Tau Positron Emission Tomography Tracers Research Articles

A review of the flortaucipir literature for positron emission tomography imaging of tau neurofibrillary tangles.

Alzheimer's disease is defined by the presence of β-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer's disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer's disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer's disease; non-Alzheimer's disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer's disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer's disease.

Tau in dementia with Lewy bodies.

Neurofibrillary tangles are present in a proportion of people with dementia with Lewy bodies and may be associated with worse cognition. Recent advances in biomarkers for Alzheimer's disease include second-generation tau positron emission tomography as well as the detection of phosphorylated tau at threonine 181 (p-tau181) in plasma. This study aimed to investigate tau in people with dementia with Lewy bodies using a second-generation tau positron emission tomography tracer as well as plasma p-tau181. Twenty-seven participants (mean age 74.7 ± 5.5) with clinically diagnosed probable dementia with Lewy bodies underwent comprehensive clinical assessment and positron emission tomography imaging (18F-MK6240 and 18F-NAV4694). Plasma p-tau181 levels were measured using Simoa technology. Five dementia with Lewy bodies participants (18.5%) had an abnormal tau positron emission tomography (increased tau uptake in the temporal meta-region-of-interest). Higher plasma p-tau181 concentrations correlated with higher tau deposition in the temporal region (ρ = 0.46, 95% confidence interval = [0.10, 0.72]) and classified abnormal tau positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.95 (95% confidence interval = [0.86, 0.99]). Plasma p-tau181 also correlated positively with cortical amyloid-beta binding (ρ = 0.68, 95% confidence interval = [0.40, 0.84]) and classified abnormal amyloid-beta positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.91 (95% confidence interval = [0.79, 0.99]). There was no association found between tau deposition and any of the clinical variables. Tau is a common co-pathology in dementia with Lewy bodies. Plasma p-tau181 correlated with abnormal tau and amyloid-beta positron emission tomography and may potentially be used as a marker to identify co-morbid Alzheimer's disease-related pathology in dementia with Lewy bodies. The clinical implications of tau in dementia with Lewy bodies need to be further evaluated in larger longitudinal studies.

A Multi-Criteria Decision Aid Tool for Radiopharmaceutical Selection in Tau PET Imaging.

The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer's disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)-tau pathological lesions, but this is possible only after death and only shows tau in the portion of brain sampled. Positron emission tomography (PET) imaging allows both the quantitative and qualitative analysis of pathology over the whole brain of a living subject. The ability to detect and quantify tau pathology in vivo using PET can aid in the early diagnosis of AD, provide a way to monitor disease progression, and determine the effectiveness of therapeutic interventions aimed at reducing tau pathology. Several tau-specific PET radiotracers are now available for research purposes, and one is approved for clinical use. This study aims to analyze, compare, and rank currently available tau PET radiotracers using the fuzzy preference ranking organization method for enrichment of evaluations (PROMETHEE), which is a multi-criteria decision-making (MCDM) tool. The evaluation is based on relatively weighted criteria, such as specificity, target binding affinity, brain uptake, brain penetration, and rates of adverse reactions. Based on the selected criteria and assigned weights, this study shows that a second-generation tau tracer, [18F]RO-948, may be the most favorable. This flexible method can be extended and updated to include new tracers, additional criteria, and modified weights to help researchers and clinicians select the optimal tau PET tracer for specific purposes. Additional work is needed to confirm these results, including a systematic approach to defining and weighting criteria and clinical validation of tracers in different diseases and patient populations.

