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.

Increased TSPO, COX-1, and COX-2 Uptake in Bone Marrow Within a Falx Cerebri Ossification.

Ossification is uncommon, generally asymptomatic, and often incidentally identified in imaging studies. We report on a 54-year-old man who participated as a healthy volunteer in a clinical trial using PET imaging to investigate neuroinflammation. An incidental ossified lesion in the anterior falx cerebri was revealed by MRI.

Difluoromethoxide Is a Strong Leaving Group in the Photoredox Deoxyradiofluorination of 2-Phenylpyridines.

A 2-phenyl-3-difluoromethoxy-pyridinyl moiety features in potent phosphodiesterase 4D inhibitors that are considered to be candidate radiotracers for positron emission tomography if they are labeled with fluorine-18. Fluorine-18 could be installed as desired at the 3'-phenyl position with acridinium-mediated photoredox radiodeoxyfluorination in homologues bearing variously substituted 3'-aryloxy groups. However, a distal 3-difluoromethoxide (-OCHF) group strongly competes as a leaving group, especially when an electron-deficient aryloxy group is present at position 3'.

Ligand-Based Virtual Screening as a Path to New Chemotypes for Candidate PET Radioligands for Imaging Tauopathies.

Ligand-based virtual screening (LBVS) has rarely been tested as a method for discovering new structural scaffolds for PET radioligand development. This study used LBVS to discover potential chemotype leads for developing radioligands for PET imaging of tauopathies. ZINC12, a free database of over 12 million commercially available compounds, was searched to discover novel scaffolds based on similarities to four query compounds.

Isotopologues of potassium 2,2,2-trifluoroethoxide for applications in positron emission tomography and beyond.

The 2,2,2-trifluoroethoxy group increasingly features in drugs and potential tracers for biomedical imaging with positron emission tomography (PET). Herein, we describe a rapid and transition metal-free conversion of fluoroform with paraformaldehyde into highly reactive potassium 2,2,2-trifluoroethoxide (CFCHOK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors. Moreover, we show that these transformations translate easily to fluoroform that has been labeled with either carbon-11 (t = 20.

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.

The impacts of host association and perturbation on symbiont fitness.

Unlabelled: Symbiosis can benefit hosts in numerous ways, but less is known about whether interactions with hosts benefit symbionts-the smaller species in the relationship. To determine the fitness impact of host association on symbionts in likely mutualisms, we conducted a meta-analysis across 91 unique host-symbiont pairings under a range of spatial and temporal contexts. Specifically, we assess the consequences to symbiont fitness when in and out of symbiosis, as well as when the symbiosis is under suboptimal or varying environments and biological conditions (e.

Copper(I)-free syntheses of [C/F]trifluoromethyl ketones from alkyl or aryl esters and [C/F]fluoroform.

Herein, we report a copper(I)-free method for labeling the trifluoroacetyl group with positron-emitting carbon-11 ( = 20.4 min) or fluorine-18 ( = 109.8 min) as part of our exploration of radiolabeled fluoroforms to access new radiolabeled chemotypes of interest for tracer development.

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.

Gas Phase Transformations in Carbon-11 Chemistry.

The short-lived positron-emitter carbon-11 ( = 20.4 min; β, 99.8%) is prominent for labeling tracers for use in biomedical research with positron emission tomography (PET).

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).

On the Risk of F-Regioisomer Formation in the Copper-Free Radiofluorination of Aryliodonium Precursors.

Aryliodonium precursors are widely applied for copper-free labeling of positron emission tomography (PET) tracers with fluorine-18. We assessed F-fluoroarene regioisomer formation in examples of these labeling methods. Aryliodonium ylides derived from Meldrum's acid bearing electron-donating groups react with [F]fluoride in acetonitrile to produce regioisomeric F-fluoroarenes via a competing aryne pathway.

Candidate Tracers for Imaging Colony-Stimulating Factor 1 Receptor in Neuroinflammation with Positron Emission Tomography: Issues and Progress.

The tyrosine kinase, colony-stimulating factor 1 receptor (CSF1R), has attracted attention as a potential biomarker of neuroinflammation for imaging studies with positron emission tomography (PET), especially because of its location on microglia and its role in microglia proliferation. The development of an effective radiotracer for specifically imaging and quantifying brain CSF1R is highly challenging. Here we review the progress that has been made on PET tracer development and discuss issues that have arisen and which remain to be addressed and resolved.

PET reporter systems for the brain.

Positron emission tomography (PET) can be used as a noninvasive method to longitudinally monitor and quantify the expression of proteins in the brain in vivo. It can be used to monitor changes in biomarkers of mental health disorders, and to assess therapeutic interventions such as stem cell and molecular genetic therapies. The utility of PET monitoring depends on the availability of a radiotracer with good central nervous system (CNS) penetration and high selectivity for the target protein.

Fortification of condiments and seasonings with iron for preventing anaemia and improving health.

Background: Anaemia affects approximately 1.8 billion people worldwide; over 60% of anaemia cases globally are due to iron deficiency (ID). Iron deficiency and anaemia contribute to the global burden of disease and affect physical and cognitive development in children, and work productivity and economic well-being in adults.

Within- and between-host dynamics of producer and non-producer pathogens.

For infections to be maintained in a population, pathogens must compete to colonize hosts and transmit between them. We use an experimental approach to investigate within-and-between host dynamics using the pathogen and the animal host Within-host interactions can involve the production of goods that are beneficial to all pathogens in the local environment but susceptible to exploitation by non-producers. We exposed the nematode host to ‘producer’ and two ‘non-producer’ bacterial strains (specifically for siderophore production and quorum sensing), in single infections and coinfections, to investigate within-host colonization.

Design, Methods, and Select Baseline Results from a School Nutrition Project for Adolescents in Bangladesh.

Background: The School Nutrition for Adolescents Project (SNAP) provided weekly iron and folic acid (WIFA) supplementation and menstrual hygiene management (MHM) support for girls; actions to improve water, sanitation, and hygiene (WASH) practices; and behavior change interventions to adolescents aged 10-19 y in 65 intervention schools in 2 districts of Bangladesh.

Objectives: We aimed to describe the project design and select baseline results of students and school project implementers.

Methods: Girls (n = 2244) and boys (n = 773) in 74 schools (clusters) and project implementers [headteachers (n = 74), teachers (n = 96), and student leaders (n = 91)] participated in a survey assessing nutrition, MHM, and WASH knowledge and experience.

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.

Broad-scope Syntheses of [ C/ F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts.

Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t =20.4 min) or fluorine-18 (t =109.

An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands.

A positron emission tomography (PET) radioligand for imaging phosphodiesterase 4D (PDE4D) would benefit drug discovery and the investigation of neuropsychiatric disorders. The most promising radioligand to date, namely, [C]T1650, has shown unstable quantification in humans. Structural elaboration of [C]T1650 was therefore deemed necessary.