scholarly journals Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain

2019 ◽  
Vol 17 (22) ◽  
pp. 5586-5594 ◽  
Author(s):  
Yanbo Yu ◽  
Qianwa Liang ◽  
Hui Liu ◽  
Zonghua Luo ◽  
Hongzheng Hu ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Preliminary Evaluation ◽  
Pet Tracer ◽  
The Brain

A potent carbon-11 PET tracer targeting TRPC5 was radiosynthesized successfully and the preliminary evaluation in rodents and a nonhuman primate was performed.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff–Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. Results The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = − 0.985, p = 0.015). Conclusion The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

scholarly journals Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shorena Janelidze ◽  
Erik Stomrud ◽  
Ruben Smith ◽  
Sebastian Palmqvist ◽  
Niklas Mattsson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Pet Tracer ◽  
Positron Emission ◽  
Diagnostic Work ◽  
Work Up ◽  
The Brain ◽  
Better Than

AbstractCerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

scholarly journals Evaluation of 18F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

2014 ◽  
Vol 55 (8) ◽  
pp. 1336-1341 ◽  
Author(s):  
G. I. Warnock ◽  
J. Aerts ◽  
M. A. Bahri ◽  
F. Bretin ◽  
C. Lemaire ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Synaptic Vesicle Protein ◽  
Pet Tracer ◽  
Vesicle Protein ◽  
Synaptic Vesicle Protein 2A ◽  
The Brain

scholarly journals A 11C-Labeled 1,4-Dihydroquinoline Derivative as a Potential PET Tracer for Imaging of Redox Status in Mouse Brain

2015 ◽  
Vol 35 (12) ◽  
pp. 1930-1936 ◽  
Author(s):  
Toshimitsu Okamura ◽  
Maki Okada ◽  
Tatsuya Kikuchi ◽  
Hidekatsu Wakizaka ◽  
Ming-Rong Zhang
Keyword(s):  
Mouse Brain ◽  
Initial Velocity ◽  
Brain Homogenate ◽  
Redox Balance ◽  
Redox Status ◽  
Cationic Form ◽  
Pet Tracer ◽  
Positron Emission ◽  
The Brain

A disturbance in redox balance has been implicated in the pathogenesis of a number of diseases. This study sought to examine the feasibility of imaging brain redox status using a 11C-labeled dihydroquinoline derivative ([11C]DHQ1) for positron emission tomography (PET). The lipophilic PET tracer [11C]DHQ1 was rapidly oxidized to its hydrophilic form in mouse brain homogenate. The redox modulators diphenyleneiodonium and apocynin significantly reduced the initial velocity of [11C]DHQ1 oxidation, and apocynin also caused concentration-dependent inhibition of the initial velocity. Moreover, [11C]DHQ1 readily entered the brain by diffusion after administration and underwent oxidation into the hydrophilic cationic form, which then slowly decreased. By contrast, apocynin treatment inhibited the in vivo oxidation of [11C]DHQ1 to the hydrophilic cationic form, leading to a rapid decrease of radioactivity in the brain. Thus, the difference in the [11C]DHQ1 kinetics reflects the alteration in redox status caused by apocynin. In conclusion, [11C]DHQ1 is a potential PET tracer for imaging of redox status in the living brain.

scholarly journals A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16

2021 ◽  
Author(s):  
Chao Zheng ◽  
Daniel Holden ◽  
Ming-Qiang Zheng ◽  
Richard Pracitto ◽  
Kyle C. Wilcox ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Nonhuman Primate ◽  
Specific Binding ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Time Activity ◽  
Peripheral Tissues ◽  
High Affinity ◽  
Arterial Blood ◽  
Pet Tracer

Purpose: To investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18F]SDM-16, in nonhuman primate brains. Methods: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one ) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. Results: Racemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (Ki = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was -9%, and averaged absolute TRV (aTRV) was 10% for all analyzed brain regions. Conclusion: We have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

scholarly journals A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16

2021 ◽  
Author(s):  
Chao Zheng ◽  
Daniel Holden ◽  
Ming-Qiang Zheng ◽  
Richard Pracitto ◽  
Kyle C. Wilcox ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Nonhuman Primate ◽  
Specific Binding ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Time Activity ◽  
Peripheral Tissues ◽  
High Affinity ◽  
Arterial Blood ◽  
Pet Tracer

Abstract PurposeTo investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18 F]SDM-16, in nonhuman primate brains. MethodsThe racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1yl)methyl)pyrrolidin-2-one) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. ResultsRacemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (K i = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [ 18 F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was -9±8%, and averaged absolute TRV (aTRV) was 10±7% for all analyzed brain regions. ConclusionWe have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

scholarly journals A Relationship-Oriented Model of Research Participation: The Brain Health Community Registry

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 625-625
Author(s):  
Andrea Gilmore Bykovskyi ◽  
Haley Fuhr ◽  
Shannon Mullen ◽  
Laura Block ◽  
Clark Benson ◽  
...  
Keyword(s):  
Social Determinants ◽  
Unmet Needs ◽  
Research Participation ◽  
Assessment Tools ◽  
Systematic Evaluation ◽  
Preliminary Evaluation ◽  
Brain Health ◽  
Research Engagement ◽  
Health Community ◽  
The Brain