Tau positron emission tomography in tauopathies: A narrative review

Aggregation of misfolded tau in the brain is a major pathological feature common in various neurodegenerative disorders known as tauopathies, including Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, and dementia with Lewy bodies. Tauopathies are collection of diseases with varied overlapping symptoms and complicated manifestations. Consequently, it is crucial to be able to assess tau deposits <i>in vivo</i>. Over the past decade, tau-specific radioligands for positron emission tomography (PET) have been developed and tested, including first-generation compounds (e.g., <sup>18</sup>F-THK5317, <sup>18</sup>F-THK5351, <sup>18</sup>F-AV1451, and <sup>11</sup>C-PBB3) and second-generation compounds (<sup>18</sup>F-MK-6240, <sup>18</sup>F-RO-948, and <sup>18</sup>F-PI-2620). With the recent advances of tau PET tracers, assessing the pattern of tau deposition <i>in vivo</i> is possible. These methods will allow accurate diagnosis of tauopathies and monitoring of disease progression. In this mini review, we summarize current findings from studies using tau PET tracers regarding neuropathological characteristics, clinical implications, and potential applications of tau PET. We also discuss methodological considerations for appropriate use of these technologies and discuss what has been learned from these findings.

The Sensitivity of Tau Tracers for the Discrimination of Alzheimer's Disease Patients and Healthy Controls by PET.

Hyperphosphorylated tau aggregates, also known as neurofibrillary tangles, are a hallmark neuropathological feature of Alzheimer's disease (AD). Molecular imaging of tau by positron emission tomography (PET) began with the development of [18F]FDDNP, an amyloid β tracer with off-target binding to tau, which obtained regional specificity through the differing distributions of amyloid β and tau in AD brains. A concerted search for more selective and affine tau PET tracers yielded compounds belonging to at least eight structural categories; 18F-flortaucipir, known variously as [18F]-T807, AV-1451, and Tauvid®, emerged as the first tau tracer approved by the American Food and Drug Administration. The various tau tracers differ concerning their selectivity over amyloid β, off-target binding at sites such as monoamine oxidase and neuromelanin, and degree of uptake in white matter. While there have been many reviews of molecular imaging of tau in AD and other conditions, there has been no systematic comparison of the fitness of the various tracers for discriminating between AD patient and healthy control (HC) groups. In this narrative review, we endeavored to compare the binding properties of the various tau tracers in vitro and the effect size (Cohen's d) for the contrast by PET between AD patients and age-matched HC groups. The available tracers all gave good discrimination, with Cohen's d generally in the range of two-three in culprit brain regions. Overall, Cohen's d was higher for AD patient groups with more severe illness. Second-generation tracers, while superior concerning off-target binding, do not have conspicuously higher sensitivity for the discrimination of AD and HC groups. We suppose that available pharmacophores may have converged on a maximal affinity for tau fibrils, which may limit the specific signal imparted in PET studies.

High tau PET binding reveals a constellation of beta‐amyloid positivity and fast cognitive decline

AbstractBackgroundBeta‐amyloid Positron Emission Tomography (PET) efficiently detects beta‐amyloid plaques supporting the presence of a pathophysiological landmark of Alzheimer’s disease (AD) continuum, but lacks specificity regarding the prediction of future cognitive status. The increasing validation of tau PET tracers raises questions about whether a tau PET biomarker could predict clinically relevant cognitive decline and its potentially beneficial role in the assessment of individuals who belong to the AD continuum.MethodWe identified 335 subjects [cognitive normal (CN; n=217), mild cognitive impairment (MCI; n=99), dementia (n=19)] with baseline beta‐amyloid and tau PET scans that have completed a follow‐up of at least two years, from the Alzheimer’s Disease Neuroimaging Initiative dataset. First, we assessed the accuracy of tau PET to discriminate the MCI patients that will convert to AD. Based on Alzheimer’s Disease Assessment Scale–Cognitive Subscale, we used linear mixed‐effects models to define the annual rate of cognitive change of all individuals and Gaussian mixture modelling to cluster them as either fast or slow decliners. Next, group comparisons and the accuracy of tau PET to discriminate between them were tested. Finally, the association between baseline tau PET SUVR and cognitive rate of change was assessed with linear modelsResultThe individuals with beta‐amyloid positivity and fast cognitive decline showed the highest tau PET binding values independently of baseline cognitive status, compared to the other groups (beta‐amyloid negative with fast or slow decline and beta‐amyloid positive with slow decline). Baseline tau PET binding could determine fast decliners with a beta‐amyloid positive scan with an accuracy of 85% (composite temporal region of interest). Similarly, tau PET binding accuracy was high in determining MCI patients that would be both beta‐amyloid positive and show progress in their diagnosis. Linear models showed that baseline tau PET binding is related to the annual rate of cognitive decline in beta‐amyloid positive individuals.ConclusionHigh baseline tau load is coupled with both beta‐amyloid pathology and an accelerated profile of cognitive decline. Tau PET imaging could offer substantial advantages over beta‐amyloid PET imaging since it provides important information about both the underlying pathophysiology and the prognosis of the disease.

