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Stimulation of the M4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M4 PAM radiotracer, [11C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [11C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [11C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials. [ABSTRACT FROM AUTHOR]

Background: 4-Aminopyridine (4AP) is a medication for the symptomatic treatment of multiple sclerosis. Several 4AP-based PET tracers have been developed for imaging demyelination. In preclinical studies, [11C]3MeO4AP has shown promise due to its high brain permeability, high metabolic stability, high plasma availability, and high in vivo binding affinity. To prepare for the translation to human studies, we developed a cGMP-compatible automated radiosynthesis protocol and evaluated the whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP in non-human primates (NHPs). Methods: Automated radiosynthesis was carried out using a GE TRACERlab FX-C Pro synthesis module. One male and one female adult rhesus macaques were used in the study. A high-resolution CT from cranial vertex to knee was acquired. PET data were collected using a dynamic acquisition protocol with four bed positions and 13 passes over a total scan time of ~ 150 min. Based on the CT and PET images, volumes of interest (VOIs) were manually drawn for selected organs. Non-decay corrected time-activity curves (TACs) were extracted for each VOI. Radiation dosimetry and effective dose were calculated from the integrated TACs using OLINDA software. Results: Fully automated radiosynthesis of [11C]3MeO4AP was achieved with 7.3 ± 1.2% (n = 4) of non-decay corrected radiochemical yield within 38 min of synthesis and purification time. [11C]3MeO4AP distributed quickly throughout the body and into the brain. The organs with highest dose were the kidneys. The average effective dose of [11C]3MeO4AP was 4.0 ± 0.6 μSv/MBq. No significant changes in vital signs were observed during the scan. Conclusion: A cGMP-compatible automated radiosynthesis of [11C]3MeO4AP was developed. The whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP was successfully evaluated in NHPs. [11C]3MeO4AP shows lower average effective dose than [18F]3F4AP and similar average effective dose as other carbon-11 tracers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

American-style football (ASF) players experience repetitive head impacts that may result in chronic traumatic encephalopathy neuropathological change (CTE-NC). At present, a definitive diagnosis of CTE-NC requires the identification of localized hyperphosphorylated Tau (p-Tau) after death via immunohistochemistry. Some studies suggest that positron emission tomography (PET) with the radiotracer [18F]-Flortaucipir (FTP) may be capable of detecting p-Tau and thus establishing a diagnosis of CTE-NC among living former ASF players. To assess associations between FTP, football exposure, and objective neuropsychological measures among former professional ASF players, we conducted a study that compared former professional ASF players with age-matched male control participants without repetitive head impact exposure. Former ASF players and male controls underwent structural magnetic resonance imaging and PET using FTP for p-Tau and [11C]-PiB for amyloid-β. Former players underwent neuropsychological testing. The ASF exposure was quantified as age at first exposure, professional career duration, concussion signs and symptoms burden, and total years of any football play. Neuropsychological testing included measures of memory, executive functioning, and depression symptom severity. P-Tau was quantified as FTP standardized uptake value ratios (SUVR) and [11C]-PiB by distribution volume ratios (DVR) using cerebellar grey matter as the reference region. There were no significant differences in [18F]-FTP uptake among former ASF players (n = 27, age = 50 ± 7 years) compared with control participants (n = 11, age = 55 ± 4 years), nor did any participant have significant amyloid-β burden. Among ASF participants, there were no associations between objective measures of neurocognitive functioning and [18F]-FTP uptake. There was a marginally significant difference, however, between [18F]-FTP uptake isolated to the entorhinal cortex among players in age-, position-, and race-adjusted models (p = 0.05) that may represent an area of future investigation. The absence of increased [18F]-FTP uptake in brain regions previously implicated in CTE among former professional ASF players compared with controls questions the utility of [18F]-FTP PET for clinical evaluation in this population. [ABSTRACT FROM AUTHOR]

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [ 18 F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [ 18 F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [ 18 F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [ 18 F]3F4AP for the focal brain injury was higher than [ 18 F]FDG, [ 11 C]PiB, and [ 11 C]PBR28, and compared favorably to currently used MRI methods. [ABSTRACT FROM AUTHOR]

