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

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.

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

10.21203/rs.3.rs-17421/v1 ◽

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.

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Positron emission tomography imaging in evaluation of MS pathology in vivo

Multiple Sclerosis Journal ◽

10.1177/1352458518791680 ◽

2018 ◽

Vol 24 (11) ◽

pp. 1399-1412 ◽

Cited By ~ 13

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.

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

10.21203/rs.3.rs-17421/v2 ◽

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.

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Imaging Biomarkers for Monitoring the Inflammatory Redox Landscape in the Brain

Antioxidants ◽

10.3390/antiox10040528 ◽

2021 ◽

Vol 10 (4) ◽

pp. 528

Author(s):

Eduardo Felipe Alves Fernandes ◽

Dennis Özcelik

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Inflammatory Diseases ◽

Redox Homeostasis ◽

Translocator Protein ◽

Imaging Biomarkers ◽

Positron Emission ◽

Diagnostic Applications ◽

The Brain

Inflammation is one key process in driving cellular redox homeostasis toward oxidative stress, which perpetuates inflammation. In the brain, this interplay results in a vicious cycle of cell death, the loss of neurons, and leakage of the blood–brain barrier. Hence, the neuroinflammatory response fuels the development of acute and chronic inflammatory diseases. Interrogation of the interplay between inflammation, oxidative stress, and cell death in neurological tissue in vivo is very challenging. The complexity of the underlying biological process and the fragility of the brain limit our understanding of the cause and the adequate diagnostics of neuroinflammatory diseases. In recent years, advancements in the development of molecular imaging agents addressed this limitation and enabled imaging of biomarkers of neuroinflammation in the brain. Notable redox biomarkers for imaging with positron emission tomography (PET) tracers are the 18 kDa translocator protein (TSPO) and monoamine oxygenase B (MAO–B). These findings and achievements offer the opportunity for novel diagnostic applications and therapeutic strategies. This review summarizes experimental as well as established pharmaceutical and biotechnological tools for imaging the inflammatory redox landscape in the brain, and provides a glimpse into future applications.

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Progress in PET Imaging of Neuroinflammation Targeting COX-2 Enzyme

Molecules ◽

10.3390/molecules26113208 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3208

Author(s):

Jaya Prabhakaran ◽

Andrei Molotkov ◽

Akiva Mintz ◽

J. John Mann

Keyword(s):

Pet Imaging ◽

Brain Diseases ◽

Positron Emission ◽

Disease Staging ◽

Inflammatory Drugs ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

The Brain ◽

Lateral Sclerosis

Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.

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

EJNMMI Physics ◽

10.1186/s40658-019-0263-x ◽

2019 ◽

Vol 6 (1) ◽

Cited By ~ 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.

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

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-021-00133-0 ◽

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.

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Cellular sources of TSPO expression in healthy and diseased brain

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05166-2 ◽

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.

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Positron Emission Tomography in the Inflamed Cerebellum: Addressing Novel Targets among G Protein-Coupled Receptors and Immune Receptors

Pharmaceutics ◽

10.3390/pharmaceutics12100925 ◽

2020 ◽

Vol 12 (10) ◽

pp. 925

Author(s):

Margit Pissarek

Keyword(s):

G Protein ◽

Cannabinoid Receptors ◽

G Protein Coupled Receptors ◽

Translocator Protein ◽

Brain Diseases ◽

Present Contribution ◽

Binding Behavior ◽

Positron Emission ◽

Inflammatory Processes ◽

G Protein Coupled

Inflammatory processes preceding clinical manifestation of brain diseases are moving increasingly into the focus of positron emission tomographic (PET) investigations. A key role in inflammation and as a target of PET imaging efforts is attributed to microglia. Cerebellar microglia, with a predominant ameboid and activated subtype, is of special interest also regarding improved and changing knowledge on functional involvement of the cerebellum in mental activities in addition to its regulatory role in motor function. The present contribution considers small molecule ligands as potential PET tools for the visualization of several receptors recognized to be overexpressed in microglia and which can potentially serve as indicators of inflammatory processes in the cerebellum. The sphingosine 1 phosphate receptor 1 (S1P1), neuropeptide Y receptor 2 (NPY2) and purinoceptor Y12 (P2Y12) cannabinoid receptors and the chemokine receptor CX3CR1 as G-protein-coupled receptors and the ionotropic purinoceptor P2X7 provide structures with rather classical binding behavior, while the immune receptor for advanced glycation end products (RAGE) and the triggering receptor expressed on myeloid cells 2 (TREM2) might depend for instance on further accessory proteins. Improvement in differentiation between microglial functional subtypes in comparison to the presently used 18 kDa translocator protein ligands as well as of the knowledge on the role of polymorphisms are special challenges in such developments.

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

Biomedicines ◽

10.3390/biomedicines9020108 ◽

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.

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