Tau and amyloid PET imaging with 18F‐PI‐2620 and 18F‐Florbetaben in patients with early‐onset dementia and healthy controls

AbstractBackgroundAbnormal deposits of tau protein and beta‐amyloid are the two fundamental pathological features of Alzheimer's disease (AD). The research framework for AD diagnosis proposes categorizing subjects based on biomarker evidence of pathology using the ATN classification system (amyloid, tau, neurodegeneration). In‐vivo detection of amyloid pathology using positron emission tomography (PET) is well established and new generation tau PET tracers like 18F‐PI‐2620 have shown a high binding affinity for aggregated tau without significant off‐target binding. The purpose of this study is to describe the ability of 18F‐PI‐2620 to detect tau pathology in patients with early‐onset dementia (EOD) with proven amyloid pathology.MethodTen patients with EOD and positive 18F‐Florbetaben amyloid PET (age range 54‐64y, 8 with suspected early‐onset AD (EOAD) and 2 with logopenic variant primary progressive aphasia (lvPPA)), along with 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans for 75 minutes after injection of 18F‐PI‐2620 to examine the presence of tau‐pathology in cortical and deep brain regions. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultIn 9 out of 10 EOD patients, 18F‐PI‐2620 uptake was robust and extensive predominantly in cortical regions with relative sparing of deep brain regions. In the remaining EOD case, binding was low but with the same distribution pattern described for other EOD patients. In one HC, significant, specific uptake was observed predominantly in deep brain regions. 18F‐PI‐2620 administration was safe and well‐tolerated.ConclusionOur preliminary results suggest an excellent performance of the tracer 18F‐PI‐2620 to detect tau deposits in EOAD and lvPPA. Tau PET imaging with 18F‐PI‐2620, in conjunction with 18F‐Florbetaben amyloid PET, distinctly discriminates between early‐onset dementias due to AD pathology from HC. These results also support the usefulness of 18F‐PI‐2620 for visualizing tau aggregation in EOD. Finally, 18F‐Florbetaben and 18F‐PI‐2620 appear to be reliable tools for establishing the ATN biomarker status in EOD patients. Nevertheless, further studies are needed to confirm these preliminary results.

Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer's Disease and Other Tauopathies.

The detection and staging of Alzheimer’s disease (AD) using non-invasive imaging biomarkers is of substantial clinical importance. Positron emission tomography (PET) provides readouts to uncover molecular alterations in the brains of AD patients with high sensitivity and specificity. A variety of amyloid-β (Aβ) and tau PET tracers are already available for the clinical diagnosis of AD, but there is still a lack of imaging biomarkers with high affinity and selectivity for tau inclusions in primary tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick’s disease (PiD). This review aims to provide an overview of the existing Aβ and tau PET imaging biomarkers and their binding properties from in silico, in vitro, and in vivo assessment. Imaging biomarkers for pathologic proteins are vital for clinical diagnosis, disease staging and monitoring of the potential therapeutic approaches of AD. Off-target binding of radiolabeled tracers to white matter or other neural structures is one confounding factor when interpreting images. To improve binding properties such as binding affinity and to eliminate off-target binding, second generation of tau PET tracers have been developed. To conclude, we further provide an outlook for imaging tauopathies and other pathological features of AD and primary tauopathies.

