Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor.

The sphingosine-1-phosphate-5 (S1P) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS).

Assessment of a 6-arylaminobenzamide lead derivative as a potential core scaffold for S1P positron emission tomography radiotracer development.

Sphingosine-1-phosphate-5 receptors (S1P) are predominantly expressed in oligodendrocytes and as a result have been proposed as an important target in Multiple Sclerosis (MS). Selective S1P radiotracers could enable in vivo positron emission tomography (PET) imaging of oligodendrocytes activity. Here we report the synthesis, radiolabelling and first preclinical evaluation of the pharmacokinetics and binding properties of a lead 6-arylaminobenzamide derivative, 6-(mesitylamino)-2-methoxy-3-methylbenzamide (also named as TEFM180), as a potential core scaffold for development of novel S1P PET radiotracers.

Multi-organ kinetic modeling for Na[F]F pre-clinical total-body PET studies.

Background: Total-body positron emission tomography (PET), already well-established in the pre-clinical setting, makes it possible to study multi-parameters in biological systems as a whole, rather than focusing on single tissues analysis. Simultaneous kinetic analysis of multiple organs poses some daunting new challenges.

Purpose: To explore quantifying the pharmacokinetics of Na[F]F in multiple dissimilar murine organs simultaneously in vivo with total-body PET imaging using different compartmental models for each organ and a shared cardiovascular system.

Translational molecular imaging: Thrombosis imaging with positron emission tomography.

A key focus of cardiovascular medicine is the detection, treatment, and prevention of disease, with a move towards more personalized and patient-centred treatments. To achieve this goal, novel imaging approaches that allow for early and accurate detection of disease and risk stratification are needed. At present, the diagnosis, monitoring, and prognostication of thrombotic cardiovascular diseases are based on imaging techniques that measure changes in structural anatomy and biological function.

Sexually dimorphic murine brain uptake of the 18 kDa translocator protein PET radiotracer [F]LW223.

The 18 kDa translocator protein is a well-known biomarker of neuroinflammation, but also plays a role in homeostasis. PET with 18 kDa translocator protein radiotracers [C]PBR28 in humans and [F]GE180 in mice has demonstrated sex-dependent uptake patterns in the healthy brain, suggesting sex-dependent 18 kDa translocator protein expression, although humans and mice had differing results. This study aimed to assess whether the 18 kDa translocator protein PET radiotracer [F]LW223 exhibited sexually dimorphic uptake in healthy murine brain and peripheral organs.

[F]LW223 has low non-displaceable binding in murine brain, enabling high sensitivity TSPO PET imaging.

Neuroinflammation is associated with a number of brain diseases, making it a common feature of cerebral pathology. Among the best-known biomarkers for neuroinflammation in Positron Emission Tomography (PET) research is the 18 kDa translocator protein (TSPO). This study aims to investigate the binding kinetics of a novel TSPO PET radiotracer, [F]LW223, in mice and specifically assess its volume of non-displaceable binding () in brain as well as investigate the use of simplified analysis approaches for quantification of [F]LW223 PET data.

F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation.

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in , encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat gene.

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent.

Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females.

F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI and fluorine 18-labeled sodium fluoride (F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed. Purpose To evaluate the association between F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In this prospective observational cohort study (October 2017 to January 2020), participants underwent F-NaF PET/MRI.

Bimetallic gold-platinum nanoparticles as a drug delivery system coated with a new drug to target glioblastoma.

A drug delivery nanosystem of noble bimetallic nanoparticles (NPs) which consists of Au NPs capped with Pt NPs (Au@Pt NPs) is constructed and functionalised with a quinazoline based small molecule (Au@Pt@Q NPs), acting as a theranostic agent against glioblastoma. Two different hydrothermal synthetic procedures for bimetallic Au@Pt NPs are presented and the resulting nanostructures are fully characterised by means of spectroscopic and microscopic methods. The imaging and targeting capacity of the new drug delivery system is assessed through fluorescent optical microscopy and cytotoxicity evaluations.

18F-GP1 Positron Emission Tomography and Bioprosthetic Aortic Valve Thrombus.