Abstract Historically excluded and minoritized populations are significantly under-included in health studies of Alzheimer’s disease and related dementias (ADRD) despite bearing a disproportionate burden of disease—evidenced by higher incidence, prevalence, and poorer health outcomes. Meaningful progress toward identifying and alleviating causes of health disparities in ADRD necessitate effective and scalable approaches for broadening inclusion in research. Rigorous studies evaluating research participation among minoritized populations are limited and have predominantly focused on individual-level factors and behavioral change (i.e. religiosity, willingness). These approaches frequently overlook the influence of unequally distributed structural and social determinants on participation despite the compounded financial, social, emotional, and logistical consequences that result from ADRD. Using an intersectional and social justice lens, we developed the Participant and Relationship-Oriented Research Engagement Model, which characterizes research as a form of relationship and extends social determinants frameworks to the context of research participation. We report core components of the model and its application in the design and preliminary evaluation of the Brain Health Community (BHC) Registry, which features proactive and systematic evaluation of potential unmet needs among prospective participants, and connections to relevant services (i.e. respite care, adaptive devices). Preliminary testing of the model and participant feedback on the BHC suggest it is a feasible approach to research engagement, and that associated assessment tools and resource protocols are acceptable and sufficiently adaptable to heterogeneous sets of unmet needs. Primary challenges include ongoing assessment of engagement and routine changes in service ability, which can be addressed through community-based resource networks.

scholarly journals Diet, psychosocial stress, and Alzheimer’s disease-related neuroanatomy in female nonhuman primates

2020 ◽  
Author(s):  
Brett M. Frye ◽  
Suzanne Craft ◽  
Thomas C. Register ◽  
Rachel N. Andrews ◽  
Susan E. Appt ◽  
...  
Keyword(s):  
Mediterranean Diet ◽  
Nonhuman Primate ◽  
Psychosocial Stress ◽  
Western Diet ◽  
List Type ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Brain Volumes ◽  
Increase Risk ◽  
The Brain

ABSTRACTINTRODUCTIONAssociations between diet, psychosocial stress, and neurodegenerative disease, including Alzheimer’s disease (AD), have been reported, but causal relationships are difficult to determine in human studies.METHODSWe used structural magnetic resonance imaging in a well-validated nonhuman primate model of AD-like neuropathology to examine the longitudinal effects of diet (Mediterranean versus Western) and social subordination stress on brain anatomy, including global volumes, cortical thicknesses and volumes, and twenty individual regions of interest (ROIs).RESULTSWestern diet resulted in greater cortical thicknesses, total brain volumes and gray matter, and diminished cerebrospinal fluid and white matter volumes. Socially stressed subordinates had smaller whole brain volumes but larger ROIs relevant to AD than dominants.DISCUSSIONThe observation of increased size of AD-related brain areas is consistent with similar reports of mid-life volume increases predicting increased AD risk later in life. While the biological mechanisms underlying the findings require future investigation, these observations suggest that Western diet and psychosocial stress instigate pathologic changes that increase risk of AD-associated neuropathologies, whereas Mediterranean diet may protect the brain.RESEARCH IN CONTEXTSystematic review: The authors reviewed the literature with PubMed and Google Scholar and found a number of publications which are cited that suggest that AD pathogenesis begins well before the onset of symptoms.Interpretation: Our findings support the hypothesis that Western diet and psychosocial stress may instigate neuroinflammatory responses that increase risk of later developing AD-like neuropathologies, whereas the structural stasis in the Mediterranean diet group may represent a resilient phenotype.Future directions: The manuscript serves as a critical first step in describing risk and resilient phenotypes during middle age in a nonhuman primate model of AD-like neuropathology. This report lays the groundwork for ongoing efforts to determine whether neuroinflammatory profiles differed across diet and stress groups. Future studies should aim to understand the temporal emergence of functional disparities associated with the changes in brain structure observed here.HIGHLIGHTSGlobal brain volumes changed in response to Western, but not Mediterranean, diet.Western diet increased cortical thickness in multiple regions relevant to AD.Mediterranean diet did not alter cortical thicknesses relevant to AD.Brain regions associated with AD risk differed between low and high stress monkeys.Psychosocial stress may modulate the effects of diet on the brain.

scholarly journals Brain Imaging of the GLP-1 Receptor in Obesity Using 68Ga-NODAGA-Exendin-4 PET

2021 ◽  
Vol 11 (12) ◽  
pp. 1647
Author(s):  
Laura N. Deden ◽  
Jan Booij ◽  
Joanes Grandjean ◽  
Judith R. Homberg ◽  
Eric J. Hazebroek ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Receptor Expression ◽  
Receptor Agonists ◽  
Glucose Levels ◽  
Pet Tracer ◽  
Positron Emission ◽  
Obese Subjects ◽  
Glucagon Like Peptide 1 ◽  
The Brain ◽  
Stimulation Of

Stimulation of glucagon-like peptide-1 (GLP-1) receptors increases the insulin release in the pancreas during high glucose levels, and also stimulates a feeling of satiety. Likewise, synthetic GLP-1 receptor agonists derived from exendin are used successfully in the treatment of type-2 diabetes mellitus and obesity. Interestingly, preclinical and clinical studies further suggest that GLP-1 receptor agonists may decrease motor, behavioral, and cognitive symptoms in (animal models) Parkinson’s disease and Alzheimer’s disease and may slow down neurodegeneration. These observations suggest stimulation of GLP-1 receptors in the brain. The GLP-1 positron emission tomography (PET) tracer 68Ga-NODAGA-exendin-4 has been developed and successfully used for imaging in humans. In an ongoing study on the effects of bariatric surgery on GLP-1 receptor expression, we performed 68Ga-NODAGA-exendin-4 PET in obese subjects. Here we evaluated whether GLP-1 receptor binding could be visualized in the central nervous system in 10 obese subjects (seven woman; body mass index: mean ± SD: 39 ± 4.4 kg/m2) before bariatric surgery. Although we observed clear uptake in the pituitary area (mean SUVmax 4.3 ± 2.3), we found no significant uptake in other parts of the brain. We conclude that 68Ga-NODAGA-exendin-4 PET cannot be used to analyze GLP-1 receptors in the brain of obese subjects.

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