What\u2019s the cut-point?: a systematic investigation of tau PET thresholding methods

BackgroundTau positron emission tomography (PET) is increasing in popularity for biomarker characterization of Alzheimer’s disease (AD), and recent frameworks rely on tau PET cut-points to stage individuals along the AD continuum. Given the lack of standardization in tau PET thresholding methods, this study sought to systematically canvass and characterize existing studies that have derived tau PET cut-points and then directly assess different methods of tau PET thresholding in terms of their concurrent validity.MethodsFirst, a literature search was conducted in PubMed to identify studies of AD and related clinical phenotypes that used the Flortaucipir (AV-1451) tau PET tracer to derive a binary cut-point for tau positivity. Of 540 articles screened and 47 full-texts reviewed, 23 cohort studies met inclusion criteria with a total of 6536 participants. Second, we derived and compared tau PET cut-points in a 2 × 2 × 2 design that systematically varied region (temporal meta-ROI and entorhinal cortex), analytic method (receiver operating characteristics and 2 standard deviations above comparison group), and criterion/comparison variable (amyloid-beta negative cognitively unimpaired or cognitively unimpaired only) using a sample of 453 older adults from the Alzheimer’s Disease Neuroimaging Initiative.ResultsFor the systematic review, notable variability in sample characteristics, preprocessing methods, region of interest, and analytic approach were observed, which were accompanied by discrepancy in proposed tau PET cut points. The empirical follow-up indicated the cut-point derived based on 2 standard deviations above a either comparison group in either ROI best differentiated tau positive and negative groups on cerebrospinal fluid phosphorylated tau, Mini-Mental State Examination score, and delayed memory performance.ConclusionsGiven the impact of discrepant thresholds on tau positivity rates, biomarker staging, and eligibility for future clinical treatment trials, recommendations are offered to select cut-point derivations based on the unique goals and priorities of different studies.

In‐depth investigation in tau positron emission tomography tracers off‐target binding with voxel‐to‐voxel correlation analysis of tau and amyloid PET signal to histological iron and tau deposit in non‐Alzheimer tauopathies

AbstractBackgroundTau pathology strongly correlates with neuronal loss and clinical decline across tauopathies, emphasizing the need to detect and monitor tau pathology in living patients. Positron Emission Tomography(PET) using radiotracers like Flortaucipir ([18F]AV‐1451) enables good visualization of AD tau pathology. However, recent reports of its off‐targeting binding behavior raise concerns about the sensitivity and specificity of this tracer to visualize tau deposits in non‐AD tauopathies, especially with its similar pattern to iron accumulation. PET‐to‐autopsy validation has been challenging because of issues with tissue deformation and large‐scale pathological analysis. Here, we present i) an interdisciplinary approach combining immunohistochemistry, computer vision, and convolution neural network(CNN) to 3D‐reconstructed, billion‐pixel digital pathology tau and iron images of human brain hemispheres, co‐register them to PET and ii) preliminary PET‐to‐pathology voxel‐to‐voxel correlation analyses.MethodWe employed a pipeline developed in‐house combining whole‐brain processing, free‐floating immunohistochemistry and computer‐based algorithms for 2D and 3D registration. SlideNet, our CNN for segmenting tau inclusions in digital images (Fig. 1E,F), aims at generating quantitative, 3D‐tau‐maps. Iron maps are generated via Fiji's Weka segmentation (Fig. 1A‐B). Pipeline was applied to whole hemisphere sections in case#1(Cortico‐Basal‐Degeneration), case#3(TDP‐43), case#8(Frontaltemperal‐lobar‐disease w/ MAPT mutation), case#5(Alzheimer’s Disease) and case#7(Progressive‐Supranuclear‐Palsy) labeled by immunohistochemistry(CP‐13 antibody, Ser202, Fig. 2D)and Prussian Blue (Fig. 2A). Demographics of cases are shown in Table 1. We registered the resulting heatmaps (Fig. 1B,F) to MRI and PET coordinates (Fig. 3 & 1C,D,G,H), enabling voxel‐to‐voxel comparisons.ResultCNN output three categories: tau in neurons, tau in glia/processes, and background (Fig. 2E). Weka segmentation output Iron in tissue and background (Fig. 2B). Obtaining the result with proper thresholding (Fig. 2C,F) We first registered the histology‐based iron maps, Tau and Amyloid PET scans onto the 3D MRI space (Fig. 1C‐D), following with registration of 3D Tau maps to PET scans and Iron maps to analyze the effect of iron to PET tracer binding quantitatively (Fig. 1G‐H). Preliminary correlation analysis generated between MRI resolution Iron map and PET scans via MATLAB. (Table 2)ConclusionIron histological segmentations shows a mild positive association between iron deposit and Tau signal binding, showing that iron likely play a role in the Tau PET tracer off‐target binding. Ongoing regional analysis with Tau maps will provide more granular correlations, especially in areas known for off‐target binding, and we are finalizing it. (Table 2,3)

Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core

Tau aggregates represent a critical pathology in Alzheimer’s disease (AD) and other forms of dementia. The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD. Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies. To evaluate the impact of the N-atom position with respect to Tau- and off-target binding, tricyclic core analogs of PI-2620 with nitrogen atoms at different positions were prepared. Affinity to aggregated Tau was evaluated using human AD brain homogenates, and their off-target binding was evaluated in a monoamine oxidase A (MAO-A) competition assay. The novel tricyclic core derivatives all displayed inferior Tau binding or MAO-A off-target selectivity, indicating PI-2620 to be the optimal design for high affinity binding to Tau and high MAO-A selectivity.

Tau deposition and structural connectivity demonstrate differential association patterns with neurocognitive tests

Tau neurofibrillary tangles have a central role in the pathogenesis of Alzheimer’s Disease (AD). Mounting evidence indicates that the propagation of tau is assisted by brain connectivity with weakened white-matter integrity along the propagation pathways. Recent advances in tau positron emission tomography tracers and diffusion magnetic resonance imaging allow the visualization of tau pathology and white-matter connectivity of the brain in vivo. The current study aims to investigate how tau deposition and structural connectivity are associated with memory function in prodromal AD. In this study, tau accumulation and structural connectivity data from 83 individuals (57 cognitively normal participants and 26 participants with mild cognitive impairment) were associated with neurocognitive test scores. Statistical analyses were performed in 70 cortical/subcortical brain regions to determine: 1. the level of association between tau and network metrics extracted from structural connectivity and 2. the association patterns of brain memory function with tau accumulation and network metrics. The results showed that tau accumulation and network metrics were correlated in early tau deposition regions. Furthermore, tau accumulation was associated with worse performance in almost all neurocognitive tests performance evaluated in the study. In comparison, decreased network connectivity was associated with declines in the delayed memory recall in Craft Stories and Benson Figure Copy. Interaction analysis indicates that tau deposition and dysconnectivity have a synergistic effect on the delayed Benson Figure Recall. Overall, our findings indicate that both tau deposition and structural dysconnectivity are associated with neurocognitive dysfunction. They also suggest that tau-PET may have better sensitivity to neurocognitive performance than diffusion MRI-derived measures of white-matter connectivity.

A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis

PurposeThis study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer’s disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases.MethodsA total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively.ResultsComparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926–0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI.ConclusionThe temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.

Towards clinical application of tau PET tracers for diagnosing dementia due to Alzheimer's disease.

The recent development of several tau positron emission tomography (PET) tracers represents a major milestone for the Alzheimer's disease (AD) field. These tau PET tracers bind tau neurofibrillary tangles, a key neuropathological characteristic of AD that is tightly linked to synaptic loss, brain atrophy, and cognitive decline. It is notable that these tau PET tracers show low uptake in most non-AD tauopathies and other neurodegenerative disorders, resulting in a diagnostic specificity that is superior to that of amyloid beta (Aβ) PET and biofluid markers, especially at an older age when incidental Aβ pathology is common. Furthermore, tau PET tracers diagnostically outperform widely used MRI markers. Given its excellent diagnostic performance due to the combination of high sensitivity and specificity for detecting tau pathology in AD dementia, we hypothesize that tau PET can become an important diagnostic tool in specialized clinics for the differential diagnosis of dementia syndromes where AD is among the major possible underlying diseases.

