Positron Emission Tomography Techniques to Measure Active Inflammation, Fibrosis and Angiogenesis in Hypertensive Heart Failure

Heart failure, which is responsible for a high number of deaths worldwide, can develop due to chronic hypertension. Heart failure can involve and progress through several different pathways, including: fibrosis, inflammation, and angiogenesis. Early and specific detection of changes in the myocardium during the transition to heart failure can be made via the use of molecular imaging techniques, including positron emission tomography (PET). Traditional cardiovascular PET techniques, such as myocardial perfusion imaging and sympathetic innervation imaging, have been established at the clinical level but are often lacking in pathway and target specificity that is important for assessment of heart failure. Therefore, there is a need to identify new PET imaging markers of inflammation, fibrosis and angiogenesis that could aid diagnosis, staging and treatment of hypertensive heart failure. This review will provide an overview of key mechanisms underlying hypertensive heart failure and will present the latest developments in PET probes for detection of cardiovascular inflammation, fibrosis and angiogenesis. Currently, selective PET probes for detection of angiogenesis remain elusive but promising PET probes for specific targeting of inflammation and fibrosis are rapidly progressing into clinical use

Automated Radiosynthesis of cis- and trans-4-[18F]Fluoro-L-proline using [18F]Fluoride

The positron emission tomography imaging agents cis- and trans-4-[18F]fluoro-l-proline are used for the detection of numerous diseases such as pulmonary fibrosis and various carcinomas. These imaging agents are typically prepared by nucleophilic fluorination of 4-hydroxy-l-proline derivatives, with [18F]fluoride, followed by deprotection. Although effective radiofluorination reactions have been developed, the overall radiosynthesis process is suboptimal due to deprotection methods that are performed manually, require multiple steps, or involve harsh conditions. Here we describe the development of two synthetic routes that allow access to precursors, which undergo highly selective radiofluorination reactions and rapid deprotection, under mild acidic conditions. These methods were found to be compatible with automation, avoiding manual handling of radioactive intermediates

Parameterised Geant4 simulation for total body PET research

Total-body positron emission tomography (PET) imaging has the potential to transform medical care of a number of diseases and augment our knowledge of systems biology. Various detector designs and geometries are currently under development for total-body PET imaging of humans. This variety, in particular the variation in axial field-of-view (aFOV), motivates a need to compare the performance of these devices in a consistent simulated environment. We present an open-source Geant4 simulation package that allows variation of relevant parameters such as the detector aFOV and the tracer radioisotope from the command line. Two simplified detector geometries based on the Siemens Biograph Vision Quadra and United Imaging uEXPLORER models are supported with variable granularity. The intrinsic radioactivity of the detector crystals is fully simulated. The simulation can be viewed with the built-in GUI, and the results are saved in a plain text format for easy analysis. Example Python analysis code is provided with the simulation, demonstrating calculation of the noise equivalent count rate (NECR) figure of merit using an approximation to the NEMA NU 2-2012 standard method. A good agreement between the simulated count rate performance and experimental data is observed for both geometries. The differences in results are attributed to simplifications in the simulation code, namely not accounting for the light-collection efficiency or readout dead-time. We demonstrate the importance of assessing the scanner performance using appropriate phantom length which significantly affects the obtained results. A dependence between the detector aFOV and the length of the source, with peak NECR plateauing as the detector extends beyond the region of interest is also presented.Comment: 13 pages in total, 6 figure

A novel 18F-labelled high affinity agent for PET imaging of the translocator protein

The translocator protein (TSPO) is an important target for imaging focal neuroinflammation in diseases such as brain cancer, stroke and neurodegeneration, but current tracers for non-invasive imaging of TSPO have important limitations. We present the synthesis and evaluation of a novel 3-fluoromethylquinoline-2-carboxamide, AB5186, which was prepared in eight steps using a one-pot two component indium(III)-catalysed reaction for the rapid and efficient assembly of the 4-phenylquinoline core. Biological assessment and the implementation of a physicochemical study showed AB5186 to have low nanomolar affinity for TSPO, as well as optimal plasma protein binding and membrane permeability properties. Generation of [18F]-AB5186 through 18F incorporation was achieved in good radiochemical yield and subsequent in vitro and ex vivo autoradiography revealed the ability of this compound to bind with specificity to TSPO in mouse glioblastoma xenografts. Initial positron emission tomography imaging of a glioma bearing mouse and a healthy baboon support the potential for [18F]-AB5186 use as a radiotracer for non-invasive TSPO imaging in vivo

Assessing the impact of different penalty factors of the Bayesian reconstruction algorithm Q.Clear on in vivo low count kinetic analysis of [11C]PHNO brain PET-MR studies

INTRODUCTION: Q.Clear is a Bayesian penalised likelihood (BPL) reconstruction algorithm available on General Electric (GE) Positron Emission Tomography (PET)-Computed Tomography (CT) and PET-Magnetic Resonance (MR) scanners. This algorithm is regulated by a β value which acts as a noise penalisation factor and yields improvements in signal to noise ratio (SNR) in clinical scans, and in contrast recovery and spatial resolution in phantom studies. However, its performance in human brain imaging studies remains to be evaluated in depth. This pilot study aims to investigate the impact of Q.Clear reconstruction methods using different β value versus ordered subset expectation maximization (OSEM) on brain kinetic modelling analysis of low count brain images acquired in the PET-MR. METHODS: Six [(11)C]PHNO PET-MR brain datasets were reconstructed with Q.Clear with β100–1000 (in increments of 100) and OSEM. The binding potential relative to non-displaceable volume (BP(ND)) were obtained for the Substantia Nigra (SN), Striatum (St), Globus Pallidus (GP), Thalamus (Th), Caudate (Cd) and Putamen (Pt), using the MIAKAT™ software. Intraclass correlation coefficients (ICC), repeatability coefficients (RC), coefficients of variation (CV) and bias from Bland–Altman plots were reported. Statistical analysis was conducted using a 2-way ANOVA model with correction for multiple comparisons. RESULTS: When comparing a standard OSEM reconstruction of 6 iterations/16 subsets and 5 mm filter with Q.Clear with different β values under low counts, the bias and RC were lower for Q.Clear with β100 for the SN (RC = 2.17), Th (RC = 0.08) and GP (RC = 0.22) and with β200 for the St (RC = 0.14), Cd (RC = 0.18)and Pt (RC = 0.10). The p-values in the 2-way ANOVA model corroborate these findings. ICC values obtained for Th, St, GP, Pt and Cd demonstrate good reliability (0.87, 0.99, 0.96, 0.99 and 0.96, respectively). For the SN, ICC values demonstrate poor reliability (0.43). CONCLUSION: BP(ND) results obtained from quantitative low count brain PET studies using [(11)C]PHNO and reconstructed with Q.Clear with β < 400, which is the value used for clinical [(18)F]FDG whole-body studies, demonstrate the lowest bias versus the typical iterative reconstruction method OSEM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-022-00883-1

A systems-level analysis of total-body PET data reveals complex skeletal metabolism networks in vivo

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. in vitro 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 in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network, which could not be identified using single tissue simplistic PET standard uptake values analysis. The application of our approach could reveal new physiological and pathological tissue interactions beyond skeletal metabolism, due to PET radiotracers diversity and the advent of clinical total-body PET systems