scholarly journals Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1874
Author(s):  
Ines Moreno-Gonzalez ◽  
George A. Edwards ◽  
Omar Hasan ◽  
Nazaret Gamez ◽  
Jonathan E. Schulz ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Tau Protein ◽  
Corticobasal Degeneration ◽  
Motor Memory ◽  
Longitudinal Assessment ◽  
Pet Tracer ◽  
Hyperphosphorylated Tau Protein ◽  
Learning Impairment ◽  
Tau Aggregation

Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

scholarly journals Evaluation of [68Ga]Ga-NODAGA-RGD for PET Imaging of Rat Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Arghavan Jahandideh ◽  
Mia Ståhle ◽  
Jenni Virta ◽  
Xiang-Guo Li ◽  
Heidi Liljenbäck ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Cell Surface Receptor ◽  
Myocardial Inflammation ◽  
Autoimmune Myocarditis ◽  
Inflammatory Lesions ◽  
Pet Tracer ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant

The 68Gallium-labeled 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid conjugated radiolabelled arginine-glycine-aspartic acid peptide ([68Ga]Ga-NODAGA-RGD) is a positron emission tomography (PET) tracer binding to cell surface receptor αvβ3 integrin that is upregulated during angiogenesis and inflammation. We studied whether αvβ3 targeting PET imaging can detect myocardial inflammation in a rat model of autoimmune myocarditis. To induce myocarditis, rats (n = 8) were immunized with porcine cardiac myosin in complete Freund's adjuvant on days 0 and 7. Control rats (n = 8) received Freund's adjuvant alone. On day 21, in vivo PET/CT imaging with [68Ga]Ga-NODAGA-RGD followed by ex vivo autoradiography and immunohistochemistry were carried out. Inflammatory lesions were detected histologically in the myocardium of 7 out of 8 immunized rats. In vivo PET images showed higher [68Ga]Ga-NODAGA-RGD accumulation in the myocardium of rats with inflammation than the non-inflamed myocardium of control rats (SUVmean 0.4 ± 0.1 vs. 0.1 ± 0.02; P = 0.00006). Ex vivo autoradiography and histology confirmed that [68Ga]Ga-NODAGA-RGD uptake co-localized with inflammatory lesions containing αvβ3 integrin-positive capillary-like structures. A non-specific [68Ga]Ga-DOTA-(RGE)2 tracer showed 76% lower uptake than [68Ga]Ga-NODAGA-RGD in the inflamed myocardium. Our results indicate that αvβ3 integrin-targeting [68Ga]Ga-NODAGA-RGD is a potential PET tracer for the specific detection of active inflammatory lesions in autoimmune myocarditis.

scholarly journals Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jing Zhao ◽  
Yu-liang Wang ◽  
Xin-bei Li ◽  
Si-yuan Gao ◽  
Shao-yu Liu ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Biological Evaluation ◽  
Brain Parenchyma ◽  
C6 Glioma ◽  
Small Animal Pet ◽  
Matrix Metalloproteinase 2 ◽  
Normal Brain ◽  
High Accumulation ◽  
Pet Tracer

Purposes. Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. Procedures. [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). Results. [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. Conclusions. Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.

scholarly journals Integrin VLA-4 as a PET imaging biomarker of hyper-adhesion in transgenic sickle mice

2020 ◽  
Vol 4 (17) ◽  
pp. 4102-4112
Author(s):  
Lydia A. Perkins ◽  
Lea Nyiranshuti ◽  
Lynda Little-Ihrig ◽  
Joseph D. Latoche ◽  
Kathryn E. Day ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Imaging Biomarker ◽  
Noninvasive Method ◽  
Cell Disease ◽  
Pet Tracer ◽  
Positron Emission ◽  
Late Antigen ◽  
Radionuclide Tracer ◽  
First Time

Abstract In sickle cell disease (SCD), very late antigen-4 (VLA-4 or integrin α4β1) mediates the adhesion of reticulocytes to inflamed, proinflammatory endothelium, a key process in promoting vaso-occlusive episodes (VOEs). We hypothesized that a radionuclide tracer targeting VLA-4 could be harnessed as a positron emission tomography (PET) imaging biomarker of VOEs. We tested the VLA-4 peptidomimetic PET tracer 64Cu-CB-TE1A1P-PEG4-LLP2A (64Cu-LLP2A) for imaging hyper-adhesion–associated VOEs in the SCD Townes mouse model. With lipopolysaccharide (LPS)-induced VOEs, 64Cu-LLP2A uptake was increased in the bone marrow of the humeri and femurs, common sites of VOEs in SCD mice compared with non-SCD mice. Treatment with a proven inhibitor of VOEs (the anti-mouse anti-P-selectin monoclonal antibody [mAb] RB40.34) during LPS stimulation led to a reduction in the uptake of 64Cu-LLP2A in the humeri and femurs to baseline levels, implying blockade of VOE hyper-adhesion. Flow cytometry with Cy3-LLP2A demonstrated an increased percentage of VLA-4–positive reticulocytes in SCD vs non-SCD mice in the bone and peripheral blood after treatment with LPS, which was abrogated by anti-P-selectin mAb treatment. These data, for the first time, show in vivo imaging of VLA-4–mediated hyper-adhesion, primarily of SCD reticulocytes, during VOEs. PET imaging with 64Cu-LLP2A may serve as a valuable, noninvasive method for identifying sites of vaso-occlusion and may provide an objective biomarker of disease severity and anti-P-selectin treatment efficacy in patients with SCD.

