Imaging the 5-HT receptor with PET: Evaluation of 5-HT and 5-HT affinity of pimavanserin in the primate brain.

Two complimentary techniques were used to estimate occupancy of pimavanserin (a selective 5-HT inverse agonist) to 5-HT and 5-HT receptors in non-human primate brains. One employed the 5-HT selective radioligand [C]CIMBI-36 combined with quantification of binding potentials in brain regions known to be enriched in 5-HT (cortex) or 5-HT (choroid plexus) receptors to estimate occupancy. Pimavanserin was 6-10 fold more potent displacing [C]CIMBI-36 from cortex (ED = 0.

Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

The metabotropic glutamate receptor 2 (mGluR) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity ( mGluR = 1.

Labeling of Bruton's Tyrosine Kinase (BTK) Inhibitor [C]BIO-2008846 in Three Different Positions and Measurement in NHP Using PET.

Bruton's tyrosine kinase (BTK) is pivotal in B-cell signaling and a target for potential anti-cancer and immunological disorder therapies. Improved selective reversible BTK inhibitors are in demand due to the absence of direct BTK engagement measurement tools. Promisingly, PET imaging can non-invasively evaluate BTK expression.

Exploring the Interactions between two Ligands, UCB-J and UCB-F, and Synaptic Vesicle Glycoprotein 2 Isoforms.

modeling was applied to study the efficiency of two ligands, namely, and , to bind to isoforms of the synaptic vesicle glycoprotein 2 (SV2) that are involved in the regulation of synaptic function in the nerve terminals, with the ultimate goal to understand the selectivity of the interaction between and to different isoforms of SV2. Docking and large-scale molecular dynamics simulations were carried out to unravel various binding patterns, types of interactions, and binding free energies, covering hydrogen bonding and nonspecific hydrophobic interactions, water bridge, π-π, and cation-π interactions. The overall preference for bonding types of and with particular residues in the protein pockets can be disclosed in detail.

High Contrast PET Imaging of Subcortical and Allocortical Amyloid-β in Early Alzheimer's Disease Using [11C]AZD2184.

Background: Deposits of amyloid-β (Aβ) appear early in Alzheimer's disease (AD).

Objective: The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET).

Methods: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184.

Advancements in Microfluidic Cassette-Based iMiDEV™ Technology for Production of L-[C]Methionine and [C]Choline.

Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[C]methionine and [C]choline, was performed, using a microfluidic cassette and an iMiDEV module by employing a dose-on-demand approach for the synthesis process.

Synthesis of [C]BIIB104, an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Positive Allosteric Modulator, and Evaluation of the Bio-Distribution in Non-Human Primate Brains Using Positron Emission Tomography.

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans.

Validation of a good manufacturing practice procedure for the production of [C]AZD4747, a CNS penetrant KRAS inhibitor.

AZD4747 is a KRAS inhibitor recently shown to cross the non-human primate blood-brain barrier efficiently. In the current study, a GMP-compliant production of [C]AZD4747 was developed to enable PET studies in human subjects. The validated procedure afforded [C]AZD4747 as an injectable solution in good radioactivity yield (1656 ± 532 MBq), excellent radiochemical purity (100%), and a molar activity of 77 ± 13 GBq/μmol at the end of the synthesis, which took 46 ± 1 min from the end of the bombardment.

Microfluidic-based production of [Ga]Ga-FAPI-46 and [Ga]Ga-DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer.

Background: The demand for Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([Ga]Ga-FAPI-46) in late-phase studies, whereas [Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models.

Development of a PET Tracer for OGA with Improved Kinetics in the Living Brain.

-GlcNAcylation is thought to play a role in the development of tau pathology in Alzheimer's disease because of its ability to modulate tau's aggregation propensity. -GlcNAcylation is regulated by 2 enzymes: -GlcNAc transferase and -GlcNAcase (OGA). Development of a PET tracer would therefore be an essential tool for developing therapeutic small-molecule inhibitors of OGA, enabling clinical testing of target engagement and dose selection.

The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases.

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson's disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls.

Microsome Mediated in Vitro Metabolism: A Convenient Method for the Preparation of the PET Radioligand Metabolite [F]FE-PE2I-OH for Translational Dopamine Transporter Imaging.

Undesired radiometabolites can be detrimental to the development of positron emission tomography (PET) radioligands. Methods for quantifying radioligand metabolites in brain tissue include ex vivo studies in small animals or labeling and imaging of the radiometabolite(s) of interest. The latter is a time- and resource-demanding process, which often includes multistep organic synthesis.

PET Evaluation of the Novel F-18 Labeled Reversible Radioligand [F]GEH200449 for Detection of Monoamine Oxidase-B in the Non-Human Primate Brain.

