Synthesis and preclinical evaluation of [C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor.

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Main Body: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted.

Brain Serotonin Release Is Reduced in Patients With Depression: A [C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge.

Background: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT receptor agonist positron emission tomography (PET) radioligand [C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge.

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer's disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [F]BCPP-EF, and the presynaptic vesicular protein SV2A with [C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling.

A Web-Based Stress Management Intervention for University Students in Indonesia (Rileks): Feasibility Study Using a Pretest-Posttest Design.

Background: University students are susceptible to excessive stress. A web-based stress management intervention holds promise to improve stress but is still at a novel stage in Indonesia.

Objective: The aim of this paper was to report the feasibility of the intervention we developed-Rileks-among university students in Indonesia in terms of acceptability and usability, and to propose recommendations for future improvements.

Psychoeducation for breast cancer: A systematic review and meta-analysis.

Background: Psychoeducation has emerged as an intervention for women with breast cancer (BC). This meta-analysis evaluated the effectiveness of psychoeducation on adherence to diagnostic procedures and medical treatment, anxiety, depression, quality of life (QoL), and BC knowledge among patients with BC symptoms or diagnosis and BC survivors.

Methods: A systematic literature search (in PubMed, Embase, PsycINFO and Cochrane) for randomised controlled trials (RCTs) comparing the effects of psychoeducation to control among patients with BC symptoms or diagnosis and BC survivors.

Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [C]PHNO PET.

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041).

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Transdiagnostic Internet Intervention for Indonesian University Students With Depression and Anxiety: Evaluation of Feasibility and Acceptability.

Background: University students with depression and anxiety do not easily receive or seek treatment; therefore, internet-based interventions have been suggested to be a promising way to improve treatment accessibility and availability. However, it has not been examined whether a guided, culturally adapted, transdiagnostic, internet-based intervention is effective for treating symptoms of depression, anxiety, or both among university students in Indonesia.

Objective: This study aims to investigate the feasibility (acceptability and satisfaction, usability, and uptake) of a guided, culturally adapted, transdiagnostic, internet-based intervention among university students with symptoms of depression, anxiety, or both in Indonesia.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January-June 2020).

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field.

Results: This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Acute acetate administration increases endogenous opioid levels in the human brain: A [C]carfentanil molecular imaging study.

Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain.

Test-retest variability and reference region-based quantification of F-BCPP-EF for imaging mitochondrial complex I in the human brain.

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand F-BCPP-EF. Here we evaluate the test-retest reproducibility of F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio - SUVR). Thirty healthy volunteers had a 90-min dynamic F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test-retest analysis.

DREADD Activation of Pedunculopontine Cholinergic Neurons Reverses Motor Deficits and Restores Striatal Dopamine Signaling in Parkinsonian Rats.

The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson's disease (PD), which correlates with axial motor deficits. PPN-deep brain stimulation (DBS) can alleviate certain symptoms, but its mechanism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD.

F-Trifluoromethanesulfinate Enables Direct C-H F-Trifluoromethylation of Native Aromatic Residues in Peptides.

F labeling strategies for unmodified peptides with [F]fluoride require F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H F-trifluoromethylation. We report a one-step route to [F]CFSONH from [F]fluoride and its application to direct [F]CF incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin.

Preclinical evaluation of [F]FB-A20FMDV2 as a selective marker for measuring αβ integrin occupancy using positron emission tomography in rodent lung.

Purpose: Integrin αβ belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αβ in rodent lung to support human translational studies.

Methods: The synthesis of [F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process.

A self-help intervention for reducing time to diagnosis in Indonesian women with breast cancer symptoms.

Objective: We investigated the effectiveness of a self-help intervention named PERANTARA, which aims to improve adherence to diagnostic procedures among women with breast cancer (BC) symptoms to reduce the time to a definitive diagnosis.

Methods: With a cluster randomized crossover design across four hospitals, PERANTARA and treatment as usual (TAU) or TAU only was provided at successive periods in a randomly determined order. The main outcome was the time between the first medical consultation and the definitive diagnosis.

Clinical quantification of the integrin αvβ6 by [F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study).

Purpose: The RGD-integrin, αvβ6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFβ). This study sought to quantify expression of αvβ6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvβ6-selective [F]FB-A20FMDV2 PET ligand.

Methods: [F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease.

Preclinical In Vitro and In Vivo Characterization of Synaptic Vesicle 2A-Targeting Compounds Amenable to F-18 Labeling as Potential PET Radioligands for Imaging of Synapse Integrity.

Purpose: Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [C]UCB-J and [F]UCB-H derived from the anti-epileptic drug levitaracetam (Keppra®). An industry-utilized "de-risking" approach was used to carry out initial pharmacological characterization and to assess potential next-generation candidates amenable to F-18 radiolabeling for preliminary evaluation.

Procedures: Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (K) and maximal binding capacity (B) of [H]UCB-J.

Serotonin release measured in the human brain: a PET study with [C]CIMBI-36 and d-amphetamine challenge.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain.

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury.

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans.

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: F-BCPP-EF, C-SA-4503, and C-UCB-J.

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands-F-BCPP-EF, C-SA-4503, and C-UCB-J-for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases.

A Self-Help Guided Psychoeducational Intervention for Indonesian Women with Breast Cancer Symptoms: Development and Pilot Feasibility Study.

Background: Delay in the diagnosis of breast cancer (BC) may lead to an advanced stage of the disease and a poor prognosis. A psychoeducational intervention can be crucial in helping women with BC symptoms complete the examination procedures and reduce diagnosis delay of BC. Objective: To develop a psychoeducational intervention to reduce the delay of BC diagnosis among Indonesian women with BC symptoms.

Web-Based Stress Management Program for University Students in Indonesia: Systematic Cultural Adaptation and Protocol for a Feasibility Study.

Background: The number of university students experiencing stress is increasing, which often leads to adverse effects such as poor grades, academic probation, and emotional problems. Unfortunately, most of these problems remain untreated because of limited professional resources and fear of stigma. Several Web-based stress management interventions are now available for student populations, but these treatments are not yet available in Indonesia.

Guided internet-based transdiagnostic intervention for Indonesian university students with symptoms of anxiety and depression: A pilot study protocol.

Background: There is an increasing prevalence of mental health problems among university student populations. In Indonesia, treatment rates are low among university students because of the high cost of treatment, stigma and the limited availability of mental care services. Internet-based interventions have been found to be effective in treating anxiety and depression in Western countries.

Test-Retest Reliability of EQ-5D-5L Valuation Techniques: The Composite Time Trade-Off and Discrete Choice Experiments.

Objectives: To explore the test-retest reliability of the composite time trade-off (C-TTO) and discrete choice experiment (DCE) used in the Indonesian five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) valuation study.

Methods: A representative sample aged 17 years and older was recruited from the Indonesian general population by stratified quota sampling with respect to residence, sex, and age. Trained interviewers conducted computer-assisted face-to-face interviews using the EuroQol valuation technology.