Analysis of amyloid and tau deposition in Alzheimer's disease using 11C-Pittsburgh compound B and 18F-THK 5351 positron emission tomography imaging.

This study aims to determine the deposition of 11C-Pittsburgh compound B (11C-PiB) and 18F-THK 5351 using a normal database of the optimal cut-off-points for standardized uptake value ratios (SUVRs) in Alzheimer's disease (AD) patients. Sixteen AD patients and 24 cognitively normal individuals were enrolled in this study. The optimal cutoff points for the SUVR from the normal database were used for quantitative analysis. P-mod software with the Automated Anatomical Labeling merged atlas was employed to generate automatic volumes of interest to identify different brain regions, and the SUVRs of AD patients were compared with those of the age-matched normal controls. The correlation between PiB and THK5351 deposition at matching brain regions was identified. The mean regional 11C-PiB SUVRs of the AD patients were significantly higher than the healthy controls (P < 0.05). The 11C-PiB SUVR cut-offs were 1.46–1.81, with sensitivity ranging from 81.25% to 93.75% and specificity of 100%. The mean SUVRs of 18F-THK 5351 in various regions were also significantly higher in the AD patients than in the healthy controls (P < 0.05). The inferior temporal gyrus yielded an optimum SUVR cut-off-points of 1.5 with 80% sensitivity and 83.33% specificity. The correlation of PiB and THK5351 SUVR was reported at precuneus, parietal, and occipital brain areas, with spearman's rho of 0.67, 0.66, and 0.72, respectively. Our findings allow determination of the SUVRs of 11C-PiB and 18F-THK-5351 amyloid and tau positron emission tomography tracers for clinical use, according to the normal database of the optimal cut-off-points for SUVRs in AD patients.

Tauvid™: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer's Disease.

Tauvid has been approved by the U.S. Food and Drug Administration (FDA) in 2020 for positron emission tomography (PET) imaging of adult patients with cognitive impairments undergoing evaluation for Alzheimer’s disease (AD) based on tau pathology. Abnormal aggregation of tau proteins is one of the main pathologies present in AD and is receiving increasing attention as a diagnostic and therapeutic target. In this review, we summarised the production and quality control of Tauvid, its clinical application, pharmacology and pharmacokinetics, as well as its limitation due to off-target binding. Moreover, a brief overview on the second-generation of Tau PET tracers is provided. The approval of Tauvid marks a step forward in the field of AD research and opens up opportunities for second-generation tau tracers to advance tau PET imaging in the clinic.

Structure-Activity and Brain Kinetics Relationships of 18F-Labeled Benzimidazopyridine Derivatives as Tau PET Tracers.

Noninvasive imaging of tau aggregates with a positron emission tomography (PET) tracer is useful for the diagnosis and staging of Alzheimer's disease (AD). Recently, we found that benzimidazopyridine (BIP) is an attractive scaffold for developing PET and single photon computed emission tomography tracers targeting tau aggregates. In this study, we designed and synthesized five novel 18F-labeled compounds with various substituted groups or atoms at the 7-position of the BIP scaffold. In in vitro autoradiographic studies, all 18F-labeled BIP derivatives selectively bound to tau aggregates deposited in AD brain sections. On the other hand, the initial brain uptake of these compounds was affected by the type of substituted group or halogen atom introduced into the 7-position of the BIP scaffold. Among these compounds, [18F]Me-BIPF showed the highest brain uptake (6.79% ID/g at 2 min postinjection) and 2 min/60 min ratio (3.59). These results suggest that appropriate introduction of the substituted group or atom into the 7-position of the BIP scaffold may be effective for developing useful tau PET tracers.