Background: Cromolyn is an anti-neuroinflammatory modulator with a multifactorial mechanism of action that has been shown to inhibit amyloid-β (Aβ) aggregation and enhance microglial uptake and clearance of Aβ.Objective: We report the effects of fluoro-cromolyn derivatives on microglial cell toxicity and microglial clearance of Aβ42.Methods: Microglial cell toxicity for cromolyn derivatives were determined in naive BV2 microglial cells. Microglial clearance assays were performed with Aβ42 in naive BV2 microglial cell line and single cell clone BV2 line expressing CD33WT. PET imaging was performed for three F-18 analogs in a rhesus macaque.Results: All compounds but derivative 8 exhibited low microglial cell toxicity. Cromolyn 1 and derivatives 2, 4, and 7 displayed an increased uptake on Aβ42 in naïve BV2 microglial cells. Derivative 4 increased Aβ42 uptake in a dose-dependent manner and at 75μM resulted in a one-fold increase in Aβ42 uptake in BV2-CD33WT. PET imaging for three [18F]cromolyn analogs revealed the order of brain tracer penetration to be 4a > 10 > 2a. Tracer 4a exhibited enhanced uptake in areas of high perfusion (putamen, grey matter, and cerebellum) and lower signal in areas of lower perfusion (caudate, thalamus, and white matter).Conclusion: Substantial uptake of Aβ42 in both naïve BV2 and BV2-CD33WT cells observed with 4 indicate conversion of microglial cells from a pro-inflammatory to an activation state favoring Aβ phagocytosis/clearance. These findings suggest that a fluoro-cromolyn analog could reduce fibril-prone Aβ42in vivo and thereby serve as a therapeutic for the treatment and prevention of AD. [ABSTRACT FROM AUTHOR]

Purpose: [18F]MK6240 was developed for PET imaging of tau aggregates, which are implicated in Alzheimer's disease. The goal of this work was to evaluate the kinetics of [18F]MK6240 and to investigate different strategies for in-vivo quantification of tau aggregates in humans. Methods: Thirty-five subjects, consisting of 18 healthy controls (CTRL), 11 subjects with mild cognitive impairment (MCI) and six with Alzheimer's Disease (AD), underwent dynamic [18F]MK6240 PET scans. Arterial blood measurements were collected in 16 subjects (eight CTRLs, six MCIs and two AD) to measure whole blood and plasma concentration time courses. Radiometabolite analysis was performed on a subset of plasma samples. Various compartmental model configurations as well as the Logan and multilinear analysis (MA1) graphical methods with arterial plasma input function were tested. Simplified reference tissue methods were investigated, including Logan distribution volume ratio (DVR), multilinear reference tissue method (MRTM2), and static SUV ratio using the cerebellum as a reference region. Results: Whole blood:plasma ratio stabilized to 0.66 ± 0.01 after 15 min. Percent parent in plasma (%PP) followed a single exponential and ranged from 0 to 10% at 90 min. [18F]MK6240 in gray matter peaked quickly (SUV > 2 at ~3 min). The preferred compartmental model was a reversible two-tissue compartment model, with the blood contribution included as a model parameter (2T4k1v). Compartmental and graphical analysis methods with arterial input functions yielded concordant results, but rapid metabolism raised challenges for blood-based quantification. MCI and AD subjects demonstrated a broad range of VT as compared to CTRL subjects. DVR from MRTM2 and Logan reference tissue methods correlated with DVR calculated indirectly from compartmental modeling, but underestimation was observed in data sets with very high binding (DVR > 3). SUVR also underestimated indirect DVR from blood-based analyses in high binding regions, although a non-linear relationship was exhibited. Conclusions: [18F]MK6240 exhibited a wide dynamic range of uptake, with binding patterns in MCI/AD subjects consistent with neurofibrillary tau deposition patterns. Linearized reference tissue methods using an estimated average tissue-to-plasma efflux constant k ′ 2 ¯ and static SUVR agreed well with blood-based methods for most data sets; however, discrepancies were noted in the highest binding cases. Caution should therefore be exercised in application of simplified methods to such data sets, and in quantitative interpretation of corresponding outcomes. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Evaluation of pharmacokinetic modeling strategies for in‑vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects" which appeared on 5 January 2023.

