[F]NP3-627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System.

We describe the identification of a candidate positron emission tomography (PET) imaging agent for the NLRP3 protein. NLRP3 plays a critical role in the immune system and has proven a difficult target for the development of imaging agents due to its low and cell-specific expression profile. A recently described series of pyridazine-based inhibitors, with improved permeability and brain-penetration properties, was used as a starting point for the development of a suitable PET imaging agent.

Exposure to a sensory functional ingredient in the pig model modulates the blood-oxygen-level dependent brain responses to food odor and acute stress during pharmacological MRI in the frontostriatal and limbic circuits.

Introduction: In the present study, we examined the effects of a supplementation with a sensory functional ingredient (FI, D16729, Phodé, France) containing vanillin, furaneol, diacetyl and a mixture of aromatic fatty acids on the behavioural and brain responses of juvenile pigs to acute stress.

Methods: Twenty-four pigs were fed from weaning with a standard granulated feed supplemented with the functional ingredient D16729 (FS animals, = 12) or a control formulation (CT animals, = 12). After a feed transition (10 days after weaning), the effects of FI were investigated on eating behaviour during two-choice feed preference tests.

A practical approach to the optimization of positron emission tomography imaging agents for the central nervous system.

The discovery of novel imaging agents for positron emission tomography (PET) relies on medicinal chemistry best practices, including a good understanding of molecular and pharmacological properties required for the acquisition of relevant, high-quality images. This short note reviews the characteristics of a series of clinically successful imaging agents, providing guidance for the optimization of such molecular tools. PET imaging plays an important role in staging disease and in helping clinical dose selection, which is critical for the efficient development of drug candidates.

The short neuropeptide F (sNPF) promotes the formation of appetitive visual memories in honey bees.

Motivation can critically influence learning and memory. Multiple neural mechanisms regulate motivational states, among which signalling via specific neuropeptides, such as NPY in vertebrates and NPF and its short variant sNPF in invertebrates, plays an essential role. The honey bee () is a privileged model for the study of appetitive learning and memory.

Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights.

Background: Siponimod (BAF312), a selective S1P/S1P agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P/S1P-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells.

Objective: Generate preclinical evidence confirming siponimod's CNS penetration and activity.

Preclinical Evaluation of [C]YC-72-AB85 for Visualization of Heat Shock Protein 90 in Brain and Cancer with Positron Emission Tomography.

Aberrant Hsp90 has been implied in cancer and neurodegenerative disorders. The development of a suitable Hsp90 Positron emission tomography (PET) probe can provide quantification of the expression levels of Hsp90 as a biomarker for diagnosis and follow-up of cancer and central nervous system (CNS) disease progression. In this respect, [C]YC-72-AB85 was evaluated as an Hsp90 PET probe in B16.

Positron Emission Tomography Imaging of Autotaxin in Thyroid and Breast Cancer Models Using [F]PRIMATX.

Autotaxin (ATX) is a secreted enzyme responsible for producing lysophosphatidic acid (LPA). The ATX/LPA signaling axis is typically activated in wound healing and tissue repair processes. The ATX/LPA axis is highjacked and upregulated in the progression and persistence of several chronic inflammatory diseases, including cancer.

Evaluation of 5H-Thiazolo[3,2-α]pyrimidin-5-ones as Potential GluN2A PET Tracers.

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([ F]7b) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([ H ]15b), which was used for the successful development of a radioligand binding assay.

A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo.

Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat f , and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it.

[ F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor-Bearing Mice.

Autotaxin (ATX) is a secreted enzyme with tissue levels associated with tissue injury, which increase during wound healing and chronic fibrotic diseases. We selected [ F](R,E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-((5-(2-fluoroethoxy)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)prop-2-en-1-one ([ F]PRIMATX, [ F]2), a tracer for positron emission tomography, to image ATX expression in vivo. It successfully differentiates expression levels in lung tissue samples from idiopathic pulmonary fibrosis patients, and allows the detection of ATX-expressing tumors in living mice, confirming its potential for development as a clinical imaging agent.

PET Imaging of T Cells: Target Identification and Feasibility Assessment.

Imaging T cells using positron emission tomography (PET) would be highly useful for diagnosis and monitoring in immunology and oncology patients. There are, however, no obvious targets that can be used to develop imaging agents for this purpose. We evaluated several potential target proteins with selective expression in T cells, and for which lead molecules were available: protein kinase C isozyme θ (PKC θ), lymphocyte-specific protein tyrosine kinase (Lck), zeta-chain-associated protein kinase 70 (ZAP70), and interleukin-2-inducible T-cell kinase (Itk).

Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres.

Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.

Ligand Specific Efficiency (LSE) Index for PET Tracer Optimization.

Ligand efficiency indices are widely used to guide chemical optimization in drug discovery, due to their predictive value in the early steps of optimization. At later stages, however, as more complex properties become critical for success, indices relying on calculated, rather than experimental, parameters become less informative. This problem is particularly acute when developing positron emission tomography (PET) imaging agents, for which nonspecific binding (NSB) to membranes and non-target proteins is a frequent cause of failure.

