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

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

Contrast Media & Molecular Imaging ◽

10.1155/2018/5272014 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Se Jong Oh ◽

Hae-June Lee ◽

Kyung Jun Kang ◽

Sang Jin Han ◽

Yong Jin Lee ◽

...

Keyword(s):

Specific Binding ◽

Volume Ratio ◽

Immunohistochemical Analysis ◽

Graphical Analysis ◽

Amyloid Pet ◽

Reference Tissue ◽

Amyloid A ◽

Pet Tracer ◽

5Xfad Mice ◽

The Brain

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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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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Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain

10.1101/600080 ◽

2019 ◽

Author(s):

Jonas E Svensson ◽

Martin Schain ◽

Pontus Plavén-Sigray ◽

Simon Cervenka ◽

Mikael Tiger ◽

...

Keyword(s):

Temporal Cortex ◽

Binding Potential ◽

Validity And Reliability ◽

Reference Tissue ◽

Pet Tracer ◽

Binding Data ◽

Healthy Control ◽

The Mean ◽

Cortical Regions ◽

Simplified Reference Tissue Model

Abstract[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET is not a suitable tool for D2/3R binding quantification in extrastriatal regions.

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The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17746179 ◽

2017 ◽

Vol 38 (4) ◽

pp. 659-668 ◽

Cited By ~ 14

Author(s):

Annette Johansen ◽

Hanne D Hansen ◽

Claus Svarer ◽

Szabolcs Lehel ◽

Sebastian Leth-Petersen ◽

...

Keyword(s):

Receptor Agonist ◽

Binding Potential ◽

Reference Tissue ◽

Tissue Model ◽

Background Ratio ◽

Significant Difference ◽

Methoxy Groups ◽

Simplified Reference Tissue Model ◽

Pet Scans ◽

The Brain

[11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.

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A reference tissue forward model for improved PET accuracy using within-scan displacement studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211065212 ◽

2021 ◽

pp. 0271678X2110652

Author(s):

Joseph B Mandeville ◽

Michael A Levine ◽

John T Arsenault ◽

Wim Vanduffel ◽

Bruce R Rosen ◽

...

Keyword(s):

Radioactive Decay ◽

Forward Model ◽

Binding Potential ◽

Reference Tissue ◽

Primate Model ◽

Tissue Model ◽

Pet Tracer ◽

Reference Tissue Model ◽

Simplified Reference Tissue Model ◽

Improved Accuracy

We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified reference tissue model (SRTM) by incorporating a non-zero dissociation time constant from the specifically bound compartment. The forward computational approach avoided errors associated with noisy and nonorthogonal basis functions using an inverse linear model. Compared to analysis by a multilinear single-compartment reference tissue model (MRTM), fFTRM provided improved accuracy for estimation of binding potentials at early times in the scan, with no worse reproducibility across sessions. To test the model’s ability to identify small focal changes in binding potential using a within-scan challenge, we employed a nonhuman primate model of focal dopamine release elicited by deep brain microstimulation remote to ventral striatum (VST) during imaging by simultaneous PET and fMRI. The new model reported an unambiguously lateralized response in VST consistent with fMRI, whereas the MRTM-derived response was not lateralized and was consistent with simulations of model bias. The proposed model enabled better accuracy in PET [11C]raclopride displacement studies and may also facilitate challenges sooner after injection, thereby recovering some sensitivity lost to radioactive decay of the PET tracer.

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Comparative Assessment of Parametric Neuroreceptor Mapping Approaches Based on the Simplified Reference Tissue Model Using [11C]ABP688 PET

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.190 ◽

2015 ◽

Vol 35 (12) ◽

pp. 2098-2108 ◽

Cited By ~ 6

Author(s):

Seongho Seo ◽

Su J Kim ◽

Yu K Kim ◽

Jee-Young Lee ◽

Jae M Jeong ◽

...

Keyword(s):

Least Squares ◽

Nuclear Imaging ◽

Volume Ratio ◽

Parametric Image ◽

Reference Tissue ◽

Tissue Model ◽

Positron Emission ◽

Reference Tissue Model ◽

Image Production ◽

Simplified Reference Tissue Model

In recent years, several linearized model approaches for fast and reliable parametric neuroreceptor mapping based on dynamic nuclear imaging have been developed from the simplified reference tissue model (SRTM) equation. All the methods share the basic SRTM assumptions, but use different schemes to alleviate the effect of noise in dynamic-image voxels. Thus, this study aimed to compare those approaches in terms of their performance in parametric image generation. We used the basis function method and MRTM2 (multilinear reference tissue model with two parameters), which require a division process to obtain the distribution volume ratio (DVR). In addition, a linear model with the DVR as a model parameter (multilinear SRTM) was used in two forms: one based on linear least squares and the other based on extension of total least squares (TLS). Assessment using simulated and actual dynamic [11C]ABP688 positron emission tomography data revealed their equivalence with the SRTM, except for different noise susceptibilities. In the DVR image production, the two multilinear SRTM approaches achieved better image quality and regional compatibility with the SRTM than the others, with slightly better performance in the TLS-based method.