Introduction: Chronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE. Objective: To study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples. Methods: We performed [18F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains. Results: Despite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD. Conclusion: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies. [ABSTRACT FROM AUTHOR]

6-(fluoro- 18 F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ 18 F]MK6240) has high affinity and selectivity for hyperphosphorylated tau and readily crosses the blood-brain barrier. This study investigated whether the early phase of [ 18 F]MK6240 can be used to provide a surrogate index of cerebral perfusion. Methods: Forty-nine subjects who were cognitively normal (CN), had mild cognitive impairment (MCI), or had Alzheimer's disease (AD) underwent paired dynamic [ 18 F]MK6240 and [ 11 C]Pittsburgh compound B (PiB) PET, as well as structural MRI to obtain anatomic information. Arterial blood samples were collected in a subset of 24 subjects for [ 18 F]MK6240 scans to derive metabolite-corrected arterial input functions. Regional time-activity curves were extracted using atlases available in the Montreal Neurologic Institute template space and using FreeSurfer. The early phase of brain time-activity curves was analyzed using a 1-tissue-compartment model to obtain a robust estimate of the rate of transfer from plasma to brain tissue, K 1 (mL⋅cm -3 ⋅min -1 ), and the simplified reference tissue model 2 was investigated for noninvasive estimation of the relative delivery rate, R 1 (unitless). A head-to-head comparison with R 1 derived from [ 11 C]PiB scans was performed. Grouped differences in R 1 were evaluated among CN, MCI, and AD subjects. Results: Regional K 1 values suggested a relatively high extraction fraction. R 1 estimated noninvasively from simplified reference tissue model 2 agreed well with R 1 calculated indirectly from the blood-based compartment modeling ( r = 0.99; mean difference, 0.024 ± 0.027), suggesting that robust estimates were obtained. R 1 measurements obtained with [ 18 F]MK6240 correlated strongly and overall agreed well with those obtained from [ 11 C]PiB ( r = 0.93; mean difference, -0.001 ± 0.068). Statistically significant differences were observed in regional R 1 measurements among CN, MCI, and AD subjects, notably in the temporal and parietal cortices. Conclusion: Our results provide evidence that the early phase of [ 18 F]MK6240 images may be used to derive a useful index of cerebral perfusion. The early and late phases of a [ 18 F]MK6240 dynamic acquisition may thus offer complementary information about the pathophysiologic mechanisms of the disease., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels K v 1.1 and K v 1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe a novel tracer for K v 1 channels, [ 11 C]3-methyl-4-aminopyridine ([ 11 C]3Me4AP). [ 11 C]3Me4AP was efficiently synthesized via Pd(0)-Cu(I) comediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [ 11 C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a one-tissue compartment model can accurately model the regional brain time-activity curves. Compared to the related tracers [ 18 F]3-fluoro-4-aminopyridine ([ 18 F]3F4AP) and [ 11 C]3-methoxy-4-aminopyridine ([ 11 C]3MeO4AP), [ 11 C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood-brain barrier and slower kinetics, suggesting higher binding affinity consistent with in vitro studies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic.

An array of triazolopyridines based on JNJ-46356479 ( 6 ) were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates 8-10 featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound 6 in the cAMP GloSensor assays. Radiolabeling of compounds 8 and 9 (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/μmol; and excellent radiochemical purity, >98%. Preliminary characterization of [ 18 F] 8 and [ 18 F] 9 in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [ 18 F] 9 in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [ 18 F] 6 . Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [ 18 F] 9 . As a selective ligand, [ 18 F] 9 has the potential to be developed for translational studies.

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[ 11 C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2 H -pyrano[2,3- b ]pyridine-7-carboxamide ([ 11 C] 13 , [ 11 C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [ 11 C] 13 was synthesized via the O -[ 11 C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol ( n = 5) and excellent radiochemical purity (>99%). PET imaging of [ 11 C] 13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 ( 9 ) and MNI-137 ( 26 ), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [ 11 C] 13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [ 11 C] 13 is a potential candidate for translational PET imaging of the mGluR2 function.

Background: Alzheimer's disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models., Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS)., Methods: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment., Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28., Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

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 K v 1.1 and K v 1.2. Carbon-11 labeled radiotracers present the advantage of allowing for multiple scans on the same subject in the same day. Here, we describe [ 11 C]3MeO4AP, a novel 11 C-labeled version of the K + channel tracer [ 18 F]3F4AP, and characterize its imaging properties in two non-human primates including a monkey with a focal brain injury sustained during a surgical procedure 3 years prior to imaging. Our findings show that [ 11 C]3MeO4AP is brain permeable, metabolically stable and has high plasma availability. When compared with [ 18 F]3F4AP, [ 11 C]3MeO4AP shows very high correlation in volumes of distribution ( V T ), confirming a common target. [ 11 C]3MeO4AP shows slower washout than [ 18 F]3F4AP, suggesting stronger binding. Finally, similar to [ 18 F]3F4AP, [ 11 C]3MeO4AP is highly sensitive to the focal brain injury. All these features make it a promising radioligand for imaging demyelinated lesions.