scholarly journals [18F]FEPPA Pet Imaging for Monitoring CD68 Positive Microglia/Macrophage Neuroinflammation in Nonhuman Primates

2020 ◽  
Author(s):  
Matthew Zammit ◽  
Yunlong Tao ◽  
Miles Olsen ◽  
Jeanette Metzger ◽  
Scott Vermilyea ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Macrophage Activation ◽  
Nonhuman Primates ◽  
Rhesus Macaques ◽  
Induced Pluripotent Stem Cell ◽  
Asymmetry Index ◽  
Translocator Protein ◽  
Imaging Data ◽  
Positron Emission

Abstract Purpose: The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [18F]FEPPA has the sensitivity for detecting changes in CD68 positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA).Methods: In vivo positron emission tomography (PET) imaging with [18F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration. Results: Based on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [18F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = -0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [18F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman’s ρ = 0.94; p = 0.005). Conclusion: These findings reveal that [18F]FEPPA PET is an effective marker for detecting increased CD68 positive microglial/macrophage activation and demonstrate sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.

scholarly journals [18f]Feppa Pet Imaging For Monitoring Neuroinflammation In Nonhuman Primates

2020 ◽  
Author(s):  
Matthew Zammit ◽  
Yunlong Tao ◽  
Miles Olsen ◽  
Jeanette Metzger ◽  
Scott Vermilyea ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Microglial Activation ◽  
Nonhuman Primates ◽  
Rhesus Macaques ◽  
Induced Pluripotent Stem Cell ◽  
Asymmetry Index ◽  
Translocator Protein ◽  
Imaging Data ◽  
Positron Emission

Abstract Purpose The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [ 18 F]FEPPA has the sensitivity for detecting changes in microglial activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA). Methods In vivo positron emission tomography (PET) imaging with [ 18 F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration. Results Based on visual inspection of the imaging data and assessment of radiotracer uptake, nonhuman primates with allogeneic grafts showed increased [ 18 F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = -0.110 ± 0.025. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral nucleus (p = 0.0004). [ 18 F]FEPPA PET standard uptake values normalized to the contralateral putamen (SUV norm ) showed a positive correlation with CD68 immunoreactivity ratings in the monkeys (Pearson’s r = 0.83; p = 0.0008). Conclusion These findings reveal that [ 18 F]FEPPA PET is an effective marker for detecting increased microglial activation and demonstrate sufficient sensitivity to detect small changes in neuroinflammation in vivo following allogeneic cell engraftment.

scholarly journals TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases?

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Bérenger Largeau ◽  
Anne-Claire Dupont ◽  
Denis Guilloteau ◽  
Maria-João Santiago-Ribeiro ◽  
Nicolas Arlicot
Keyword(s):  
Pet Imaging ◽  
Inflammatory Diseases ◽  
Protein A ◽  
Translocator Protein ◽  
Brain Diseases ◽  
Disease Heterogeneity ◽  
Peripheral Tissues ◽  
Positron Emission ◽  
Potential Biomarker

Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatoryfociare crucial for an adequate care for patients. In brain diseases,in vivopositron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal’s quantification.

Positron emission tomography imaging in evaluation of MS pathology in vivo

2018 ◽  
Vol 24 (11) ◽  
pp. 1399-1412 ◽  
Author(s):  
Heidi Högel ◽  
Eero Rissanen ◽  
Anna Vuorimaa ◽  
Laura Airas
Keyword(s):  
Positron Emission Tomography ◽  
Pet Imaging ◽  
Human Subjects ◽  
Positron Emission Tomography Imaging ◽  
Translocator Protein ◽  
Emission Tomography ◽  
Amyloid Pet ◽  
Positron Emission ◽  
Density Evaluation

Positron emission tomography (PET) gives an opportunity to quantitate the expression of specific molecular targets in vivo and longitudinally in brain and thus enhances our possibilities to understand and follow up multiple sclerosis (MS)-related pathology. For successful PET imaging, one needs a relevant target molecule within the brain, to which a blood–brain barrier–penetrating specific radioligand will bind. 18-kDa translocator protein (TSPO)-binding radioligands have been used to detect activated microglial cells at different stages of MS, and remyelination has been measured using amyloid PET. Several PET ligands for the detection of other inflammatory targets, besides TSPO, have been developed but not yet been used for imaging MS patients. Finally, synaptic density evaluation has been successfully tested in human subjects and gives opportunities for the evaluation of the development of cortical and deep gray matter pathology in MS. This review will discuss PET imaging modalities relevant for MS today.

