scholarly journals Potential of [11C]UCB-J as a PET tracer for islets of Langerhans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emmi Puuvuori ◽  
Johanna Rokka ◽  
Per-Ola Carlsson ◽  
Zhanchun Li ◽  
Jonas Eriksson ◽  
...  
Keyword(s):  
Islets Of Langerhans ◽  
Radioligand Binding ◽  
Ex Vivo ◽  
Negative Control ◽  
Sprague Dawley ◽  
In Vitro Autoradiography ◽  
Potential Marker ◽  
Pet Tracer ◽  
Ex Vivo Autoradiography

AbstractBiomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [11C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [11C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague–Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [11C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [11C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [11C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [11C]UCB-J does not appear to have sufficient sensitivity for this application.

scholarly journals Sapap3 deletion causes dynamic synaptic density abnormalities: a longitudinal [11C]UCB-J PET study in a model of obsessive–compulsive disorder-like behaviour

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dorien Glorie ◽  
Jeroen Verhaeghe ◽  
Alan Miranda ◽  
Stef De Lombaerde ◽  
Sigrid Stroobants ◽  
...  
Keyword(s):  
Mouse Model ◽  
Obsessive Compulsive Disorder ◽  
Ex Vivo ◽  
Obsessive Compulsive ◽  
Synaptic Density ◽  
Compulsive Disorder ◽  
In Vitro Autoradiography ◽  
Ex Vivo Autoradiography ◽  
The Brain

Abstract Background Currently, the evidence on synaptic abnormalities in neuropsychiatric disorders—including obsessive–compulsive disorder (OCD)—is emerging. The newly established positron emission tomography (PET) ligand ((R)-1-((3-((11)C-methyl-(11)C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([11C]UCB-J) provides the opportunity to visualize synaptic density changes in vivo, by targeting the synaptic vesicle protein 2A (SV2A). Here, we aim to evaluate such alterations in the brain of the SAP90/PSD-95-associated protein 3 (Sapap3) knockout (ko) mouse model, showing an abnormal corticostriatal neurotransmission resulting in OCD-like behaviour. Methods Longitudinal [11C]UCB-J µPET/CT scans were acquired in Sapap3 ko and wildtype (wt) control mice (n = 9/group) to study SV2A availability. Based on the Logan reference method, we calculated the volume of distribution (VT(IDIF)) for [11C]UCB-J. Both cross-sectional (wt vs. ko) and longitudinal (3 vs. 9 months) volume-of-interest-based statistical analysis and voxel-based statistical parametric mapping were performed. Both [11C]UCB-J ex vivo autoradiography and [3H]UCB-J in vitro autoradiography were used for the validation of the µPET data. Results At the age of 3 months, Sapap3 ko mice are already characterized by a significantly lower SV2A availability compared to wt littermates (i.a. cortex − 12.69%, p < 0.01; striatum − 14.12%, p < 0.001, thalamus − 13.11%, p < 0.001, and hippocampus − 12.99%, p < 0.001). Healthy ageing in control mice was associated with a diffuse and significant (p < 0.001) decline throughout the brain, whereas in Sapap3 ko mice this decline was more confined to the corticostriatal level. A strong linear relationship (p < 0.0001) was established between the outcome parameters of [11C]UCB-J µPET and [11C]UCB-J ex vivo autoradiography, while such relationship was absent for [3H]UCB-J in vitro autoradiography. Conclusions [11C]UCB-J PET is a potential marker for synaptic density deficits in the Sapap3 ko mouse model for OCD, parallel to disease progression. Our data suggest that [11C]UCB-J ex vivo autoradiography is a suitable proxy for [11C]UCB-J PET data in mice.

scholarly journals A Tumbling Magnetic Microrobot System for Biomedical Applications

Micromachines ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 861
Author(s):  
Elizabeth E. Niedert ◽  
Chenghao Bi ◽  
Georges Adam ◽  
Elly Lambert ◽  
Luis Solorio ◽  
...  
Keyword(s):  
Ultrasound Imaging ◽  
Biomedical Applications ◽  
Imaging System ◽  
Ex Vivo ◽  
Negative Control ◽  
Circular Path ◽  
Rotational Axis ◽  
Significant Difference

A microrobot system comprising an untethered tumbling magnetic microrobot, a two-degree-of-freedom rotating permanent magnet, and an ultrasound imaging system has been developed for in vitro and in vivo biomedical applications. The microrobot tumbles end-over-end in a net forward motion due to applied magnetic torque from the rotating magnet. By turning the rotational axis of the magnet, two-dimensional directional control is possible and the microrobot was steered along various trajectories, including a circular path and P-shaped path. The microrobot is capable of moving over the unstructured terrain within a murine colon in in vitro, in situ, and in vivo conditions, as well as a porcine colon in ex vivo conditions. High-frequency ultrasound imaging allows for real-time determination of the microrobot’s position while it is optically occluded by animal tissue. When coated with a fluorescein payload, the microrobot was shown to release the majority of the payload over a 1-h time period in phosphate-buffered saline. Cytotoxicity tests demonstrated that the microrobot’s constituent materials, SU-8 and polydimethylsiloxane (PDMS), did not show a statistically significant difference in toxicity to murine fibroblasts from the negative control, even when the materials were doped with magnetic neodymium microparticles. The microrobot system’s capabilities make it promising for targeted drug delivery and other in vivo biomedical applications.

Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension

2002 ◽  
Vol 282 (6) ◽  
pp. H2084-H2090 ◽  
Author(s):  
Yasuko Iwakiri ◽  
Ming-Hung Tsai ◽  
Timothy J. McCabe ◽  
Jean-Philippe Gratton ◽  
David Fulton ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Specific Activity ◽  
Ex Vivo ◽  
Active Form ◽  
Initial Increase ◽  
No Production ◽  
Portal Vein Ligation ◽  
Sprague Dawley ◽  
Perfusion Studies

Akt, also known as protein kinase B, is a serine/threonine kinase. Akt becomes active when phosphorylated by the activation of receptor tyrosine kinases, G protein-coupled receptors, and mechanical forces such as shear stress. Studies in vitro have shown that Akt can directly phosphorylate endothelial nitric oxide (NO) synthase (eNOS) and activate the enzyme, leading to NO production. The aim of this study was to test the hypothesis that the phosphorylation of eNOS plays a role in the enhanced NO production observed in early portal hypertension. Male Sprague-Dawley rats were subjected to either sham or portal vein ligation (PVL), and mesenteric arterial beds were used for ex vivo perfusion studies. Mesenteric arterial beds from PVL rats had an approximately 60–70% decrease in response to methoxamine (an α1-agonist and vasoconstrictor) compared with the sham group ( P < 0.01). When N G-monomethyl-l-arginine (a NOS inhibitor) was added to the perfusion, the difference in perfusion pressure between the two groups was abolished, suggesting that enhanced NO production in the PVL group blunted the response to the vasoconstrictor. The reduced responsiveness in PVL was not due to changes in eNOS expression but was due to an increase in enzyme-specific activity, suggesting posttranslational modification of eNOS. The phosphorylation of eNOS at Ser1176 was significantly increased by twofold ( P < 0.05) in the PVL group. Furthermore, PVL significantly increased Akt phosphorylation (an active form of Akt) by threefold ( P< 0.05). When vessels were treated with wortmannin (10 nM) to block the phosphatidylinositol-3-OH-kinase/Akt pathway, NO-induced vasodilatation was significantly reduced. These results suggest that the phosphorylation of eNOS by Akt activates the enzyme and may be the first step leading to an initial increase in NO production in portal hypertension.

scholarly journals Studies to Elucidate the Mechanism of Cardio Protective and Hypotensive Activities of Anogeissus acuminata (Roxb. ex DC.) in Rodents

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3471
Author(s):  
Fatima Saqib ◽  
Muhammad Arif Aslam ◽  
Khizra Mujahid ◽  
Luigi Marceanu ◽  
Marius Moga ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Sprague Dawley ◽  
Positive Effects ◽  
Creatine Kinase Mb

Anogeissus acuminata (Roxb. ex DC.) is a folkloric medicinal plant in Asia; including Pakistan; used as a traditional remedy for cardiovascular disorders. This study was planned to establish a pharmacological basis for the trivial uses of Anogeissus acuminata in certain medical conditions related to cardiovascular systems and to explore the underlying mechanisms. Mechanistic studies suggested that crude extract of Anogeissus acuminata (Aa.Cr) produced in vitro cardio-relaxant and vasorelaxant effects in isolated paired atria and aorta coupled with in vivo decrease in blood pressure by invasive method; using pressure and force transducers connected to Power Lab Data Acquisition System. Moreover; Aa.Cr showed positive effects in left ventricular hypertrophy in Sprague Dawley rats observed hemodynamically by a decrease in cardiac cell size and fibrosis; along with absence of inflammatory cells; coupled with reduced levels of angiotensin converting enzyme (ACE) and renin concentration along with increased concentrations of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). In Acute Myocardial Infarction (AMI) model; creatine kinase (CK), creatine kinase-MB (CK-MB) and lactic acid dehydrogenase (LDH levels) were found to be decreased; along with decreased necrosis; edema and recruitment of inflammatory cells histologically. In vivo and ex vivo studies of Anogeissus acuminata provided evidence of vasorelaxant; hypotensive and cardioprotective properties facilitated through blockage of voltage-gated Ca++ ion channel; validating its use in cardiovascular diseases

In vitro and ex vivo autoradiography of the NK-1 antagonist [3H]-LY686017 in Guinea pig brain

