Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

Background: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), F-9-fluoropropyldihydrotetrabenazine (F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP).

Objective: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP.

F-FP-DTBZ PET/CT detectable associations between monoaminergic depletion in the putamen with rigidity and the pallidus with tremor in Parkinson's disease.

Introduction: The motor subtypes of Parkinson's disease (PD) are widely accepted and implemented. However, the motor subtypes have been thought to represent different stages of PD recently because some patients experience tremor-dominant (TD) conversion to the non-tremor-dominant subtype, such as postural instability-gait difficulty (PIGD). In this study, we explore the monoaminergic denervation features of the striatal and extra-striatal areas in patients with different subtypes of PD with F-9-fluoropropyl-(+)-dihydrotetrabenazine (F-FP-DTBZ) PET/CT.

Corrigendum: Diagnostic value of striatal F-FP-DTBZ PET in Parkinson's disease.

[This corrects the article DOI: 10.3389/fnagi.2022.

Brain microglia activation and peripheral adaptive immunity in Parkinson's disease: a multimodal PET study.

Background: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear.

Objectives: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity.

Methods: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease.

Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H).

Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a cytochrome P450 family enzyme that maintains the homeostasis of brain cholesterol. Soticlestat, a potent and selective CH24H inhibitor, is in development as a therapeutic agent for Dravet syndrome and Lennox-Gastaut syndrome. Herein, we report the discovery of aryl-piperidine derivatives as potent and selective CH24H positron emission tomography (PET) tracers which can be used for dose guidance of a clinical CH24H inhibitor and as a diagnostic tool for CH24H-related pathology.

Evaluation of ()-, ()-, and ()-F-OF-NB1 for Imaging GluN2B Subunit-Containing -Methyl-d-Aspartate Receptors in Nonhuman Primates.

Despite 2 decades of research, no -methyl-d-aspartate (NMDA) glutamate receptor (GluN) subtype 2B (GluN1/2B) radioligand is yet clinically validated. Previously, we reported on ()-F-OF-NB1 as a promising GluN1/2B PET probe in rodents and its successful application for the visualization of GluN2B-containing NMDA receptors in postmortem brain tissues of patients with amyotrophic lateral sclerosis. In the current work, we report on the characterization of ()-, ()-, and ()-F-OF-NB1 in nonhuman primates.

Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: -[C]NR2B-Me, -[F]of-Me-NB1, and -[F]of-NB1.

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: -[C]NR2B-Me, -[F]OF-Me-NB1, and -[F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques.

Characterization in nonhuman primates of (R)-[F]OF-Me-NB1 and (S)-[F]OF-Me-NB1 for imaging the GluN2B subunits of the NMDA receptor.

Purpose: GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[F]OF-Me-NB1 was reported to be more specific and selective than (S)-[F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[F]OF-Me-NB1 and (S)-[F]OF-Me-NB1 in nonhuman primates.

Preclinical characterization of [F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase.

Purpose: Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24S-hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) is being pursued as a drug for treatment of seizures in developmental and epileptic encephalopathies. Herein, we describe the successful discovery and the preclinical validation of the novel radiolabeled CH24H ligand (3-[F]fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone ([F]T-008) and its tritiated analog, [H]T-008.

Design, Synthesis, and Evaluation of [F]T-914 as a Novel Positron-Emission Tomography Tracer for Lysine-Specific Demethylase 1.

Histone methylation is associated with the pathophysiology of neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) catalyzes histone demethylation in a flavin adenine dinucleotide (FAD)-dependent manner. Thus, inhibiting LSD1 enzyme activity could offer a novel way to treat neurodevelopmental disorders.

Design, Synthesis, and Evaluation of (2-Aminocyclopropyl)phenyl Derivatives as Novel Positron Emission Tomography Imaging Agents for Lysine-Specific Demethylase 1 in the Brain.

Dysregulation of histone H3 lysine 4 (H3K4) methylation is implicated in the pathogenesis of neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) determines the methylation status of H3K4 through flavin adenine dinucleotide (FAD)-mediated histone demethylation. Therefore, LSD1 inhibition in the brain can be a novel therapeutic option for treating these disorders.

Dopamine D Receptor Agonist PET Tracer Development: Assessment in Nonhuman Primates.

