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Radiosynthesis, in vivo biological evaluation, and imaging of brain lesions with [123I]-CLINME, a new SPECT tracer for the translocator protein
Get PDFThe high affinity translocator protein (TSPO) ligand 6-chloro-2-(4′-iodophenyl)-3-(N,N-methylethyl)imidazo[1,2-a]pyridine-3-acetamide (CLINME) was radiolabelled with iodine-123 and assessed for its sensitivity for the TSPO in rodents. Moreover neuroinflammatory changes on a unilateral excitotoxic lesion rat model were detected using SPECT imaging. [123I]-CLINME was prepared in 70–80% radiochemical yield. The uptake of [123I]-CLINME was evaluated in rats by biodistribution, competition, and metabolite studies. The unilateral excitotoxic lesion was performed by injection of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid unilaterally into the striatum. The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography. In vivo studies with [123I]-CLINME indicated a biodistribution pattern consistent with TPSO distribution and the competition studies with PK11195 and Ro 5-4864 showed that [123I]-CLINME is selective for this site. The metabolite study showed that the extractable radioactivity was unchanged [123I]-CLINME in organs which expresses TSPO. SPECT/CT imaging on the unilateral excitotoxic lesion indicated that the mean ratio uptake in striatum (lesion : nonlesion) was 2.2. Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography. These results indicated that [123I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT. © 2015 F. Mattner et al
Optimisation of [11C]raclopride production using a synthra GPextent system
No full textThe dopamine D2 receptor radiotracer [(11)C]Raclopride is used extensively in clinical and preclinical imaging. Currently, a wide range of methods to produce [(11)C]Raclopride have been developed using traditional vessel reactions as well as cartridge or captive solvent. This work reports the optimisation of the production of [(11)C]Raclopride using a Synthra GPextent, comparing various methods. With optimised conditions, we were able to obtain 4±2% (ndc) yield of [(11)C]Raclopride (100 GBq [(11)C]CO2, n = 42) in 25 min. The radiochemical purity was >95% with specific activities of 135±41 MBq/nmol at end of synthesis. © 2014 Bentham Science Publisher
Hydrogen bonding interactions in poly(ε-caprolactone–dimethyl siloxane–ε-caprolactone)/poly(hydroxyether of bisphenol A) triblock copolymer/homopolymer blends and the effect on crystallization, microphase separation and self-assembly
No full textThis study investigated the self-assembled microphase separated morphologies that are obtained in bulk, by the complexation of a semicrystalline poly(ε-caprolactone–dimethyl siloxane–ε-caprolactone) (PCL–PDMS–PCL) triblock copolymer and a homopolymer, poly(hydroxyether of bisphenol A) (PH) in tetrahydrofuran (THF). In these blends, microphase separation takes place due to the disparity in intermolecular interactions; specifically, the homopolymer interacts with PCL blocks through hydrogen bonding interactions. The crystallization, microphase separation and crystalline structures of a triblock copolymer/homopolymer blends were investigated. The phase behavior of the complexes was investigated using small-angle X-ray scattering and transmission electron microscopy. At low PH concentrations, PCL interacts relatively weakly with PH, whereas in complexes containing more than 50 wt% PH, the PCL block interacts significantly with PH, leading to the formation of composition-dependent nanostructures. SAXS and TEM results indicate that the lamellar morphology of neat PCL–PDMS–PCL triblock copolymer changes into disordered structures at 40–60 wt% PH. Spherical microdomains were obtained in the order of 40–50 nm in complexes with 80 wt% PH. At this concentration, the complexes show a completely homogenous phase of PH/PCL, with phase-separated spherical PDMS domains. The formation of these nanostructures and changes in morphology depends on the strength of hydrogen bonding between PH/PCL blocks and also the phase separated PDMS blocks. © 2015 Elsevier Ltd
Development and validation of competition binding assays for affinity to the extracellular matrix receptors, αvβ3 and αIIbβ3 integrin
No full textThe RGD (Arg-Gly-Asp) binding integrins αvβ3 and αIIbβ3 are integral components of various pathological and physiological processes, including tumor angiogenesis, osteoclast function, and thrombus formation. Because of this, there is interest in identifying novel compounds and proteins binding to these receptors as well as investigating the mechanism of these interactions. In this article, we describe the development and validation of competition binding assays for determining the affinity of test compounds to αvβ3 and αIIbβ3 integrin. Assays were successfully developed for each receptor, and the affinity of known compounds was comparable to published results. However, the inability of binding between αIIbβ3 integrin and the labeled echistatin protein ligand to reach equilibrium resulted in an assay that did not meet the assumptions of the competition binding model. Nevertheless, there was good agreement between this assay and known literature values, and intra- and interassay variability was acceptable. Binding by conformation-specific antibodies provided evidence that solid-phase bound αIIbβ3 receptor was in an activated conformation. This study also demonstrated that current models and methods for determining receptor affinity are simplistic and fail to account for common receptor–ligand interactions such as nondissociable interactions and varying receptor activation states. © 2012 by Elsevier Inc
Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice
No full textChronic inflammation is involved in the pathogenesis of obesity and type 2 diabetes. Recently teasaponin, an extract from tea, has been shown to have antiinflammatory effects. We examined the effect of teasaponin on obesity, inflammation, glucose metabolism, and central leptin sensitivity in obese mice fed a high-fat (HF) diet for 16 weeks. Intraperitoneal injections of teasaponin (10 mg/kg, daily) for 21 days significantly decreased the food intake and body weight of HF diet-induced obese mice. Teasaponin treatment also reduced the protein levels of proinflammatory cytokines (TNF-α, IL-6, and/or IL-1β) and nuclear factor-κB signaling (phosphorylated inhibitory-κB kinase and phosphorylated inhibitory-κBα) in adipose tissue and the liver. The antiinflammatory effects of teasaponin were associated with improved glycemic status in the treated animals, evidenced by improved glucose tolerance, homeostasis model assessment, and fasting plasma insulin. In the hypothalamus, teasaponin decreased both proinflammatory cytokines and inflammatory signaling in the mediobasal hypothalamus. Teasaponin treatment also enhanced the anorexigenic effect of central leptin administration, restored leptin phosphorylated signal transducer and activator of transcription-3 (p-STAT3) signaling in the arcuate nucleus, and increased hypothalamic expression of the anorexigenic peptide proopiomelanocortin. These results identify a potential novel application for teasaponin as an antiobesity and antiinflammatory agent. © 2013, Oxford University Pres
