Age- and sex-specific differences in myocardial sympathetic tone and left ventricular remodeling following myocardial injury.

Background: Presentations and outcomes of acute myocardial infarction (MI) differ between women and men, with the worst outcomes being reported in younger women. Mental stress induced ischemia and sympathetic activation have been suggested to play a prominent role in the pathogenesis of MI in younger women, however, the impact of sex hormones on these parameters remains unknown.

Methods: The effect of sex hormones and age on myocardial infarct size and myocardial sympathetic activity (MSA) was assessed in male and female, as well as young (4-6 months) and aged (20-22 months) FVB/N mice (n = 106, 60 gonadectomized and 46 sham-operated animals) who underwent in vivo [C]meta-hydroxyephedrine ([C]mHED) positron emission tomography (PET) and cardiac magnetic resonance (CMR) imaging 24 h after a 30 min myocardial ischemic injury.

Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs.

Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction.

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes.

Characterization of ()- and ()-[F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing -Methyl-d-Aspartate Receptors.

The -methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [F]OF-NB1 in rodents. Particularly, the ()- and ()- enantiomers were evaluated using docking, autoradiography, PET imaging, and biodistribution studies.

Synthesis and Biological Evaluation of Enantiomerically Pure () and ()[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors.

GluN2B subunit-containing methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ()[F]OF-NB1 and ()[F]OF-NB1 as well as to assess their and performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents.

Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density.

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking.

Evaluation of [F]RoSMA-18-d as a CB2 PET Radioligand in Nonhuman Primates.

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [F]RoSMA-18-d, which proved to be highly suitable for and mapping of CB2 in rodents.

Imaging increased metabolism in the spinal cord in mice after middle cerebral artery occlusion.

Emerging evidence indicates crosstalk between the brain and hematopoietic system following cerebral ischemia. Here, we investigated metabolism and oxygenation in the spleen and spinal cord in a transient middle cerebral artery occlusion (tMCAO) model. Sham-operated and tMCAO mice underwent [F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) to assess glucose metabolism.

Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives.

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications.

Synthesis and Biological Evaluation of Enantiomerically Pure ()- and ()-[F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors.

GluN2B subunit-containing -methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation.

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer's disease.

Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease. The cannabinoid type 2 receptor (CBR) is an emerging target for neuroinflammation and therapeutics of Alzheimer's disease. Here, we aim to assess the alterations in brain CBR levels and evaluate novel CBR imaging tracers in the arcAß mouse model of Alzheimer's disease amyloidosis.

Biodistribution and dosimetry of the GluN2B-specific NMDA receptor PET radioligand (R)-[C]Me-NB1.

Background: The NMDA receptor (NMDAR) plays a key role in the central nervous system, e.g., for synaptic transmission.

Development and Validation of [H]OF-NB1 for Preclinical Assessment of GluN1/2B Candidate Drugs.

GluN2B-enriched -methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer's disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [H]ifenprodil shows poor selectivity in drug screening. To this end, we developed a tritium-labeled form of OF-NB1, a recently reported selective GluN1/2B positron emission tomography imaging (PET) agent, with a molar activity of 1.

Evaluation of ()-, ()-, and ()-F-OF-NB1 for Imaging GluN2B Subunit-Containing -Methyl-d-Aspartate Receptors in Nonhuman Primates.

Despite 2 decades of research, no -methyl-d-aspartate (NMDA) glutamate receptor (GluN) subtype 2B (GluN1/2B) radioligand is yet clinically validated. Previously, we reported on ()-F-OF-NB1 as a promising GluN1/2B PET probe in rodents and its successful application for the visualization of GluN2B-containing NMDA receptors in postmortem brain tissues of patients with amyotrophic lateral sclerosis. In the current work, we report on the characterization of ()-, ()-, and ()-F-OF-NB1 in nonhuman primates.

Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: -[C]NR2B-Me, -[F]of-Me-NB1, and -[F]of-NB1.

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: -[C]NR2B-Me, -[F]OF-Me-NB1, and -[F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques.

Characterization in nonhuman primates of (R)-[F]OF-Me-NB1 and (S)-[F]OF-Me-NB1 for imaging the GluN2B subunits of the NMDA receptor.

Purpose: GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[F]OF-Me-NB1 was reported to be more specific and selective than (S)-[F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[F]OF-Me-NB1 and (S)-[F]OF-Me-NB1 in nonhuman primates.

In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI.

Purpose: Stroke is one of the most prevalent vascular diseases. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptor (CBR) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI).

First-in-Humans Brain PET Imaging of the GluN2B-Containing -methyl-d-aspartate Receptor with ()-C-Me-NB1.

The -methyl-d-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer disease and in the treatment of major depression by fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of interest as diagnostic and therapeutic targets. Recently, ()-C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits.

Prodrug Approach toward the Development of a PET Radioligand for Imaging the GluN2A Subunits of the NMDA Receptor.

A straightforward synthesis of a fluorine-18-labeled prodrug of AFA233 is reported. The key step in the preparation of [F]AFA233-prodrug is the selective deprotection of the -butyl protection groups of the quinoxalinedione moiety without cleavage of the -butyl--acyl-2-thioethyl protection groups on the phosphate esters. In addition, the preparation of the nonradioactive prodrug reference compound of AFA233 is reported.

Regional brain mGlu5 receptor occupancy following single oral doses of mavoglurant as measured by [C]-ABP688 PET imaging in healthy volunteers.

Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [C]-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using [C]-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20-40 years. This study comprised three periods and six subjects were divided into two cohorts.

Identification of a PET Radiotracer for Imaging of the Folate Receptor-α: A Potential Tool to Select Patients for Targeted Tumor Therapy.

The aim of this study was to identify a folate receptor-α (FRα)-selective PET agent potentially suitable for the selection of patients who might profit from FRα-targeted therapies. The 6 and 6 isomers of F-aza-5-methyltetrahydrofolate (MTHF) were assessed regarding their binding to FRα and FRβ, expressed on cancer and inflammatory cells, respectively, and compared with F-AzaFol, the folic acid-based analog. FR selectivity was investigated using FRα-transfected (RT16) and FRβ-transfected (D4) CHO cells.

Neuroimaging with Radiopharmaceuticals Targeting the Glutamatergic System.

Radiopharmacy at ETH has worked on the development of novel PET tracers for neuro-, cardiac- and tumor imaging for many years. In this paper, our efforts on targeting the glutamatergic system of the metabotropic glutamate receptor subtype 5 (mGluR5) and the ionotropic -methyl-D-aspartate (NMDA) receptor are summarized. We briefly described the principles of positron emission tomography (PET) tracer development for the central nervous system (CNS) and the radiolabeling methods used in our laboratory.