Non-catechol-based high-affinity selective dopamine D receptor (D1R) agonists were recently described, and candidate PET ligands were selected on the basis of favorable properties. The objective of this study was to characterize in vivo in nonhuman primates 2 novel D1R agonist PET radiotracers, racemic F-MNI-800 and its more active atropisomeric (-)-enantiomer, F-MNI-968. Ten brain PET experiments were conducted with F-MNI-800 on 2 adult rhesus macaques and 2 adult cynomolgus macaques, and 8 brain PET experiments were conducted with F-MNI-968 on 2 adult rhesus macaques and 2 adult cynomolgus macaques.

Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use.

The advent of preclinical research scanners for imaging of small animals has added confidence into the multi-step decision-making process of radiotracer discovery and development. Furthermore, it has expanded the utility of imaging techniques available to dissect clinical questions, fostering a cyclic interaction between the clinical and the preclinical worlds. Significant efforts from medicinal chemistry have also made available several high-affinity and selective compounds amenable for radiolabeling, that target different receptors, transporters and enzymes .

Evaluation of Dosimetry, Quantitative Methods, and Test-Retest Variability of F-PI-2620 PET for the Assessment of Tau Deposits in the Human Brain.

F-PI-2620 is a next-generation tau PET tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry, and quantitative methods of F-PI-2620 in the human brain. Full kinetic modeling to quantify tau load was investigated.

Tau PET imaging with F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study.

F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this first-in-humans study was to evaluate the ability of F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess the safety and tolerability of this new tau PET tracer.

Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes.

Several studies have demonstrated that intrastriatal injections of fibrillar α-synuclein in rodent brain induced a Parkinson's disease-like propagation of Lewy body pathology with significant nigrostriatal neurodegeneration. This study evaluated the pathological features when exogenous α-synuclein preformed fibrils were injected into the putamen of non-human primates. Eight cynomolgus monkeys received unilateral intraputamen injections of α-synuclein preformed fibrils and four monkeys received sham surgery.

Discovery and preclinical characterization of [F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer's disease and other tauopathies.

Purpose: Tau deposition is a key pathological feature of Alzheimer's disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aβ) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies.

[F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer's disease.

Objective: Neurofibrillary tangles (NFTs), consisting of intracellular aggregates of the tau protein, are a pathological hallmark of Alzheimer's disease (AD). Here we report the identification and initial characterization of Genentech Tau Probe 1 ([F]GTP1), a small-molecule PET probe for imaging tau pathology in AD patients.

Methods: Autoradiography using human brain tissues from AD donors and protein binding panels were used to determine [F]GTP1 binding characteristics.

Imaging histamine H3 receptors with [ F]FMH3: Test-retest and occupancy studies in the non-human primate.

A positron emission tomography (PET) radioligand, [ F]FMH3, has been developed to interrogate histamine receptor subtype 3 (H3R), where dysfunction at this site is linked with obesity, sleep abnormality, and cognitive disorders. [ F]FMH3 was evaluated for imaging central H3R sites in non-human primates through test-retest (TRT) and dose-receptor occupancy studies with two selective H3R antagonists in order to support clinical investigations. Two adult female baboons underwent [ F]FMH3 PET brain scans in the HR+, at repeated baseline (n = 7) and following administration of escalating doses of ABT-239 (0.

Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of F-JNJ-64413739, a PET Radioligand for P2X7 Receptors.

The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in the brain, and antagonism of the P2X7 receptor is a novel therapeutic strategy to dampen adenosine triphosphate-dependent IL-1β signaling. PET ligands for the P2X7 receptor will not only be valuable to assess central target engagement of drug candidates but also hold promise as surrogate markers of central neuroinflammation.

Evaluation of [ F]2FP3 in pigs and non-human primates.

So far, no suitable 5-HT R radioligand exists for clinical positron emission tomography (PET) imaging. [ F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non-human primates (NHPs).

F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT receptor agonist for PET neuroimaging.

Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerative disorders. Currently, all available 5-HT receptor PET radiopharmaceuticals that are radiolabeled with fluorine-18 are antagonists. As agonists bind preferentially to the high-affinity state of receptors, it would be of great interest to develop agonist radioligands which could provide a measure of the functional 5-HT receptors in pathophysiological processes.

Comparison between [F]fluorination and [F]fluoroethylation reactions for the synthesis of the PDE10A PET radiotracer [F]MNI-659.

Introduction: 2-(2-(3-(4-(2-[F]Fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([F]MNI-659, [F]1) is a useful PET radiotracer for imaging phosphodiesterase 10A (PDE10A) in human brain. [F]1 has been previously prepared by direct [F]fluorination of a tosylate precursor 2 with [F]F. The aim of this study was to determine the conditions for the [F]fluorination reaction to obtain [F]1 of high quality and with sufficient radioactivity for clinical use in our institute.