Tau Protein Aggregation in Alzheimer's Disease: Recent Advances in the Development of Novel Therapeutic Agents

2020 ◽  
Vol 26 (15) ◽  
pp. 1682-1692
Author(s):  
Kadja L.C. Monteiro ◽  
Marcone G. dos S. Alcântara ◽  
Thiago M. de Aquino ◽  
Edeildo F. da Silva-Júnior
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Tau Protein ◽  
Therapeutic Agents ◽  
Model Systems ◽  
Aggregation Inhibitors ◽  
Disease Modifying Agents ◽  
Tau Aggregation

: Major research in Alzheimer’s disease (AD) related to disease-modifying agents is concentrated on pharmacological approaches related to diagnostic markers, neurofibrillary tangles and amyloid plaques. Although most studies focus on anti-amyloid strategies, investigations on tau protein have produced significant advances in the modulation of the pathophysiology of several neurodegenerative diseases. Since the discovery of phenothiazines as tau protein aggregation inhibitors (TAGIs), many additional small molecule inhibitors have been discovered and characterized in biological model systems, which exert their interaction effects by covalent and noncovalent means. In this paper, we summarize the latest advances in the discovery and development of tau aggregation inhibitors using a specialized approach in their chemical classes. The design of new TAGIs and their encouraging use in in vivo and clinical trials support their potential therapeutic use in AD.

scholarly journals Preclinical In Vitro and In Vivo Evaluation of [18F]FE@SUPPY for Cancer PET Imaging: Limitations of a Xenograft Model for Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
T. Balber ◽  
J. Singer ◽  
N. Berroterán-Infante ◽  
M. Dumanic ◽  
L. Fetty ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pet Imaging ◽  
Xenograft Model ◽  
Preclinical Study ◽  
Colon Tissue ◽  
In Vivo Evaluation ◽  
Pet Tracer ◽  
Ht 29

Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of F18FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of F18FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of F18FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of F18FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using F18FE@SUPPY.

scholarly journals Advances in [18F]Trifluoromethylation Chemistry for PET Imaging

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6478
Author(s):  
Felix Francis ◽  
Frank Wuest
Keyword(s):  
Pet Imaging ◽  
Imaging Technique ◽  
Structural Motif ◽  
Pharmaceutical Chemistry ◽  
High Yield ◽  
Continuous Growth ◽  
Molar Activity ◽  
Pet Tracer ◽  
Positron Emission

Positron emission tomography (PET) is a preclinical and clinical imaging technique extensively used to study and visualize biological and physiological processes in vivo. Fluorine-18 (18F) is the most frequently used positron emitter for PET imaging due to its convenient 109.8 min half-life, high yield production on small biomedical cyclotrons, and well-established radiofluorination chemistry. The presence of fluorine atoms in many drugs opens new possibilities for developing radioligands labelled with fluorine-18. The trifluoromethyl group (CF3) represents a versatile structural motif in medicinal and pharmaceutical chemistry to design and synthesize drug molecules with favourable pharmacological properties. This fact also makes CF3 groups an exciting synthesis target from a PET tracer discovery perspective. Early attempts to synthesize [18F]CF3-containing radiotracers were mainly hampered by low radiochemical yields and additional challenges such as low radiochemical purity and molar activity. However, recent innovations in [18F]trifluoromethylation chemistry have significantly expanded the chemical toolbox to synthesize fluorine-18-labelled radiotracers. This review presents the development of significant [18F]trifluoromethylation chemistry strategies to apply [18F]CF3-containing radiotracers in preclinical and clinical PET imaging studies. The continuous growth of PET as a crucial functional imaging technique in biomedical and clinical research and the increasing number of CF3-containing drugs will be the primary drivers for developing novel [18F]trifluoromethylation chemistry strategies in the future.

scholarly journals Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2335 ◽  
Author(s):  
Max Holzer ◽  
Nico Schade ◽  
Ansgar Opitz ◽  
Isabel Hilbrich ◽  
Jens Stieler ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Tau Protein ◽  
Kinase Inhibitors ◽  
Neuronal Degeneration ◽  
Protein Kinase Inhibitors ◽  
Tau Hyperphosphorylation ◽  
Hyperphosphorylated Tau Protein ◽  
Viable Approach ◽  
Gsk 3Β ◽  
Tau Aggregation

The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges.

