PET Quantification in Healthy Humans of Cyclooxygenase-2, a Potential Biomarker of Neuroinflammation.

Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)--(thiophen-2-ylmethyl)pyrimidin-4-amine ([C]MC1) to detect COX-2 density in a healthy human brain. The specificity of [C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents.

Development and Evaluation in Rat and Monkey of a Candidate Homochiral Radioligand for PET Studies of Brain Receptor Interacting Protein Kinase 1: [F]()-1-(5-(3-Fluorophenyl)-4,5-dihydro-1-pyrazol-1-yl)-2,2-dimethylpropan-1-one.

Receptor interacting protein kinase 1 (RIPK1) crucially upregulates necroptosis and is a key driver of inflammation. An effective PET radioligand for imaging brain RIPK1 would be useful for further exploring the role of this enzyme in neuroinflammation and for assisting drug discovery. Here, we report our progress on developing a PET radioligand for RIPK1 based on the phenyl-1-dihydropyrazole skeleton of a lead RIPK1 inhibitor, GSK'963.

[F]SF51, a novel F-labeled PET radioligand for translocator protein 18kDa (TSPO) in brain, works well in monkeys but fails in humans.

[F]SF51 is a novel radioligand for imaging translocator protein 18 kDa (TSPO) that previously displayed excellent imaging properties in nonhuman primates. This study assessed its performance in human brain and its dosimetry. Seven healthy participants underwent brain PET imaging to measure TSPO binding using a two-tissue compartment model (2TCM) to calculate total distribution volume ().

[C]PS13 Demonstrates Pharmacologically Selective and Substantial Binding to Cyclooxygenase-1 in the Human Brain.

Our laboratory recently developed [C]PS13 as a PET radioligand to selectively measure cyclooxygenase-1 (COX-1). The cyclooxygenase enzyme family converts arachidonic acid into prostaglandins and thromboxanes, which mediate inflammation. The total brain uptake of [C]PS13, which is composed of both specific binding and background uptake, can be accurately quantified with gold standard methods of compartmental modeling.

A meta-analysis of idiopathic granulomatous mastitis treatments for remission and recurrence prevention.

Purpose: The major aim of our meta-analysis was to review the effectiveness of various treatment modalities for achieving successful remission and preventing recurrence for women with idiopathic granulomatous mastitis (IGM). This knowledge is instrumental in developing evidence-based guidelines for clinicians to improve management strategies and outcomes for patients with IGM.

Methods: A systematic literature search was performed on MEDLINE (Ovid), Embase (Elsevier), PubMed, Cochrane Library, Web of Science, and Google Scholar; studies published to 19 January 2022 were included.

Evaluation of [F]fluoroestradiol and ChRERα as a gene expression PET reporter system in rhesus monkey brain.

Positron emission tomography (PET) reporter systems are a valuable means of estimating the level of expression of a transgene in vivo. For example, the safety and efficacy of gene therapy approaches for the treatment of neurological and neuropsychiatric disorders could be enhanced via the monitoring of exogenous gene expression levels in the brain. The present study evaluated the ability of a newly developed PET reporter system [F]fluoroestradiol ([F]FES) and the estrogen receptor-based PET reporter ChRERα, to monitor expression levels of a small hairpin RNA (shRNA) designed to suppress choline acetyltransferase (ChAT) expression in rhesus monkey brain.

Mental Healthcare Needs and Experiences of LGBT+ Individuals in Malaysia: Utility, Enablers, and Barriers.

Access to mental healthcare is undoubtedly of major importance for LGBT+ people worldwide, given the high prevalence of mental health difficulties due to minority stress exposures. This study drew mixed-method survey data from the community-based KAMI Survey ( = 696) to examine the enablers, barriers, and unmet needs experiences of LGBT+ individuals in accessing mental healthcare services in Malaysia. First, we present findings from a series of descriptive analyses for sociodemographic differences in unmet needs for mental healthcare, barriers, and satisfaction levels with different types of mental healthcare.

Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and C-Labeled Radioligands That Avoid Radiometabolite Contamination.

Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites.

Synthesis and preclinical evaluation of [C]uPSEM792 for PSAM-GlyR based chemogenetics.

Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs).

In vivo evaluation of a novel F-labeled PET radioligand for translocator protein 18 kDa (TSPO) in monkey brain.

Purpose: [F]SF51 was previously found to have high binding affinity and selectivity for 18 kDa translocator protein (TSPO) in mouse brain. This study sought to assess the ability of [F]SF51 to quantify TSPO in rhesus monkey brain.