scholarly journals Development of a blood sample detector for multi-tracer positron emission tomography using gamma spectroscopy

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Carlos Velasco ◽  
Adriana Mota-Cobián ◽  
Jesús Mateo ◽  
Samuel España
Keyword(s):  
Positron Emission Tomography ◽  
Blood Sample ◽  
Pet Imaging ◽  
Spectroscopic Analysis ◽  
Gamma Spectroscopy ◽  
Emission Tomography ◽  
Blood Samples ◽  
Positron Emission

Abstract Background Multi-tracer positron emission tomography (PET) imaging can be accomplished by applying multi-tracer compartment modeling. Recently, a method has been proposed in which the arterial input functions (AIFs) of the multi-tracer PET scan are explicitly derived. For that purpose, a gamma spectroscopic analysis is performed on blood samples manually withdrawn from the patient when at least one of the co-injected tracers is based on a non-pure positron emitter. Alternatively, these blood samples required for the spectroscopic analysis may be obtained and analyzed on site by an automated detection device, thus minimizing analysis time and radiation exposure of the operating personnel. In this work, a new automated blood sample detector based on silicon photomultipliers (SiPMs) for single- and multi-tracer PET imaging is presented, characterized, and tested in vitro and in vivo. Results The detector presented in this work stores and analyzes on-the-fly single and coincidence detected events. A sensitivity of 22.6 cps/(kBq/mL) and 1.7 cps/(kBq/mL) was obtained for single and coincidence events respectively. An energy resolution of 35% full-width-half-maximum (FWHM) at 511 keV and a minimum detectable activity of 0.30 ± 0.08 kBq/mL in single mode were obtained. The in vivo AIFs obtained with the detector show an excellent Pearson’s correlation (r = 0.996, p < 0.0001) with the ones obtained from well counter analysis of discrete blood samples. Moreover, in vitro experiments demonstrate the capability of the detector to apply the gamma spectroscopic analysis on a mixture of 68Ga and 18F and separate the individual signal emitted from each one. Conclusions Characterization and in vivo evaluation under realistic experimental conditions showed that the detector proposed in this work offers excellent sensibility and stability. The device also showed to successfully separate individual signals emitted from a mixture of radioisotopes. Therefore, the blood sample detector presented in this study allows fully automatic AIFs measurements during single- and multi-tracer PET studies.

scholarly journals Optimised GMP-compliant production of [18F]DPA-714 on the Trasis AllinOne module

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Klaudia A. Cybulska ◽  
Vera Bloemers ◽  
Lars R. Perk ◽  
Peter Laverman
Keyword(s):  
Significant Degree ◽  
Translocator Protein ◽  
Positron Emission ◽  
Leaving Group ◽  
Inflammatory Processes ◽  
Single Production ◽  
Translocator Protein 18 Kda ◽  
Radiochemical Yields ◽  
Specific Ligand

Abstract Background The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [18F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [18F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity. Results [18F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [18F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100∘C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [18F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [18F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies. Conclusion To the best of our knowledge, the process presented herein is the most efficient [18F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.

scholarly journals Cellular sources of TSPO expression in healthy and diseased brain

2021 ◽  
Author(s):  
Erik Nutma ◽  
Kelly Ceyzériat ◽  
Sandra Amor ◽  
Stergios Tsartsalis ◽  
Philippe Millet ◽  
...  
Keyword(s):  
Cell Activity ◽  
Brain Regions ◽  
Cellular Level ◽  
Translocator Protein ◽  
Disease Stage ◽  
Animal Models Of Disease ◽  
Positron Emission ◽  
Neuropsychiatric Diseases ◽  
Tspo Expression

AbstractThe 18 kDa translocator protein (TSPO) is a highly conserved protein located in the outer mitochondrial membrane. TSPO binding, as measured with positron emission tomography (PET), is considered an in vivo marker of neuroinflammation. Indeed, TSPO expression is altered in neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. This review describes the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in central nervous system diseases. A discussion of methods of analysis and of quantification of TSPO is also presented. Overall, it appears that the alterations of TSPO binding, their cellular underpinnings, and the functional significance of such alterations depend on many factors, notably the pathology or the animal model under study, the disease stage, and the involved brain regions. Thus, further studies are needed to fully determine how changes in TSPO binding occur at the cellular level with the ultimate goal of revealing potential therapeutic pathways.

