug product in 8 mL of 0.9% sodium chloride for injection. A novel radio-TLC method was developed and validated to demonstrate feasibility to quantitate [ 13 N]ammonia and separate it from all known radiochemical impurities. Conclusions The process for automated synthesis of [ 13 N]ammonia simplifies and automates the purification and formulation of [ 13 N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [ 13 N]ammonia. The novel radio-TLC method has simplified [ 13 N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [ 18 F]fludeoxyglucose (FDA/USP recognized name for 2-[ 18 F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [ 13 N]ammonia and the novel radio-TLC method have been accepted and approved by the US Food and Drug Administration (FDA) for the cGMP manufacture of [ 13 N]ammonia.

We and others have shown that [ 18 F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [ 18 F]-MK-6240 and [ 18 F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [ 18 F]-MK-6240 closely parallels that of [ 18 F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [ 18 F]-Flortaucipir, [ 18 F]-MK-6240 and [ 18 F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers.

We and others have shown that [18F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [18F]-MK-6240 and [18F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [18F]-MK-6240 closely parallels that of [18F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers.We and others have shown that [18F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [18F]-MK-6240 and [18F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [18F]-MK-6240 closely parallels that of [18F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers.

[13N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [13N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [13N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time. Due to its short half-life of 10 min, FDA and USP regulations allow [13N]ammonia to be tested in quality control (QC) sub-batches with limited quality control testing performed on the sub-batches for patient use. The current EP and the original USP method for the determination of the radiochemical purity and identity of [13N]ammonia depended on an HPLC method using a conductivity detector and a solvent free of other salts. This HPLC method created issues in a modern cGMP high volume PET manufacturing facility where the HPLC is used with salt containing mobile phase buffers for quality control analysis of other PET radiopharmaceuticals. Flushing of the HPLC system of residual salt buffers which may interfere with the [13N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [13N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC.BACKGROUND[13N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [13N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [13N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time. Due to its short half-life of 10 min, FDA and USP regulations allow [13N]ammonia to be tested in quality control (QC) sub-batches with limited quality control testing performed on the sub-batches for patient use. The current EP and the original USP method for the determination of the radiochemical purity and identity of [13N]ammonia depended on an HPLC method using a conductivity detector and a solvent free of other salts. This HPLC method created issues in a modern cGMP high volume PET manufacturing facility where the HPLC is used with salt containing mobile phase buffers for quality control analysis of other PET radiopharmaceuticals. Flushing of the HPLC system of residual salt buffers which may interfere with the [13N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [13N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC.We have developed and validated a streamlined automated synthesis for [13N]ammonia which provides the drug product in 8 mL of 0.9% sodium chloride for injection. A novel radio-TLC method was developed and validated to demonstrate feasibility to quantitate [13N]ammonia and separate it from all known radiochemical impurities.RESULTSWe have developed and validated a streamlined automated synthesis for [13N]ammonia which provides the drug product in 8 mL of 0.9% sodium chloride for injection. A novel radio-TLC method was developed and validated to demonstrate feasibility to quantitate [13N]ammonia and separate it from all known radiochemical impurities.The process for automated synthesis of [13N]ammonia simplifies and automates the purification and formulation of [13N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [13N]ammonia. The novel radio-TLC method has simplified [13N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [18F]fludeoxyglucose (FDA/USP recognized name for 2-[18F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [13N]ammonia and the novel radio-TLC method have been accepted and approved by the US Food and Drug Administration (FDA) for the cGMP manufacture of [13N]ammonia.CONCLUSIONSThe process for automated synthesis of [13N]ammonia simplifies and automates the purification and formulation of [13N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [13N]ammonia. The novel radio-TLC method has simplified [13N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [18F]fludeoxyglucose (FDA/USP recognized name for 2-[18F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [13N]ammonia and the novel radio-TLC method have been accepted and approved by the US Food and Drug Administration (FDA) for the cGMP manufacture of [13N]ammonia.

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick's disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick's disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.

Metabotropic glutamate receptor 2 (mGluR2) has been extensively studied for the treatment of various neurological and psychiatric disorders. Understanding of the mGluR2 function is pivotal in supporting the drug discovery targeting mGluR2. Herein, the positive allosteric modulation of mGluR2 was investigated via the in vivo positron emission tomography (PET) imaging using 2-((4-(2-[11C]methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-imidazo[4,5-b]pyridine ([11C]mG2P001).Distinct from the orthosteric compounds, pretreatment with the unlabeled mG2P001, a potent mGluR2 positive allosteric modulator (PAM), resulted in a significant increase instead of decrease of the [11C]mG2P001 accumulation in rat brain detected by PET imaging. Subsequent in vitro studies with [3H]mG2P001 revealed the cooperative binding mechanism of mG2P001 with glutamate and its pharmacological effect that contributed to the enhanced binding of [3H]mG2P001 in transfected CHO cells expressing mGluR2. The in vivo PET imaging and quantitative analysis of [11C]mG2P001 in non-human primates (NHPs) further validated the characteristics of [11C]mG2P001 as an imaging ligand for mGluR2. Self-blocking studies in primates enhanced accumulation of [11C]mG2P001 dose- and delivery-dependently. Altogether, these studies show that [11C]mG2P001 is a sensitive biomarker for mGluR2 expression and the binding is affected by the tissue glutamate concentration. Competing Interest Statement The authors have declared no competing interest.

Abstract Demyelination, the loss of the protecting sheath of neurons, contributes to disability in many neurological diseases. In order to fully understand its role in different diseases and to monitor treatments aiming at reversing this process, it would be valuable to have PET radiotracers that can detect and quantify molecular changes involved in demyelination such as the uncovering and upregulation of the axonal potassium channels Kv1.1 and Kv1.2. Carbon-11 labeled radiotracers present the advantage of allowing for multiple scans on the same subject in the same day. Here, we describe [11C|3MeO4AP, a novel 11C-labeled version of the K+ channel tracer [18F]3F4AP, and characterize its imaging properties in two nonhuman primates including a monkey with a focal brain injury sustained during a surgical procedure three years prior to imaging. Our findings show that [11C]3MeO4AP is brain permeable, metabolically stable and has high plasma availability. When compared with [18F]3F4AP, [11C]3MeO4AP shows very high correlation in volumes of distribution (VT) confirming a common target. [11C]3MeO4AP shows slower washout than [18F]3F4AP suggesting stronger binding. Finally, similar to [18F]3F4AP, [11C]3MeO4AP is highly sensitive to the focal brain injury. All these features make it a promising radioligand for imaging demyelinated lesions. Competing Interest Statement PB is a named coinventor on patents concerning [18F]3F4AP and [11C]3MeO4AP. All other authors declare no conflicts of interest related to this work.