Methods: Positron emission tomography (PET) imaging was performed in monkey brain (n = 3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28.

Discovery of a High-Affinity Fluoromethyl Analog of [C]5-Cyano--(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands.

[C] has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of with higher affinity to provide the potential for labeling with longer-lived fluorine-18 ( = 109.8 min) and for delivery of higher CSF1R-specific PET signal .

Candidate 3-benzazepine-1-ol type GluN2B receptor radioligands (C-NR2B-Me enantiomers) have high binding in cerebellum but not to σ1 receptors.

Introduction: We recently reported C-NR2B-SMe ([S-methyl-C](R,S)-7-thiomethoxy-3-(4-(4-methyl-phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol) and its enantiomers as candidate radioligands for imaging the GluN2B subunit within rat N-methyl-D-aspartate receptors. However, these radioligands gave unexpectedly high and displaceable binding in rat cerebellum, possibly due to cross-reactivity with sigma-1 (σ1) receptors. This study investigated C-labeled enantiomers of a close analogue (7-methoxy-3-(4-(p-tolyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol; NR2B-Me) of C-NR2B-SMe as new candidate GluN2B radioligands.

-A Focus Group and Survey Study on Women's Attitudes towards Risk-Based Breast Cancer Screening and Personalised Risk Assessments.

Singapore launched a population-based organised mammography screening (MAM) programme in 2002. However, uptake is low. A better understanding of breast cancer (BC) risk factors has generated interest in shifting from a one-size-fits-all to a risk-based screening approach.

Whole-Body PET Imaging in Humans Shows That C-PS13 Is Selective for Cyclooxygenase-1 and Can Measure the In Vivo Potency of Nonsteroidal Antiinflammatory Drugs.

Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H, which has proinflammatory effects. The recently developed PET radioligand C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of C-PS13 binding to COX-1 in humans and assess the utility of C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs.

First-in-Human Evaluation of F-PF-06445974, a PET Radioligand That Preferentially Labels Phosphodiesterase-4B.

Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand F-PF-06445974 in the brains of rodents, monkeys, and humans.

Naloxone's dose-dependent displacement of [C]carfentanil and duration of receptor occupancy in the rat brain.

The continuous rise in opioid overdoses in the United States is predominantly driven by very potent synthetic opioids, mostly fentanyl and its derivatives (fentanyls). Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX's dose-dependence on both its rate of displacement of [C]carfentanil ([C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain.

When Health Intersects with Gender and Sexual Diversity: Medical Students' Attitudes Towards LGBTQ Patients.

A central tenet of the health professions is that of equitable access to health care. However, disparities in equitable healthcare provision continues to be a challenge in many societies due to prejudices against the LGBTQ community. This study was aimed at exploring the attitudes of medical students toward LGBTQ patients in Malaysia.

In Vivo Evaluation of 6 Analogs of C-ER176 as Candidate F-Labeled Radioligands for 18-kDa Translocator Protein.

Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand C-ER176 can successfully image 18-kDa translocator protein (TSPO), a biomarker of inflammation, in the human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic C labeling and in vivo performance in the monkey brain to select the most promising among 6 fluorine-containing analogs of ER176 for subsequent labeling with longer-lived F.

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising F-Labeled Ligand.

Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 ( = 109.

Functional Selectivity of a Biased Cannabinoid-1 Receptor (CBR) Antagonist.

Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CBR antagonist (MRI-1891) highly biased toward inhibiting CBR-induced β-arrestin-2 (βArr2) recruitment over G-protein activation. In obese wild-type and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CBR occupancy.

[C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

Previous work found that [C]deschloroclozapine ([C]DCZ) is superior to [C]clozapine ([C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hMDi) was injected into the right amygdala of a male rhesus macaque.

Region- and voxel-based quantification in human brain of [F]LSN3316612, a radioligand for O-GlcNAcase.

Background: Previous studies found that the positron emission tomography (PET) radioligand [F]LSN3316612 accurately quantified O-GlcNAcase in human brain using a two-tissue compartment model (2TCM). This study sought to assess kinetic model(s) as an alternative to 2TCM for quantifying [F]LSN3316612 binding, particularly in order to generate good-quality parametric images.

Methods: The current study reanalyzed data from a previous study of 10 healthy volunteers who underwent both test and retest PET scans with [F]LSN3316612.