Early Detection of Aβ Deposition in the 5xFAD Mouse by Amyloid PET

Purpose. 18F-FC119S is a positron emission tomography (PET) tracer for imaging β-amyloid (Aβ) plaques in Alzheimer’s disease (AD). The aim of this study is to evaluate the efficacy of 18F-FC119S in quantitating Aβ deposition in a mouse model of early amyloid deposition (5xFAD) by PET. Method. Dynamic 18F-FC119S PET images were obtained in 5xFAD (n=5) and wild-type (WT) mice (n=7). The brain PET images were spatially normalized to the M. Mirrione T2-weighted mouse brain MR template, and the volumes of interest were then automatically drawn on the cortex, hippocampus, thalamus, and cerebellum. The specific binding of 18F-FC119S to Aβ was quantified as the distribution volume ratio using Logan graphical analysis with the cerebellum as a reference tissue. The Aβ levels in the brain were also confirmed by immunohistochemical analysis. Result. For the 5xFAD group, radioactivity levels in the cortex, the hippocampus, and the thalamus were higher than those for the WT group. In these regions, specific binding was approximately 1.2-fold higher in 5xFAD mice than in WT. Immunohistochemistry supported these findings; the 5xFAD showed severe Aβ deposition in the cortex and hippocampus in contrast to the WT group. Conclusion. These results demonstrated that 18F-FC119S PET can successfully distinguish Aβ depositions in 5xFAD mice from WT.

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Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211031035 ◽

2021 ◽

pp. 0271678X2110310

Author(s):

Suzanne L Baker ◽

Karine Provost ◽

Wesley Thomas ◽

AJ Whitman ◽

Mustafa Janabi ◽

...

Keyword(s):

Entorhinal Cortex ◽

Volume Ratio ◽

Graphical Analysis ◽

Pet Scan ◽

Amyloid Pet ◽

Reference Tissue ◽

Pet Tracer ◽

Significant Difference ◽

Distribution Volume Ratio ◽

Simplified Reference Tissue Model

The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.

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Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [18F]T-401 and PET

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211058285 ◽

2021 ◽

pp. 0271678X2110582

Author(s):

Yasushi Hattori ◽

Chie Seki ◽

Jun Maeda ◽

Yuji Nagai ◽

Kazunobu Aoyama ◽

...

Keyword(s):

Rhesus Monkey ◽

Specific Binding ◽

Rank Order ◽

Endocannabinoid System ◽

Compartment Model ◽

Graphical Analysis ◽

Monoacylglycerol Lipase ◽

Serine Hydrolase ◽

Time Activity ◽

The Brain

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [18F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [18F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume ( VT), and the rank order of VT was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [18F]T-401 retentions in the brain, and VT. Lassen's graphical analysis indicated a VND of 0.69 mL/cm3 and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [18F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.

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The Use of Alternative Forms of Graphical Analysis to Balance Bias and Precision in PET Images

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.123 ◽

2010 ◽

Vol 31 (2) ◽

pp. 535-546 ◽

Cited By ~ 10

Author(s):

Jean Logan ◽

David Alexoff ◽

Joanna S Fowler

Keyword(s):

Volume Ratio ◽

Image Data ◽

Compartment Model ◽

Graphical Analysis ◽

Distribution Volume ◽

Good Precision ◽

Reference Tissue ◽

Positron Emission ◽

Distribution Volume Ratio ◽

Uptake Data

Graphical analysis (GA) is an efficient method for estimating total tissue distribution volume ( VT) from positron emission tomography (PET) uptake data. The original GA produces a negative bias in VT in the presence of noise. Estimates of VT using other GA forms have less bias but less precision. Here, we show how the bias terms are related between the GA methods and how using an instrumental variable (IV) can also reduce bias. Results are based on simulations of a two-compartment model with VT's ranging from 10.5 to 64 mL/cm3 and from PET image data with the tracer [11C]DASB ([11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile). Four estimates of VT (or distribution volume ratio (DVR) using a reference tissue) can be easily computed from different formulations of GA including the IV. As noise affects the estimates from all four differently, they generally do not provide the same estimates. By taking the median value of the four estimates, we can decrease the bias and reduce the effect of large values contributing to noisy images. The variance of the four estimates can serve as a guide to the reliability of the median estimate. This may provide a general method for the generation of parametric images with little bias and good precision.

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

Journal of Neuroinflammation ◽

10.1186/s12974-020-01962-7 ◽

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.

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SCIDOT-39. K16ApoE ENHANCES Aβ-ASSOCIATED 11C-PiB DEPOSITION AND PET SIGNAL IN APP/PS1 TRANSGENIC MICE

Neuro-Oncology ◽

10.1093/neuonc/noz175.1175 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi279-vi280

Author(s):

Desmond Brown ◽

Gobinda Sarkar ◽

Teresa Decklever ◽

Geoffry Curran ◽

Ameet Sarkar ◽

...