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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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Comparison of 18F-FDG and 67Ga-citrate in sarcoidosis imaging

Nuklearmedizin ◽

10.3413/nukmed-0085 ◽

2008 ◽

Vol 47 (01) ◽

pp. 18-23 ◽

Cited By ~ 26

Author(s):

M. Wehrschuetz ◽

B. Bisail ◽

M. Woltsche ◽

T. Schwarz ◽

H. Lanz ◽

...

Keyword(s):

Fdg Pet ◽

Complete Agreement ◽

Pet Tracer ◽

Positron Emission ◽

Significant Difference ◽

Kappa Value ◽

18F Fdg ◽

Primary Assessment ◽

67Ga Citrate

SummaryAim: 67Ga citrate has been used long and successfully to diagnose and stage sarcoidosis. 18F-fluorodeoxyglucose (18F-FDG) has been suggested as a positron emission tomography (PET) tracer for sarcoidosis imaging. This study aimed to analyze possible advantages of 18F-FDG-PET over 67Ga citrate scintigraphy during the primary assessment of patients with sarcoidosis. Patients and methods: Twentyfour patients (11 men, 13 women, aged 52 years ±12.4) with histologically proven sarcoidosis were investigated with 18F-FDG and 67Ga citrate. Equipment included a fullring PET scanner (ECAT EXACT HR+, Siemens/CTI, Knoxville TN, USA) and a double-headed gamma camera (ECAM, Siemens, Illinois, USA) for scintigraphy. The mean time difference between the two studies was 6.5 days (range: 5–8 days). Results: There was a significant difference in the detection of pulmonary and nonpulmonary sarcoidosis lesions between planar 67Ga citrate scans and 18F-FDG-PET images (<0.0021). A total of 64 lesions were detected with 67Ga citrate scans in the thorax and elsewhere with a mean of 2.6 lesions (4%) per patient, while 85 lesions were found with 18F-FDG-PET, with a mean of 3.5 lesions (4.1%) per patient. There was complete agreement between 18F-FDG and 67Ga citrate in thoracic manifestations in four (16.6%) patients, and in non-thoracic manifestations in five (20.8%) patients. The interobserver variability showed a kappa value of 0.79. Conclusion: 67Ga citrate and 18F-FDG are useful tracers for diagnostic evaluation of thoracic sarcoidosis. 18F-FDG seems to be more suitable for imaging the mediastinum, the bi-hilar lymph nodes, the posterior regions of the lungs and non-thoracic lesions. Further prospective studies are needed to clarify the role of both tracers in early diagnosis and staging of sarcoidosis, and to resolve questions concerning medical treatment and follow-up.

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DDRE-21. PNOC015: PHASE 1 STUDY OF MTX110 DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.266 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii66-ii66

Author(s):

Sabine Mueller ◽

Cassie Kline ◽

Javier Villanueva-Meyer ◽

Carly Hoffman ◽

Shannon Raber ◽

...

Keyword(s):

Phase 1 ◽

Volume Ratio ◽

Diffuse Intrinsic Pontine Glioma ◽

Newly Diagnosed ◽

Convection Enhanced Delivery ◽

Catheter Position ◽

Pharmacodynamic Effects ◽

Distribution Volume Ratio ◽

Previously Treated ◽

Grade 3

Abstract OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.

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Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study

Journal of Psychopharmacology ◽

10.1177/0269881120965912 ◽

2021 ◽

pp. 026988112096591

Author(s):

Abhishekh H Ashok ◽

Jim Myers ◽

Gary Frost ◽

Samuel Turton ◽

Roger N Gunn ◽

...

Keyword(s):

Human Brain ◽

Sodium Acetate ◽

Statistical Significance ◽

Imaging Study ◽

Pet Scan ◽

Endogenous Opioid ◽

Reference Tissue ◽

Healthy Human ◽

Fourfold Increase ◽

Positron Emission

Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Methods: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. Results: Following sodium acetate administration, 2.5–6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. Conclusions: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

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