scholarly journals Harnessing PET to track micro- and nanoplastics in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Outi Keinänen ◽  
Eric J. Dayts ◽  
Cindy Rodriguez ◽  
Samantha M. Sarrett ◽  
James M. Brennan ◽  
...  
Keyword(s):  
Sea Water ◽  
Accurate Determination ◽  
Nuclear Imaging ◽  
Imaging Data ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
20 Nm ◽  
Pharmacokinetic Behavior

AbstractThe proliferation of plastics in the environment continues at an alarming rate. Plastic particles have been found to be persistent and ubiquitous pollutants in a variety of environments, including sea water, fresh water, soil, and air. In light of this phenomenon, the scientific and medical communities have become increasingly wary of the dangers posed to human health by chronic exposure to microplastics (< 5 mm diameter) and nanoplastics (< 100 nm diameter). A critical component of the study of the health effects of these pollutants is the accurate determination of their pharmacokinetic behavior in vivo. Herein, we report the first use of molecular imaging to track polystyrene (PS) micro- and nanoplastic particles in mammals. To this end, we have modified PS particles of several sizes—diameters of 20 nm, 220 nm, 1 µm, and 6 µm—with the chelator desferrioxamine (DFO) and radiolabeled these DFO-bearing particles with the positron-emitting radiometal zirconium-89 (89Zr; t1/2 ~ 3.3 d). Subsequently, positron emission tomography (PET) was used to visualize the biodistribution of these radioplastics in C57BL/6J mice at 6, 12, 24, and 48 h after ingestion. The imaging data reveal that the majority of the radioplastics remain in the gastrointestinal tract and are eliminated through the feces by 48 h post-ingestion, a result reinforced by acute biodistribution studies. Ultimately, this work suggests that nuclear imaging—and PET in particular—can be a sensitive and effective tool in the urgent and rapidly growing effort to study the in vivo behavior and potential toxicity of micro- and nanoplastics.

scholarly journals 11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 108
Author(s):  
Michael R. Kilbourn
Keyword(s):  
Pet Imaging ◽  
In Vivo Imaging ◽  
Dopamine Synthesis ◽  
Dopamine System ◽  
Synaptic Release ◽  
Positron Emission ◽  
The Central Nervous System ◽  
Pet Radiotracers ◽  
Selection Of

The applications of positron emission tomography (PET) imaging to study brain biochemistry, and in particular the aspects of dopamine neurotransmission, have grown significantly over the 40 years since the first successful in vivo imaging studies in humans. In vivo PET imaging of dopaminergic functions of the central nervous system (CNS) including dopamine synthesis, vesicular storage, synaptic release and receptor binding, and reuptake processes, are now routinely used for studies in neurology, psychiatry, drug abuse and addiction, and drug development. Underlying these advances in PET imaging has been the development of the unique radiotracers labeled with positron-emitting radionuclides such as carbon-11 and fluorine-18. This review focuses on a selection of the more accepted and utilized PET radiotracers currently available, with a look at their past, present and future.

Changes in synaptic density in the subacute phase after ischemic stroke: A 11C-UCB-J PET/MR study

2021 ◽  
pp. 0271678X2110477
Author(s):  
Laura Michiels ◽  
Nathalie Mertens ◽  
Liselot Thijs ◽  
Ahmed Radwan ◽  
Stefan Sunaert ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Standardized Uptake Value ◽  
Brain Regions ◽  
Asymmetry Index ◽  
Cerebellar Hemisphere ◽  
Future Research ◽  
Stroke Patients ◽  
Synaptic Density ◽  
Positron Emission

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratiolesion/controls = 0.67 ± 0.28, p = 0.00023). Moreover, 11C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = −0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = −0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.

STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging

2021 ◽  
Vol 118 (36) ◽  
pp. e2105390118 ◽  
Author(s):  
Keke Liang ◽  
Evan R. Abt ◽  
Thuc M. Le ◽  
Arthur Cho ◽  
Amanda M. Dann ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Cell Metabolism ◽  
Nucleotide Metabolism ◽  
Type I Interferons ◽  
Ductal Adenocarcinoma ◽  
Type I ◽  
Flt Pet ◽  
Positron Emission ◽  
Pharmacodynamic Biomarkers

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling–induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling–dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist–based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

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