Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [ C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs.

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.

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [ C]PBR28 and Machine Learning Analysis.

Background: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA.

Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study.

Background: The protein kinase ataxia telangiectasia mutated (ATM) mediates cellular response to DNA damage induced by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is a novel, highly potent, selective ATM inhibitor designed to cross the blood-brain barrier (BBB) and currently evaluated with radiotherapy in a phase I study in patients with brain malignancies.

Nondisplaceable Binding Is a Potential Confounding Factor in C-PBR28 Translocator Protein PET Studies.

The PET ligand C-PBR28 (-((2-(methoxy-C)-phenyl)methyl)--(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, V, is frequently the reported outcome measure. Since V is the sum of the ligand-specific distribution volume (V) and the nondisplaceable-binding distribution volume (V), differences in V across subjects and groups will have an impact on V Here, we used a recently developed method for simultaneous estimation of V (SIME) to disentangle contributions from V and V Data from 4 previously published C-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls).

Quantification and reliability of [C]VC - 002 binding to muscarinic acetylcholine receptors in the human lung - a test-retest PET study in control subjects.

Background: The radioligand [C]VC-002 was introduced in a small initial study long ago for imaging of muscarinic acetylcholine receptors (mAChRs) in human lungs using positron emission tomography (PET). The objectives of the present study in control subjects were to advance the methodology for quantification of [C]VC-002 binding in lung and to examine the reliability using a test-retest paradigm. This work constituted a self-standing preparatory step in a larger clinical trial aiming at estimating mAChR occupancy in the human lungs following inhalation of mAChR antagonists.

First Radiolabeling of a Ganglioside with a Positron Emitting Radionuclide: PET Demonstrates Low Exposure of Radiofluorinated GM1 in Non-human Primate Brain.

Gangliosides are biologically important glycolipids widely distributed in vertebrate cells. An important member of the ganglioside family is the monosialylganglioside GM1, which has been suggested as a potential therapeutic for Parkinson's disease. In the current study, a late-stage radiofluorination protocol was developed, in which fluorine-18 was introduced by substitution of a terminal tosyl group in the fatty acid backbone of GM1.

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [C]PBR28 HRRT PET study.

Purpose: The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C]PBR28.

Methods: [C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.

A PET study in healthy subjects of brain exposure of C-labelled osimertinib - A drug intended for treatment of brain metastases in non-small cell lung cancer.

Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of C-labelled osimertinib administered intravenously in subjects with an intact blood-brain barrier.

Test-retest reliability and convergent validity of (R)-[C]PK11195 outcome measures without arterial input function.

Purpose: The PET radioligand (R)-[C]PK11195 is used to quantify the 18-kDa translocator protein (TSPO), a marker for glial activation. Since there is no brain region devoid of TSPO, an arterial input function (AIF) is ideally required for quantification of binding. However, obtaining an AIF is experimentally demanding, is sometimes uncomfortable for participants, and can introduce additional measurement error during quantification.

PET imaging of [C]PBR28 in Parkinson's disease patients does not indicate increased binding to TSPO despite reduced dopamine transporter binding.

Purpose: To examine the hypothesis that cerebral binding to the 18 kDa translocator protein (TSPO), a marker of microglia activation, is elevated in Parkinson's disease (PD), and to assess the relationship between brain TSPO binding and dopaminergic pathology in PD.

Methods: The radioligand [C]PBR28 was used for quantitative assessment of brain TSPO in 16 control subjects and 16 PD patients. To analyse the relationship between dopaminergic pathology and brain TSPO binding, PET studies of the dopamine transporter (DAT) were undertaken in PD patients using the DAT radioligand [F]FE-PE2I.

GABA receptor occupancy by subtype selective GABA modulators: PET studies in humans.

Rationale: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA receptor positive modulators with limited sedative effects.

Objectives: The current study aimed to confirm target engagement at GABA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABA receptor occupancy, and tolerability.

In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.

Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells.

Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson's disease.

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase.

A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.

There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization.

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR.

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET).

A randomized, double-blind, placebo-controlled crossover study of α4β 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder.

Rationale: Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4β2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD.

Objectives: The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks.

A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers.

Aim: To investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan.

Methods: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart.

Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate.

Introduction: N-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure.

Methods: AZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety.

AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects.

The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO.

Individual differences in the proneness to have flow experiences are linked to dopamine D2-receptor availability in the dorsal striatum.

Flow is a subjective experience of high but effortless attention, enjoyment, and low self-awareness that can occur during the active performance of challenging tasks. The dispositional proneness to experience flow is associated with personality traits that are known to be influenced by dopaminergic neural systems. Here, for the first time, we investigated relations between flow proneness and dopaminergic function.

Melatonin secretion in children with epilepsy.

This study examined melatonin (MLT) system in children with epilepsy. Diurnal patterns of salivary MLT, urinary metabolite 6-sulphatoxymelatonin, core body temperature, pulse and blood pressure were measured in 51 children with epilepsy (6.6-17.

Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects.

Background: Positron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented.

Diurnal melatonin patterns in children: ready to apply in clinical practice?

Experimental and clinical studies suggest that endogenous melatonin plays an important role in pediatric sleep regulation. This finding led to the introduction of exogenous melatonin to treat sleep disturbances. Optimizing the treatment algorithm involves a review of melatonin measurements and interpretations in clinical practice.