[F]SynVest-1 PET imaging in people with Parkinson's disease.

The [F]SynVest-1 radiotracer targets the synaptic vesicle glycoprotein 2A (SV2A) and is a proxy of presynaptic density. Parkinson's disease is associated with synaptic dysfunction. Here we investigated synaptic density via the [F]SynVest-1 radiotracer in people with PD compared with healthy controls, with reference to how it compares to the previous SV2A radiotracer, [11C]UCB-J.

First-in-human PET neuroimaging of [F]OXD-2314.

Purpose: This first-in-human positron emission tomography (PET) study evaluates [F]OXD-2314, a radiopharmaceutical designed for imaging tau in non-Alzheimer's disease tauopathies.

Methods: Synthesis of [F]OXD-2314 was automated using a commercial module and validated for human use. Dynamic PET imaging was performed in healthy control subjects (2 female, 2 male, ages 49-65 years).

Fatty acid amide hydrolase in major depressive episodes: A [C]CURB positron emission tomography study.

The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [C]CURB λk, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [C]CURB positron emission tomography and FAAH genotyping.

Synthesis, Radiosynthesis, in Vitro and in Vivo Evaluation of the GABA-Benzodiazepine Receptor Agonist [C]RO6899880.

The aim of this study is to synthesize and evaluate the GABA-benzodiazepine receptor agonist radiotracer ()-10-chloro-1-(3-(methoxy-C)pyrrolidine-1-carbonyl)-3-phenyl-6,7-dihydro-4-pyrido[2,1-]isoquinolin-4-one ([C]RO6899880) using and experiments to determine its suitability for human positron emission tomography (PET) neuroimaging studies. RO6899880 and its desmethyl precursor were synthesized over multiple steps in 3% and 2% yields, respectively. Reaction of the precursor with [C]CHI in DMF with NaOH at 23 °C for 5 min followed by HPLC purification and formulation produced [C]RO6899880 with a radiochemical yield of 4.

In Vivo Visualization and Quantification of Brain Heat Shock Protein 90 with [C]HSP990 in Healthy Aging and Neurodegeneration.

Heat shock protein 90 (Hsp90) is essential for maintaining cellular proteostasis and may play an important role in the development of neurodegenerative proteinopathies. Therefore, we aimed to develop an Hsp90-specific PET brain tracer to quantify Hsp90 expression in the brain in vivo in order to explore its potential as a biomarker for neurodegenerative disease characterization and to support Hsp90-targeted drug development. We developed the radiosynthesis of ()-2-amino-7-(4-fluoro-2-(6-(methoxy-C)pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-]pyrimidin-5(6)-one, [C]HSP990, and validated the tracer using in vitro autoradiography, in vitro brain homogenate saturation binding, ex vivo biodistribution, and in vivo PET imaging in rodent models of Alzheimer disease (AD) and Parkinson disease versus healthy age-matched and young controls.

Fatty acid amide hydrolase in comorbid borderline personality disorder and major depressive disorder: Imaging with [C]CURB PET.

Borderline personality disorder (BPD) is highly comorbid with major depressive disorder (MDD), and the comorbid condition is associated with poorer treatment outcomes, which necessitates the investigation of transdiagnostic biomarkers. Previous research suggests that fatty acid amide hydrolase (FAAH), an endocannabinoid enzyme, is elevated in the prefrontal cortex (PFC) in BPD; however, no study has examined FAAH density in individuals with comorbid conditions. We hypothesized that FAAH level would be elevated in the prefrontal cortex, anterior cingulate cortex and hippocampus of comorbid BPD + MDD compared to healthy controls, as these brain regions are linked to the pathobiology of both disorders.

Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [F]FMPEP- and [F]MAGL-2102.

The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging.

Radiosynthesis, Characterization, and PET Neuroimaging of [F]F-4 for Tau Protein: A First-in-Human PET Study.

[F]PI-2620 is a promising radiopharmaceutical for positron emission tomography (PET) imaging of both Alzheimer's disease (AD) and non-Alzheimer's disease (non-AD) tauopathies in humans. An array of fluorinated derivatives of the carbazole scaffold of PI-2620 were synthesized and evaluated. binding assays with [H]PI-2620 in human tissues with AD, progressive supranuclear palsy, and corticobasal degeneration, combined with predictions of blood-brain barrier permeability, led to the selection and radiosynthesis of [F]F-4 as a promising radiotracer.

Ionic Liquid Aided [C]CO Fixation for Synthesis of C-carbonyls.

Tributyl(ethyl)phosphonium oxopentenolate ([P][Pen]) is an ionic liquid developed to capture CO and has shown ability to catalyze carbonylation reactions in organic chemistry. Carbon-11 (C, t=20.4 min) labeled CO is a highly versatile building block for the synthesis of positron emission tomography (PET) radiotracers that are applied for medical imaging.

Cigarette smoking is associated with reduced neuroinflammation and better cognitive control in people living with HIV.

People living with HIV (HIV+) are roughly twice as likely to smoke cigarettes (Smok+) as the general population. With the advent of effective antiretroviral therapies, it is increasingly important to understand the effects of chronic HIV infection and cigarette smoking on brain function and cognition since HIV+ individuals have heightened neuroinflammation and cognitive deficits even with such therapies. Based on prior studies demonstrating that smoking reduces a marker for neuroinflammation in HIV- individuals, we hypothesized that HIV+/Smok+ individuals would have less neuroinflammation and better cognitive control than HIV+/Smok- individuals.

PET in neurotherapeutic discovery and development.