MS565: A SPECT Tracer for Evaluating the Brain Penetration of BAF312 (Siponimod).

BAF312 (siponimod) is a sphingosine-1-phosphate (S1P) receptor modulator in clinical development for the treatment of multiple sclerosis, with faster organ/tissue distribution and elimination kinetics than its precursor FTY720 (fingolimod). Our aim was to develop a tracer to better quantify the penetration of BAF312 in the human brain, with the potential to be labeled for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Although the PET radioisotopes (11)C and (18)F could have been introduced in BAF312 without modifying its structure, they do not have decay kinetics compatible with the time required for observing the drug's organ distribution in patients.

Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors.

Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various "dual" orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [(3)H]-BBAC ((S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide).

Solution structures of the prototypical 18 kDa translocator protein ligand, PK 11195, elucidated with 1H/13C NMR spectroscopy and quantum chemistry.

Eighteen kilodalton translocator protein (TSPO) is an important target for drug discovery and for clinical molecular imaging of brain and peripheral inflammatory processes. PK 11195 [1a; 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinoline carboxamide] is the major prototypical high-affinity ligand for TSPO. Elucidation of the solution structure of 1a is of interest for understanding small-molecule ligand interactions with the lipophilic binding site of TSPO.

BZM055, an iodinated radiotracer candidate for PET and SPECT imaging of myelin and FTY720 brain distribution.

FTY720 (fingolimod, Gilenya®) is a sphingosine 1-phosphate (S1P) receptor modulator that shows significant therapeutic efficacy after oral administration to patients of multiple sclerosis. Because FTY720 does not contain any atom whose PET or SPECT radioisotope would have a half-life compatible with its pharmacokinetic properties, it cannot be used directly for imaging. Instead, we propose BZM055 as a surrogate tracer to study its pharmacokinetics and organ distribution in patients and, given that FTY720 accumulates in myelin sheaths, for myelin imaging.

A rapid vesicle electrokinetic chromatography method for the in vitro prediction of non-specific binding for potential PET ligands.

High non-specific binding (NSB) is one of the most common reasons for candidate failure in potential positron emission tomography (PET) radiotracer development. It is of interest to develop high throughput in vitro methods for predicting non-specific binding prior to radiolabeling, which would help guide radiotracer candidate selection and assist decision making in new radiotracer discovery. We evaluated several electrokinetic chromatographic (EKC) systems to help identify PET ligands with low non-specific binding characteristics by mimicking the ligand-brain tissue interaction.

Single-step high-yield radiosynthesis and evaluation of a sensitive 18F-labeled ligand for imaging brain peripheral benzodiazepine receptors with PET.

Elevated levels of peripheral benzodiazepine receptors (PBR) are associated with activated microglia in their response to inflammation. Hence, PBR imaging in vivo is valuable for investigating brain inflammatory conditions. Sensitive, easily prepared, and readily available radioligands for imaging with positron emission tomography (PET) are desirable for this purpose.

Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo.

We sought to develop (11)C-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl- N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline ( 3, PBR01) and N-(2-methoxybenzyl)- N-(4-phenoxypyridin-3-yl)acetamide ( 10, PBR28). 3 was hydrolyzed to 4, which was esterified with [ (11)C]iodomethane to provide [ (11)C] 3.

Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors.

Objectives: Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are thereby biomarkers of neuroinflammation. We developed a PET ligand with an aryloxyanilide structure, [O-methyl-(11)C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([(11)C]PBR28), to image PBRs. The objectives of the current study were to evaluate kinetics of brain uptake, and the influence of the peripheral binding on the arterial input function in rhesus monkey.

Kinetic evaluation in nonhuman primates of two new PET ligands for peripheral benzodiazepine receptors in brain.

Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are, thereby, biomarkers of cellular inflammation in brain. We recently developed two PET ligands with an aryloxyanilide structure to image PBRs and now evaluate the kinetics of these radiotracers in monkey to determine whether they are suitable to explore in human. Baseline and receptor-blocking scans were performed with [(11)C]PBR01 and [(18)F]PBR06 in conjunction with serial measurements of the arterial plasma concentration of parent radiotracer separated from radiometabolite.

PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat.

Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia. We recently developed a promising positron emission tomography (PET) ligand, [11C]PBR28, with high affinity and excellent ratio of specific to nonspecific binding. We assessed the ability of [11C]PBR28 PET to localize PBRs in a rat permanent middle cerebral artery occlusion (MCAO) model of neuroinflammation.

Syntheses of 11C- and 18F-labeled carboxylic esters within a hydrodynamically-driven micro-reactor.

Carboxylic esters were successfully labeled with one of two short-lived positron-emitters, carbon-11 or fluorine-18, within a hydrodynamically-driven micro-reactor. The non-radioactive methyl ester was obtained at room temperature; its yield increased with higher substrate concentration and with reduced infusion rate. Radioactive methyl ester was obtained from the reaction of (10 mM) with in 56% decay-corrected radiochemical yield (RCY) at an infusion rate of 10 microL min(-1), and when the infusion rate was reduced to 1 microL min(-1), the RCY increased to 88%.

Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease.

This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group.