Solvothermal synthesis of uranium(VI) phases with aromatic carboxylate ligands: A dinuclear complex with 4-hydroxybenzoic acid and a 3D framework with terephthalic acid
No full textWith the coordination of dimethylformamide (DMF), two new uranium(VI) complexes with either 4-hydroxybenzoic acid (H2phb) or terephthalic acid (H2tph) have been synthesized under solvothermal conditions and structurally characterized. [(UO2)2(Hphb)2(phb)(DMF)(H2O)3]·4H2O (1) has a dinuclear structure constructed with both pentagonal and hexagonal bipyramidal uranium polyhedra linked through a µ2-bridging ligand via both chelating carboxylate arm and alcohol oxygen bonding, first observation of such a coordination mode of 4-hydroxybenzoate for 5 f ions. [(UO2)(tph)(DMF)] (2) has a three-dimensional (3D) framework built with pentagonal bipyramidal uranium polyhedra linked with µ4-terephthalate ligands. The 3D channeled structure is facilitated by the unique carboxylate bonding with nearly linear C–O–U angles and the coordination of DMF molecules. The presence of phb ligands in different coordination modes, uranyl ions in diverse environments and DMF in complex 1, and tph ligand, DMF and uranyl ion in complex 2 has been confirmed by Raman spectroscopy. In addition, their thermal stability and photoluminescence properties have been investigated. © 2015 Elsevier Inc
Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111
No full textPurpose
To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT.
Methods
In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography–tandem mass spectrometry. [18F]PBR102 and [18F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [18F]fluoride. List mode PET-CT brain imaging with arterial blood sampling was performed in non-human primates. Blood plasma measurements and metabolite analysis, using solid-phase extraction, provided the metabolite profile and metabolite-corrected input functions for kinetic model fitting. Blocking and displacement PET-CT scans, using PK11195, were performed.
Results
Microsomal analyses identified the O-de-alkylated, hydroxylated and N-de-ethyl derivatives of PBR102 and PBR111 as the main metabolites. The O-de-alkylated compounds were the major metabolites in both species; human liver microsomes were less active than those from rat. Metabolic profiles in vivo in non-human primates and previously published rat experiments were consistent with the microsomal results. PET-CT studies showed that K1 was similar for baseline and blocking studies for both radiotracers; VT was reduced during the blocking study, suggesting low non-specific binding and lack of appreciable metabolite uptake in the brain.
Conclusions
[18F]PBR102 and [18F]PBR111 have distinct metabolic profiles in rat and non-human primates. Radiometabolites contributed to non-specific binding and confounded in vivo brain analysis of [18F]PBR102 in rodents; the impact in primates was less pronounced. Both [18F]PBR102 and [18F]PBR111 are suitable for PET imaging of TSPO in vivo. In vitro metabolite studies can be used to predict in vivo radioligand metabolism and can assist in the design and development of better radioligands. © 2016 Springer-Verla
Synthesis and stability studies of Ga‐67 labeled phosphonium salts
No full textDelocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (ΔΨm). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC50 > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined. © 2016 John Wiley & Sons, Ltd
Dose modelling comparison for terrestrial biota: IAEA EMRAS II Biota Working Group's Little Forest Burial Ground scenario
Get PDFRadiological doses to terrestrial biota have been examined in a model inter-comparison study that emphasised the identification of factors causing variability in dose estimation. Radiological dose rates were modelled for ten species representing a diverse range of terrestrial plant and animals with varying behavioural and physical attributes. Dose to these organisms may occur from a range of gamma (Co-60, Cs-137), beta (Sr-90) and alpha (Th-232, U-234 and U-238, Pu-238, Pu-239/240 and Am-241) emitting radionuclides. Whilst the study was based on a specific site - the Little Forest Burial Ground, New South Wales, and Australia - it was intended to be representative of conditions at sites throughout the world where low levels of radionuclides exist in soil due to waste disposal or similar activities
Hybrid non-rigid registration method for registering rat skeletons from micro-CT images
No full textObjectives: A hybrid non-rigid registration method for automatic rat spine detection and registration and further rat limbs registration was proposed.
Methods: We first developed an automatic algorithm to extract the rat spine from its whole-body skeleton and then detect top point on the spinous process of each vertebra starting from the first vertebra at thoracic vertebrae towards the tail. The extracted points were matched to the predefined corresponding points of the spine in a rat atlas. Their correspondences field was used to perform skeletons registration by thin-plate-spline (TPS). Further, we extend 3D shape context algorithm for landmarks matching for rat limbs between the atlas and the newly extracted skeletons. The correspondences found were used to perform the rat limb skeletons registration by TPS.
Results: Experiments were described using phantoms and actual rat skeletons. Mean square errors decrease was observed during registration process. Visually, the skeletons were successfully registered.
Conclusions: The method can improve the robustness of rat skeleton registration, even in the case of large variation in some postures and this first step work can be extended to further improve rat organs registration guided by the correspondences found from the skeletons.© 2009 by Society of Nuclear Medicin