Sex differences in off-target binding using tau positron emission tomography

PurposeOff-target binding in the skull and meninges is observed in some subjects undergoing tau positron emission tomography (PET) and could potentially differ between men and women. In this study we elucidate sex differences in tau off-target binding using three different tau PET tracers. Methods541 cognitively unimpaired amyloid-β negative participants underwent tau PET using [18F]flortaucipir (n = 165), [18F]RO948 (n = 189) and [18F]MK6240 (n = 187). Baseline SUVR-values were compared between females and males at the voxel level and using a region-of-interest (ROI) encompassing the skull/meninges. In addition, we assessed the cross-sectional relationship between baseline skull/meninges SUVR and age and assessed change in skull/meningeal SUVR values over time in a subsample with longitudinal data (n = 63). ResultsVoxel-wise analysis showed higher meningeal off-target binding in women compared to men across all three tracers. The SUVRs in the skull/meningeal ROI were highest using [18F]RO948, followed by [18F]MK6240 and [18F]flortaucipir (p < 0.001). For all tracers, females showed higher skull/meningeal ROI retention (mean SUVR ± SD [18F]flortaucipir: 0.82 ± 0.14; [18F]RO948: 1.26 ± 0.30; [18F]MK6240: 1.09 ± 0.19) compared to men ([18F]flortaucipir: 0.70 ± 0.11; [18F]RO948: 1.10 ± 0.24; [18F]MK6240: 0.97 ± 0.17) (p < 0.001). For [18F]flortaucipir and [18F]RO948, off-target binding in the skull/meninges decreased with age. ConclusionThere is an effect of sex on off-target retention in the meninges/skull across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers.

Alzheimer’s disease biomarker roadmap 2020: Second‐generation tau PET tracers

AbstractBackgroundSelective positron emission tomography (PET) tracers to target neurofibrillary tangles of the second generation have indicated to overcome some of the methodological issues observed with the tau‐tracers of the first generation. How these second‐generation tau tracers may be better suitable for clinical practice was assessed in the context of the Geneva Biomarker Roadmap Initiative during and prior to a two‐day workshop (Geneva, November 2019).MethodGuided by a framework for systematic validation of oncological diagnostic biomarkers adapted for the implementation of biomarker quantifying the pathological hallmarks of Alzheimer’s Disease (AD), we evaluated the performance of the tau‐selective tracers of the second generation. Subsequently we defined research priorities focusing on the advancement of the framework, with the goal for implementation of these PET tracers in clinical practice.ResultAll tracers identified as second generation, have provided evidence for in vitro binding to tau tangles in tissue samples of patients with and without Alzheimer’s disease. Additionally, in vivo pharmacokinetic modeling has been successfully achieved for some (e.g., 18F‐MK‐6240, 18F‐PI‐2620) but not all second‐generation tau tracers (e.g., GTP‐1, 18F‐JNJ‐067). Overall, observational cross‐sectional studies have provided preliminary evidence on the diminished extent of off‐target binding, high discriminatory ability between healthy and diseased populations and sensitivity in clinically diverse samples (e.g., 18F‐RO‐948, 18F‐MK‐6240, 18F‐PI‐2620).ConclusionA readily implementation of the tau tracer of the second‐generation in clinical practice is limited by the scarcity of comprehensive data analysis with bigger samples sizes and by the overall lack of end‐of‐life studies. However, the goal of the second‐generation tau tracers to overcome some of the methodological issues raised by the first generation tau tracers is partially achieved. Finally, the adaptation of the oncological diagnostic framework to the clinical validity of biomarkers measuring AD pathology has proven most useful in formulating new practical research goals to advance the clinical utility of the second generation tau tracer.

Radiosynthesis and quality control testing of the tau imaging positron emission tomography tracer [18 F]PM-PBB3 for clinical applications.

Recently, we produced 11 C-labeled 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([11 C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half-life) of [11 C]PBB3, we further synthesized 18 F-labeled 1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([18 F]PM-PBB3). [18 F]PM-PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [18 F]PM-PBB3 for clinical applications. [18 F]PM-PBB3 was synthesized by direct 18 F-fluorination of the tosylated derivative, followed by removal of the protecting group. [18 F]PM-PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay-corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [18 F]PM-PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV-cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [18 F]PM-PBB3 injection complied with our in-house quality control and quality assurance specifications. We have accomplished >200 production runs of [18 F]PM-PBB3 in our facility for various research purposes.