Keyword(s):

Transgenic Mice ◽

Mouse Models ◽

Pet Imaging ◽

Specific Binding ◽

Standard Uptake Value ◽

Clinical Role ◽

Pet Tracer ◽

The Brain ◽

Novel Therapeutic ◽

Increased Retention

Abstract OBJECTIVE The K16ApoE peptide enhances delivery of multiple agents across the blood-brain barrier (BBB). Transgenic mouse models are central to elucidating the underlying pathophysiology of Alzheimer’s Disease (AD) and provide a system for evaluating novel therapeutic strategies. PET imaging plays a central clinical role in diagnosing human cases of AD but has had variable performance in mouse models. We investigated the role of K16ApoE to enhance delivery of a radiolabeled PET imaging tracer, 11C-PiB and assess whether this corresponds to improved PET sensitivity in APP/PS1 transgenic mice. METHODS Brain-delivery of 11C-PiB was accomplished by successive injections of K16ApoE and 11C-PiB. Distribution of 11C-PiB to the brain and heart was quantified via dynamic PET/CT imaging and digital autoradiography. RESULTS K16ApoE increased the brain uptake of 11C-PiB in both wild-type (WT) and APP/PS1 mice. Administration of K16ApoE increased the PET standard uptake value of 11C-PiB at 5 minutes in WT mice from 1.132 to 2.963 (p=0.006) and in APP/PS1 mice from 0.842 to 3.268 (p=0.016). Enhancement peaked at 5 minutes. Binding was reversible with similarly increased kinetics in both WT and APP/PS1 mice. The absolute values were higher in APP/PS1 mice suggesting increased retention. The increased retention in APP/PS1 mice was consistent with specific binding to A-beta plaques as unlabeled PiB reduced 11C-PiB signal retention. CONCLUSION K16ApoE mediates enhancement of 11C-PiB signal in APP/PS1 mice brains with increased PET sensitivity. There is increased uptake kinetics in both WT and APP/PS1 mice with specific A-beta plaque binding in the latter. This enhanced delivery of the PET tracer has implications for development and testing of new hypotheses and the efficacy of novel therapeutic paradigms. K16ApoE has potential for improving delivery of several agents across the BBB. This has implication for delivery of diagnostic and therapeutic agents for neurodegenerative and neuro-oncologic diseases.

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Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211018904 ◽

2021 ◽

pp. 0271678X2110189

Author(s):

Mengmeng Song ◽

Leonie Beyer ◽

Lena Kaiser ◽

Henryk Barthel ◽

Thilo van Eimeren ◽

...

Keyword(s):

Kinetic Modelling ◽

Standardized Uptake Value ◽

Volume Ratio ◽

Reference Tissue ◽

Binding Characteristics ◽

Non Invasive ◽

Phase Slope ◽

Pet Tracer ◽

Linear Slope ◽

Cortical Regions

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer’s disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

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Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05164-4 ◽

2021 ◽

Author(s):

Thu Hang Lai ◽

Magali Toussaint ◽

Rodrigo Teodoro ◽

Sladjana Dukić-Stefanović ◽

Daniel Gündel ◽

...

Keyword(s):

Specific Binding ◽

Radiochemical Yield ◽

Toxicity Study ◽

In Vivo Evaluation ◽

One Pot ◽

Specific Binding Ratio ◽

Mri Studies ◽

The Brain

Abstract Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

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

EJNMMI Research ◽

10.1186/s13550-020-00710-5 ◽

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.

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Ultrafiltration Method for Plasma Protein Binding Studies and Its Limitations

Processes ◽

10.3390/pr9020382 ◽

2021 ◽

Vol 9 (2) ◽

pp. 382

Author(s):

Camelia-Maria Toma ◽

Silvia Imre ◽

Camil-Eugen Vari ◽

Daniela-Lucia Muntean ◽

Amelia Tero-Vescan

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Specific Binding ◽

Critical Role ◽

Volume Ratio ◽

Binding Studies ◽

Experimental Conditions ◽

Key Aspects

Plasma protein binding plays a critical role in drug therapy, being a key part in the characterization of any compound. Among other methods, this process is largely studied by ultrafiltration based on its advantages. However, the method also has some limitations that could negatively influence the experimental results. The aim of this study was to underline key aspects regarding the limitations of the ultrafiltration method, and the potential ways to overcome them. The main limitations are given by the non-specific binding of the substances, the effect of the volume ratio obtained, and the need of a rigorous control of the experimental conditions, especially pH and temperature. This review presents a variety of methods that can hypothetically reduce the limitations, and concludes that ultrafiltration remains a reliable method for the study of protein binding. However, the methodology of the study should be carefully chosen.

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