A Feasibility Study of [F]F-AraG Positron Emission Tomography (PET) for Cardiac Imaging-Myocardial Viability in Ischemia-Reperfusion Injury Model.

Purpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, F-labeled 2'-deoxy-2'-F-fluoro-9-β-d-arabinofuranosylguanine ([F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.

[F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue.

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue.

A feasibility study of [18F]F-AraG positron emission tomography (PET) for cardiac imaging - myocardial viability in ischemia-reperfusion injury model.

Purpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, F-labeled 2'-deoxy-2'-F-fluoro-9-β-d-arabinofuranosylguanine ([F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.

Early Oligocene kelp holdfasts and stepwise evolution of the kelp ecosystem in the North Pacific.

Kelp forests are highly productive and economically important ecosystems worldwide, especially in the North Pacific Ocean. However, current hypotheses for their evolutionary origins are reliant on a scant fossil record. Here, we report fossil hapteral kelp holdfasts from western Washington State, USA, indicating that kelp has existed in the northeastern Pacific Ocean since the earliest Oligocene.

[C]Paraoxon: Radiosynthesis, Biodistribution and In Vivo Positron Emission Tomography Imaging in Rat.

Synthesis of the acetylcholinesterase inhibitor paraoxon (POX) as a carbon-11 positron emission tomography tracer ([C]POX) and profiling in live rats is reported. Naïve rats intravenously injected with [C]POX showed a rapid decrease in parent tracer to ∼1%, with an increase in radiolabeled serum proteins to 87% and red blood cells (RBCs) to 9%. Protein and RBC leveled over 60 minutes, reflecting covalent modification of proteins by [C]POX.

Evaluating Radioactive Analogs of Doxorubicin to Quantify ChemoFilter Binding and Whole-Body Positron Emission Tomography/Magnetic Resonance Imaging for Drug Biodistribution.

Purpose: To evaluate radiolabeled doxorubicin (Dox) analogs as tracers of baseline Dox biodistribution in vivo during hepatic intra-arterial chemotherapy and to assess the efficacy of ChemoFilter devices to bind Dox in vitro.

Materials And Methods: In an in vitro static experiment, [fluorine-18]N-succinimidyl 4-fluorobenzoate ([F]SFB) and [fluorine-18]fluorobenzoyl-doxorubicin ([F]FB-Dox) were added to a beaker containing a filter material (Dowex cation exchange resin, single-stranded DNA (ssDNA) resin, or sulfonated polymer coated mesh). In an in vitro flow model, [F]FB-Dox was added into a Dox solution in phosphate-buffered saline, and the solution flowed via a syringe column containing the filter materials.

Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism.

Cold-induced thermogenesis in endotherms demands adaptive thermogenesis fueled by mitochondrial respiration and Ucp1-mediated uncoupling in multilocular brown adipocytes (BAs). However, dietary regulation of thermogenesis in BAs isn't fully understood. Here, we describe that the deficiency of Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) in BAs reduces mtDNA-encoded ETC gene expression, causes ETC proteome imbalance, and abolishes the mitochondria-fueled thermogenesis.

Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin.

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis.

Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using F-FAraG PET and MRI.

Lymphocytes and innate immune cells are key drivers of multiple sclerosis (MS) and are the main target of MS disease-modifying therapies (DMT). Ex vivo analyses of MS lesions have revealed cellular heterogeneity and variable T cell levels, which may have important implications for patient stratification and choice of DMT. Although MRI has proven valuable to monitor DMT efficacy, its lack of specificity for cellular subtypes highlights the need for complementary methods to improve lesion characterization.

Biological Distribution and Metabolic Profiles of Carbon-11 and Fluorine-18 Tracers of VX- and Sarin-Analogs in Sprague-Dawley Rats.

Organophosphorus esters (OPs) were originally developed as pesticides but were repurposed as easily manufactured, inexpensive, and highly toxic chemical warfare agents. Acute OP toxicity is primarily due to inhibition of acetylcholinesterase (AChE), an enzyme in the central and peripheral nervous system. OP inhibition of AChE can be reversed using oxime reactivators but many show poor CNS penetration, indicating a need for new clinically viable reactivators.

Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET.

Purpose: We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models.

Experimental Design: [Zr]DFO-YS5 was prepared and its binding affinity for CD46 was measured.

F-AraG PET for CD8 Profiling of Tumors and Assessment of Immunomodulation by Chemotherapy.

Most clinical trials exploring various combinations of chemo- and immunotherapy rely on serial biopsy to provide information on immune response. The aim of this study was to assess the value of F-arabinosyl guanine (F-AraG) as a noninvasive tool that profiles tumors on the basis of the key player in adaptive antitumor response, CD8+ cells, and evaluates the immunomodulatory effects of chemotherapy. To evaluate the ability of F-AraG to report on the presence of CD8+ cells within the tumor microenvironment, we imaged a panel of syngeneic tumor models (MC38, CT26, LLC, A9F1, 4T1, and B16F10) and correlated the signal intensity with the number of lymphocytes found in the tumors.

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O-(2-[ F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate [ F]-VXS.

Oxime antidotes regenerate organophosphate-inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [ F]-VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [ F]-VXS was evaluated after an LD dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes.

Sensing Living Bacteria Using d-Alanine-Derived C Radiotracers.

Incorporation of d-amino acids into peptidoglycan is a unique metabolic feature of bacteria. Since d-amino acids are not metabolic substrates in most mammalian tissues, this difference can be exploited to detect living bacteria . Given the prevalence of d-alanine in peptidoglycan muropeptides, as well as its role in several antibiotic mechanisms, we targeted this amino acid for positron emission tomography (PET) radiotracer development.

High Enantiomeric Excess In-Loop Synthesis of d-[methyl-C]Methionine for Use as a Diagnostic Positron Emission Tomography Radiotracer in Bacterial Infection.

Currently, there exists no accurate, noninvasive clinical imaging method to detect living bacteria . Our goal is to provide a positron emission tomography (PET) method to image infection by targeting bacteria-specific metabolism. Standard of care methodologies detect morphologic changes, image immunologic response to infection, or employ invasive tissue sampling with associated patient morbidity.

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

Interstitial cells of Cajal, which express the calcium-activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4-cyclohepta[]thiophene-3-carboxylic acid -tolylamide (TM-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TM-23 for inhibition of GI motility in mice.

PET/CT Imaging of Human TNFα Using [Zr]Certolizumab Pegol in a Transgenic Preclinical Model of Rheumatoid Arthritis.

Purpose: Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy.

Imaging of Activated T Cells as an Early Predictor of Immune Response to Anti-PD-1 Therapy.

Compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cell-specific PET agent, [18F]F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy.