scholarly journals Progress in PET Imaging of Neuroinflammation Targeting COX-2 Enzyme

Molecules ◽  
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.

scholarly journals PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2289
Author(s):  
Naresh Damuka ◽  
Paul Czoty ◽  
Ashley Davis ◽  
Michael Nader ◽  
Susan Nader ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Neurological Disorders ◽  
Healthy Male ◽  
Time Activity ◽  
Positron Emission ◽  
Pet Ct ◽  
Scan Data ◽  
The Brain ◽  
Human Primate

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

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.

scholarly journals 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2850 ◽  
Author(s):  
Michelle Cortes-Salva ◽  
Stal Shrestha ◽  
Prachi Singh ◽  
Cheryl Morse ◽  
Kimberly Jenko ◽  
...  
Keyword(s):  
Comparative Evaluation ◽  
Cyclooxygenase 2 ◽  
Emission Tomography ◽  
Inhibitory Potency ◽  
Positron Emission ◽  
Positron Emitter ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation.

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 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.

scholarly journals News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 252
Author(s):  
Jacopo Meldolesi
Keyword(s):  
Neurodegenerative Diseases ◽  
Imaging Techniques ◽  
Imaging Biomarkers ◽  
Positron Emission ◽  
Specific Proteins ◽  
Great Relevance ◽  
The Brain ◽  
Positive Point

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

scholarly journals Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo-Is Immunosuppression Mandatory?

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1804
Author(s):  
Urszula Kozlowska ◽  
Aleksandra Klimczak ◽  
Karolina Anna Bednarowicz ◽  
Tomasz Zalewski ◽  
Natalia Rozwadowska ◽  
...  
Keyword(s):  
Immune Reaction ◽  
Disease Model ◽  
Immunosuppressive Drugs ◽  
Therapeutic Approaches ◽  
Stem Cell Graft ◽  
Skeletal Muscle Loss ◽  
The Brain ◽  
Privileged Site ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.

The role of celecoxib as a potential inhibitor in the treatment of inflammatory diseases - a review

2021 ◽  
Vol 28 ◽  
Author(s):  
Josiane Viana Cruz ◽  
Joaquín María Campos Rosa ◽  
Njogu Mark Kimani ◽  
Silvana Giuliatti ◽  
Cleydson Breno Rodrigues dos Santos
Keyword(s):  
Side Effects ◽  
Inflammatory Diseases ◽  
Structural Basis ◽  
Potential Inhibitor ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

: This article presents a simplified view of celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) has, predominantly, two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role that is related to homeostatic effects in renal and platelets, while the latter is mainly responsible for induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and without side effects. To this end, of the generation of non-steroidal anti-inflammatory drugs from “coxibs”, celecoxib is the only potent selective COX-2 inhibitor that is still commercially available. Thus, the compound celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for COX-2 enzyme. In this review, we provide highlights where such inhibition should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs) which act as COX-2 inhibitors with lesser side effects on the human body.

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