Positron emission tomography (PET) using radioligands for the enzyme monoamine oxidase B (MAO-B) is increasingly applied as a marker for astrogliosis in neurodegenerative disorders. In the present study, a novel reversible fluorine-18 labeled MAO-B compound, [F]GEH200449, was evaluated as a PET radioligand in non-human primates. PET studies of [F]GEH200449 at baseline showed brain exposure (maximum concentration: 3.

Development of a Novel [C]CO-Labeled Positron Emission Tomography Radioligand [C]BIO-1819578 for the Detection of -GlcNAcase Enzyme Activity.

Imaging -GlcNAcase OGA by positron emission tomography (PET) could provide information on the pathophysiological pathway of neurodegenerative diseases and important information on drug-target engagement and be helpful in dose selection of therapeutic drugs. Our aim was to develop an efficient synthetic method for labeling BIO-1819578 with carbon-11 using CO for evaluation of its potential to measure levels of OGA enzyme in non-human primate (NHP) brain using PET. Radiolabeling was achieved in one-pot via a carbon-11 carbonylation reaction using [C]CO.

Characterization of a Novel M4 PAM PET Radioligand [11C]PF06885190 in Nonhuman Primates (NHP).

Muscarinic acetylcholine receptors (mAChR), including M4, draw attention as therapeutic targets for several neurodegenerative diseases including Alzheimer's disease (AD). PET imaging of M4 positive allosteric modulator (PAM) allows qualification of the distribution as well as the expression of this receptor under physiological conditions and thereby helps to assess the receptor occupancy (RO) of a drug candidate. In this study, our aims were (a) to synthesize a novel M4 PAM PET radioligand [11C]PF06885190 (b) to evaluate the brain distribution of [C]PF06885190 in nonhuman primates (NHP) and (c) to analyze its radiometabolites in the blood plasma of NHP.

Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial.

Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD).

Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity.

Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters.

[F]FE-PE2I DAT correlates with Parkinson's disease duration, stage, and rigidity/bradykinesia scores: a PET radioligand validation study.

Background: Correlations between dopamine transporter (DAT) availability and Parkinson's disease (PD) motor symptoms vary depending on the imaging modality, choice of regions of interest and clinical measures. We aimed to validate the PET radioligand [F]FE-PE2I as a clinical biomarker in PD, hypothesizing negative correlations between DAT availability in specified nigrostriatal regions with symptom duration, disease stage and motor symptom scores.

Methods: We included 41 PD patients (age 45-79 years; H&Y stage < 3) and 37 healthy control subjects in a cross-sectional study with dynamic [F]FE-PE2I PET.

Occupational Safety and Health of Women in Mining.

The mining industry plays a critical role in the U.S. economy, with active mines in every state producing materials such as those used to construct houses and roads, make medicines, and manufacture cars and electronics.

Longitudinal DAT changes measured with [F]FE-PE2I PET in patients with Parkinson's disease; a validation study.

Background: Dopamine transporter (DAT) PET provides higher resolution than DAT SPECT and opportunity for integrated imaging with MRI. The radioligand [F]FE-PE2I is highly selective for the DAT, and PET measurements with this radioligand have good reliability and repeatability in patients with non-advanced Parkinson's disease.

Objectives: To validate [F]FE-PE2I PET as measurement tool of longitudinal DAT changes in patients with Parkinson's disease.

Proof of lung muscarinic receptor occupancy by tiotropium: Translational Positron Emission Tomography studies in non-human primates and humans.

Introduction: Molecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR).

Methods: PET imaging was performed using the muscarinic radioligand [C]VC-002.

Increased odds of mortality from non-malignant respiratory disease and lung cancer are highest among US coal miners born after 1939.

Objectives: Coal miners suffer increased mortality from non-malignant respiratory diseases (NMRD), including pneumoconioses and chronic obstructive pulmonary disease, compared with the US population. We characterised mortality trends from NMRD, lung cancer and ischaemic heart disease (IHD) using data from the Federal Black Lung Program, National Coal Workers' Health Surveillance Program and the National Death Index.

Methods: We compared mortality ORs (MORs) for NMRD, lung cancer and IHD in former US coal miners to US white males.

Associations Between Cognition and Serotonin 1B Receptor Availability in Healthy Volunteers: A [11C]AZ10419369 Positron Emission Tomography Study.

Background: The serotonin system has been implicated in several psychiatric disorders. All major psychiatric disorders are associated with cognitive impairment, but treatment improving cognitive deficits is lacking, partly due to limited understanding of the neurobiology of cognitive functioning. Several markers for the serotonin system have been associated with cognitive functions.