Neuropeptides ◽  
2011 ◽  
Vol 45 (2) ◽  
pp. 157-164
Author(s):  
Susan L. Gackenheimer ◽  
Donald R. Gehlert
Keyword(s):  
Guinea Pig ◽  
Ex Vivo ◽  
Pig Brain ◽  
Ex Vivo Autoradiography ◽  
Guinea Pig Brain

scholarly journals Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1072 ◽  
Author(s):  
Sanna Hellberg ◽  
Johanna Silvola ◽  
Heidi Liljenbäck ◽  
Max Kiugel ◽  
Olli Eskola ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Mouse Strains ◽  
Aortic Tissue ◽  
Atherosclerotic Plaques ◽  
Carotid Artery Plaque ◽  
Pet Tracer ◽  
Pet Ct ◽  
Human Carotid

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR−/−ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR−/−ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.

scholarly journals Development of a CD19 PET tracer for detecting B cells in a mouse model of multiple sclerosis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Marc Y. Stevens ◽  
Haley C. Cropper ◽  
Katherine L. Lucot ◽  
Aisling M. Chaney ◽  
Kendra J. Lechtenberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Brain Tissue ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Therapeutic Success ◽  
Gamma Counting ◽  
Pet Tracer ◽  
Imaging Results ◽  
Ex Vivo Autoradiography

Abstract Background B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. The therapeutic success of monoclonal antibodies (mAbs) targeting B cells in some but not all individuals suffering from MS highlights the need for a method to stratify patients and monitor response to treatments in real-time. Herein, we describe the development of the first CD19 positron emission tomography (PET) tracer, and its evaluation in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE). Methods Female C57BL/6 J mice were induced with EAE through immunization with myelin oligodendrocyte glycoprotein (MOG1–125). PET imaging of naïve and EAE mice was performed 19 h after administration of [64Cu]CD19-mAb. Thereafter, radioactivity in organs of interest was determined by gamma counting, followed by ex vivo autoradiography of central nervous system (CNS) tissues. Anti-CD45R (B220) immunostaining of brain tissue from EAE and naïve mice was also conducted. Results Radiolabelling of DOTA-conjugated CD19-mAb with 64Cu was achieved with a radiochemical purity of 99% and molar activity of 2 GBq/μmol. Quantitation of CD19 PET images revealed significantly higher tracer binding in whole brain of EAE compared to naïve mice (2.02 ± 0.092 vs. 1.68 ± 0.06 percentage of injected dose per gram, % ID/g, p = 0.0173). PET findings were confirmed by ex vivo gamma counting of perfused brain tissue (0.22 ± 0.020 vs. 0.12 ± 0.003 % ID/g, p = 0.0010). Moreover, ex vivo autoradiography of brain sections corresponded with PET imaging results and the spatial distribution of B cells observed in B220 immunohistochemistry—providing further evidence that [64Cu]CD19-mAb enables visualization of B cell infiltration into the CNS of EAE mice. Conclusion CD19-PET imaging can be used to detect elevated levels of B cells in the CNS of EAE mice, and has the potential to impact the way we study, monitor, and treat clinical MS.

scholarly journals Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Frank Herrmann ◽  
Manuela Hessmann ◽  
Sabine Schaertl ◽  
Karola Berg-Rosseburg ◽  
Christopher J Brown ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Trinucleotide Repeat ◽  
Radioligand Binding ◽  
Ex Vivo ◽  
Binding Assays ◽  
Pharmacological Characterization ◽  
Binding Characteristics

AbstractHuntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.

Synthesis of Novel Derivatives of Quinazoline Schiff base Compound Promotes Epithelial Wound Healing

2018 ◽  
Vol 24 (13) ◽  
pp. 1395-1404
Author(s):  
Elham Bagheri ◽  
Kamelia Saremi ◽  
Fatemeh Hajiaghaalipour ◽  
Fadhil Lafta Faraj ◽  
Hapipah Mohd Ali ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Biological Activities ◽  
Inflammatory Cells ◽  
Negative Control ◽  
High Dose ◽  
Sprague Dawley ◽  
Wound Tissue

Quinazoline is an aromatic bicyclic compound exhibiting several pharmaceutical and biological activities. This study was conducted to investigate the potential wound healing properties of Synthetic Quinazoline Compound (SQC) on experimental rats. The toxicity of SQC was determined by MTT cell proliferation assay. The healing effect of SQC was assessed by in vitro wound healing scratch assay on the skin fibroblast cells (BJ-5ta) and in vivo wound healing experiment of low and high dose of SQC on adult Sprague-Dawley rats compared with negative (gum acacia) and positive control (Intrasite-gel). Hematoxylin and Eosin (H&E), Masson’s Trichrome (MT) staining and immunohistochemistry analysis were performed to evaluate the histopathological alterations and proteins expression of Bax and Hsp70 on the wound tissue after 10 days. In addition, levels of antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase), and malondialdehyde (MDA) were measured in wound tissue homogenates. The SQC significantly enhanced BJ-5ta cell proliferation and accelerated the percentage of wound closure, with less scarring, increased fibroblast and collagen fibers and less inflammatory cells compared with the negative control. The compound also increases endogenous enzymes and decline lipid peroxidation in wound homogenate.

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