Positron emission tomography (PET) is a highly sensitive, quantitative imaging technique that can track sub-nanomolar quantities of positron-emitting radionuclides throughout the body. By incorporating such radionuclides into molecules of interest, we can directly assess their pharmacokinetic and pharmacodynamic (PK/PD) characteristics in vivo without changing their physicochemical characteristics or eliciting a pharmacological response. As such, PET imaging has long been used as a tool to aid drug discovery programs from preclinical biomarker validation all the way through to clinical trials.

Emerging targets for positron emission tomography imaging in proteinopathies.

Positron emission tomography (PET) imaging of neurodegenerative disease has historically focused on a small number of established targets. The development of selective PET radiotracers for novel biological targets enables new ways to interrogate the neuropathology of proteinopathies and will advance our understanding of neurodegeneration. This perspective aims to highlight recent PET radiotracers developed for five emerging targets in proteinopathies (i.

18F-Flortaucipir (AV1451) imaging identifies grey matter atrophy in retired athletes.

Background: The long-term consequences of concussions may include pathological neurodegeneration as seen in Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Tau-PET showed promise as a method to detect tau pathology of CTE, but more studies are needed OBJECTIVE: This study aimed (1) to assess the association of imaging evidence of tau pathology with brain volumes in retired athletes and (2) to examine the relationship between tau-PET and neuropsychological functioning.

Methods: Former contact sport athletes were recruited through the Canadian Football League Alumni Association or the Canadian Concussion Centre clinic.

Ligand-based design of [F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [F]OXD-2115, using ligand-based design.

In vitro evaluation of PET radiotracers for imaging synaptic density, the acetylcholine transporter, AMPA-tarp-γ8 and muscarinic M4 receptors in Alzheimer's disease.

Several therapeutics and biomarkers that target Alzheimer's disease (AD) are under development. Our clinical positron emission tomography (PET) research programs are interested in six radiopharmaceuticals to image patients with AD and related dementias, specifically [C]UCB-J and [F]SynVesT-1 for synaptic vesicle glycoprotein 2A as a marker of synaptic density, two vesicular acetylcholine transporter PET radiotracers: [F]FEOBV and [F]VAT, as well as the transmembrane AMPA receptor regulatory protein (TARP)-γ8 tracer, [F]JNJ-64511070, and the muscarinic acetylcholine receptor (mAChR) M4 tracer [C]MK-6884. The goal of this study was to compare all six radiotracers (labeled with tritium or F) by measuring their density variability in pathologically diagnosed cases of AD, mild cognitive impairment (MCI) and normal healthy volunteer (NHV) human brains, using thin-section autoradiography (ARG).

In vitro evaluation of [H]PI-2620 and structural derivatives in non-Alzheimer's tauopathies.

Alzheimer's disease (AD) and non-AD tauopathies such as chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are characterized by the abnormal aggregation of three-repeat (3R) and/or four-repeat (4R) tau isoforms. Several tau-PET tracers have been applied for human imaging of AD and non-AD tauopathies including [F]PI-2620. Our objective is to evaluate [H]PI-2620 and two promising structural derivatives, [H]PI-2014 and [H]F-4, using in vitro saturation assays and competitive binding assays against new chemical entities based on this scaffold in human AD tissues for comparison with PSP, CBD and CTE tissues.

Development of Pyridothiophene Compounds for PET Imaging of α-Synuclein.

Aggregated α-synuclein (α-syn) protein is a pathological hallmark of Parkinson's disease (PD) and Lewy body dementia (LBD). Development of positron emission tomography (PET) radiotracers to image α-syn aggregates has been a longstanding goal. This work explores the suitability of a pyridothiophene scaffold for α-syn PET radiotracers, where 47 derivatives of a potent pyridothiophene (asyn-44; K=1.

C-Fixation Techniques.

This protocol describes the application of cyclotron-generated [C]CO fixation reactions for direct C-carboxylation reactions and [C]CO for C-carbonylations. Herein we describe one-pot methods wherein the radioactive gas is first trapped in a reaction mixture at room temperature and atmospheric pressure prior to the radiolabeling reactions. Such procedures are widely applicable to numerous small molecules to form C-labeled carboxylic acids, amides, esters, ketones, oxazolidinones, carbamates, and ureas.

First-in-Human PET Imaging of [F]SDM-4MP3: A Cautionary Tale.

[F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols.

Preliminary PET imaging of [C]evobrutinib in mouse models of colorectal cancer, SARS-CoV-2, and lung damage: Radiosynthesis via base-aided palladium-NiXantphos-mediated C-carbonylation.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [C]evobrutinib using a base-aided palladium-NiXantphos-mediated C-carbonylation reaction.

Preliminary Assessment of Reference Region Quantification and Reduced Scanning Times for [F]SynVesT-1 PET in Parkinson's Disease.

Synaptic density in the central nervous system can be measured using PET with [F]SynVesT-1. While [F]SynVesT-1 has been proven to be a powerful radiopharmaceutical for PET imaging of neurodegenerative disorders such as Parkinson's disease (PD), its currently validated acquisition and quantification protocols are invasive and technically challenging in these populations due to the arterial sampling and relatively long scanning times. The objectives of this work were to evaluate a noninvasive (reference tissue) quantification method for [F]SynVesT-1 in PD patients and to determine the minimum scan time necessary for accurate quantification.

Astrogliosis marker 11C-SL25.1188 PET in traumatic brain injury with persistent symptoms.

Traumatic brain injury (TBI) is common but little is known why up to a third of patients have persisting symptoms. Astrogliosis, a pathophysiological response to brain injury, may be a potential therapeutic target, but demonstration of astrogliosis in the brain of humans with TBI and persistent symptoms is lacking. Astroglial marker monoamine oxidase B (MAO-B) total distribution volume (11C-SL25.