Background: Bioprosthetic valve thrombosis may have implications for valve function and durability.

Objectives: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves.

Methods: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves.

A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks .

Bone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary. molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions .

Modelling [F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain.

Purpose: To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [F]LW223, kinetics in the heart and brain when using a simplified imaging approach.

Methods: Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (V) and binding potential transfer corrected (BP) using arterial or image-derived input function (IDIF).

Effects of administration route on uptake kinetics of F-sodium fluoride positron emission tomography in mice.

F-sodium fluoride (F-NaF) is a positron emission tomography (PET) radiotracer widely used in skeletal imaging and has also been proposed as a biomarker of active calcification in atherosclerosis. Like most PET radiotracers, F-NaF is typically administered intravenously. However in small animal research intravenous administrations can be challenging, because partial paravenous injection is common due to the small calibre of the superficial tail veins and repeat administrations via tail veins can lead to tissue injury therefore limiting the total number of longitudinal scanning points.

Ex vivo F-fluoride uptake and hydroxyapatite deposition in human coronary atherosclerosis.

Early microcalcification is a feature of coronary plaques with an increased propensity to rupture and to cause acute coronary syndromes. In this ex vivo imaging study of coronary artery specimens, the non-invasive imaging radiotracer, F-fluoride, was highly selective for hydroxyapatite deposition in atherosclerotic coronary plaque. Specifically, coronary F-fluoride uptake had a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity.

Tri-modal imaging of gold-dotted magnetic nanoparticles for magnetic resonance imaging, computed tomography and intravascular ultrasound: an study.

To examine the multimodal contrasting ability of gold-dotted magnetic nanoparticles (Au*MNPs) for magnetic resonance (MR), computed tomography (CT) and intravascular ultrasound (IVUS) imaging. Au*MNPs were prepared by adapting an impregnation method, without using surface capping reagents and characterized (transmission electron microscopy, x-ray diffraction and Fourier-transform infrared spectroscopy) with their cytotoxicity assessed, followed by imaging assessments. The contrast-enhancing ability of Au*MNPs was shown to be concentration-dependent across MR, CT and IVUS imaging.

Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism.

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, F-LW223, are suitable for clinical translation; and validate whether F-LW223 can detect macrophage-driven inflammation in a rat MI model.

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness.

Manganese-enhanced T mapping to quantify myocardial viability: validation with F-fluorodeoxyglucose positron emission tomography.

Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI).

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG)-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG)-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.

Standardization of Preclinical PET/CT Imaging to Improve Quantitative Accuracy, Precision, and Reproducibility: A Multicenter Study.

Preclinical PET/CT is a well-established noninvasive imaging tool for studying disease development/progression and the development of novel radiotracers and pharmaceuticals for clinical applications. Despite this pivotal role, standardization of preclinical PET/CT protocols, including CT absorbed dose guidelines, is essentially nonexistent. This study (1) quantitatively assesses the variability of current preclinical PET/CT acquisition and reconstruction protocols routinely used across multiple centers and scanners; and (2) proposes acquisition and reconstruction PET/CT protocols for standardization of multicenter data, optimized for routine scanning in the preclinical PET/CT laboratory.

Non-invasive in vivo imaging of acute thrombosis: development of a novel factor XIIIa radiotracer.

Aims: Cardiovascular thrombosis is responsible a quarter of deaths annually worldwide. Current imaging methods for cardiovascular thrombosis focus on anatomical identification of thrombus but cannot determine thrombus age or activity. Molecular imaging techniques hold promise for identification and quantification of thrombosis in vivo.

Kinetic modelling and quantification bias in small animal PET studies with [18F]AB5186, a novel 18 kDa translocator protein radiotracer.

Introduction: Positron Emission Tomography (PET) imaging with selective 18 kDa translocator protein (TSPO) radiotracers has contributed to our understanding on the role of inflammation in disease development and progression. With an increasing number of rodent models of human disease and expansion of the preclinical PET imaging base worldwide, accurate quantification of longitudinal rodent TSPO PET datasets is necessary. This is particularly relevant as TSPO PET quantification relies on invasive blood sampling due to lack of a suitable tissue reference region.