Dose Formulation, Biodistribution and PET Imaging Studies of a First-In-Class Fluorine-18 Organophosphorus Cholinesterase Inhibitor Tracer in Rat

2020 ◽  
Vol 14 ◽  
Author(s):  
Kiel D. Neumann ◽  
Joseph E. Blecha ◽  
Chih-Kai Chao ◽  
Tony Huynh ◽  
Kurt R. Zinn ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Male Rats ◽  
Imaging Data ◽  
Live Tissue ◽  
Dose Formulation ◽  
Pet Tracer ◽  
Ex Vivo Biodistribution

Background:: To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 (18F) radiolabeled positron emission tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. Objective.: We sought to evaluate the PET tracer in vivo using a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivo tracer performance to previous data collected using a CH3CN:PBS formulation. Methods:: A high molar activity [18F] tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. Results and Discussion:: An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included tracer and a single metabolite. The ex vivo biodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Conclusions:: Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we find that the i.v. dose formulation changed the in vivo profile of an organophosphorus PET tracer is considered an important finding for future organophosporus PET tracer studies.

scholarly journals PET imaging of P2X7R in the experimental autoimmune encephalomyelitis model of multiple sclerosis using [11C]SMW139

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wissam Beaino ◽  
Bieneke Janssen ◽  
Esther Kooijman ◽  
Ricardo Vos ◽  
Robert C. Schuit ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Pet Imaging ◽  
Specific Binding ◽  
Recovery Phase ◽  
Autoimmune Encephalomyelitis ◽  
Pet Tracer ◽  
The Brain ◽  
Experimental Autoimmune

Abstract Background Non-invasive imaging of the activation status of microglia and the ability to identify a pro- or anti-inflammatory environment can provide valuable insights not only into pathogenesis of neuro-inflammatory and neurodegenerative diseases but also the monitoring of the efficacy of immunomodulatory therapies. P2X7R is highly expressed on pro-inflammatory microglia and [11C]SMW139, a specific P2X7R tracer for positron emission tomography imaging, showed good pharmacokinetics, stability, and brain permeability in vivo. Our objective was to evaluate the potential of [11C]SMW139 for PET imaging of neuroinflammation in vivo in the experimental autoimmune encephalomyelitis (EAE) model. Methods We induced EAE in Lewis rats by immunization with MBP 69-88 in complete Freund’s adjuvant (CFA). We determined the affinity of [11C]SMW139 to human and rat P2X7R using saturation binding assay. Using this tracer, PET imaging was performed at the peak of disease and in the recovery phase. In vivo blocking experiments were conducted to validate the specific brain uptake of the tracer. Immunohistochemistry staining and autoradiography were performed to evaluate the level of neuroinflammation and validate the specific binding of [11C]SMW139. Results [11C]SMW139 showed good affinity for the rat P2X7R with a Kd of 20.6 ± 1.7 nM. The uptake of [11C]SMW139 was significantly higher in EAE animals at the peak of disease compared to the recovery phase but not in CFA control animals. The amplitude of increase of [11C]SMW139 uptake showed significant positive correlation with clinical scores mainly in the spinal cord (Pearson = 0.75, Spearman = 0.76; p < 0.0001). Treating EAE animals with P2X7R antagonist JNJ-47965567 blocked the uptake of [11C]SMW139 in the spinal cord, cerebellum, and brain stem, demonstrating specific accumulation of the tracer. P-glycoprotein blocking with tariquidar (30 mg/kg) did not affect tracer penetration in the brain showing that [11C]SMW139 is not a Pgp substrate. Conclusion Our data shows that [11C]SMW139 is a promising PET tracer for imaging neuroinflammation and evaluating the dynamics of pro-inflammatory microglia in the brain. This can provide crucial insights into the role of microglia in disease progression and enables the development of novel treatment strategies aimed at modulating the immune response in order to promote neuroprotection.

scholarly journals Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo

2020 ◽  
Vol 79 (9) ◽  
pp. 941-949
Author(s):  
Sarah A Weitzman ◽  
Sneha Narasimhan ◽  
Zhuohao He ◽  
Lakshmi Changolkar ◽  
Jennifer D McBride ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein A ◽  
Chromosome 17 ◽  
Intracellular Accumulation ◽  
Tau Pathology ◽  
Clinical Presentations ◽  
Hyperphosphorylated Tau Protein ◽  
Human Brains

Abstract One hallmark of neurodegenerative diseases is the intracellular accumulation of hyperphosphorylated tau protein, a neuronal microtubule-associated protein, into structures known as neurofibrillary tangles. Tauopathies are heterogeneous neurodegenerative diseases caused by the misfolding of the tau protein. It has been previously shown that the tau protein can spread from cell to cell in a prion-like manner. Tauopathies can be sporadic or familial, with the identification of pathogenic mutations in the microtubule-associated protein tau gene on chromosome 17 in the familial cases. Different frontotemporal dementia with parkinsonism-17 (FTDP-17) cases are associated with varying clinical presentations and types of neuropathology. We previously demonstrated that insoluble tau extracted from sporadic tauopathy human brains contain distinct tau strains, which underlie the heterogeneity of these diseases. Furthermore, these tau strains seeded tau aggregates that resemble human tau neuropathology in nontransgenic and 6hTau mice in vivo. Here, we show insoluble tau from human brains of FTDP-17 cases transmit different patterns of neuronal and glial tau pathology in vivo, similar to the sporadic tauopathies. This suggests that each of these tau mutations has unique properties that underlie the heterogeneity of FTDP-17 cases.

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