Explore the vast range of titles available.

Ligands targeting tau for use with positron emission tomography have rapidly been developed during the past several years, enabling the in vivo study of tau pathology in patients with Alzheimer's disease and related non-Alzheimer's disease tauopathies. Several candidate compounds have been developed, showing good in vitro characteristics with respect to their ability to bind tau deposits; off-target binding, however, has also been observed. In this short commentary, we briefly summarize the available in vivo and in vitro evidence pertaining to their off-target binding and discuss the different approaches that are needed for the future development of tau positron emission tomography tracers.

Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. Using 18F-AV-1451 (18F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. Greater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (β = −1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (β = −0.086, SE = 0.039, P = .029). Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease. •Age and amyloid-associated tau positron emission tomography (PET) differences in frontal, temporal, and occipital areas.•Entorhinal tau PET associated with lower volume in the same region.•Medial temporal tau PET related to memory decline in older cognitively normals.

Background The aim of this study was to compare the binding properties of several tau positron emission tomography tracers—THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3—head to head in the same human brain tissue. Methods Binding assays were performed to compare the regional distribution of 3 H-THK5117 and 3 H-THK5351 in postmortem tissue from three Alzheimer’s disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. Results Regional binding of 3 H-THK5117 and 3 H-THK5351 was similar, except in the temporal cortex, which showed higher 3 H-THK5117 binding. Saturation studies demonstrated two binding sites for 3 H-THK5351 ( K d1  = 5.6 nM, B max  = 76 pmol/g; K d2  = 1 nM, B max  = 40 pmol/g). Competition studies in the hippocampus between 3 H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i  = 0.1 pM; THK5117 K i  = 0.3 pM; T807 K i  = 0.2 pM) and an additional high-affinity site (THK5351 K i  = 16 nM; THK5117 K i  = 20 nM; T807 K i  = 78nM). 18 F-T807, 11 C-THK5351, and 11 C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11 C-PBB3. Unlabeled THK5351 and T807 displaced 11 C-THK5351 to a similar extent and a lower extent, respectively, compared with 11 C-PBB3. Competition with the MAO-B inhibitor 3 H- l -deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i  = 286 nM; T807 K i  = 227 nM) and the putamen (THK5117 K i  = 148 nM; T807 K i  = 135 nM). 3 H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70–80% and 60–77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3 H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. Conclusions THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off-target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3 H-THK5351.

Background and Objective: Tau-specific positron emission topography (PET) imaging enables in vivo assessment of Alzheimer's disease (AD). We aimed to investigate its performance in combination with plasma tau levels in patients with non-AD tauopathy. Methods: A total of 47 participants were enrolled, including 10 healthy controls, 16 with tauopathy parkinsonism syndromes (9 with corticobasal syndrome [CBS], 7 with progressive supranuclear palsy [PSP]), 9 with frontotemporal dementia (FTD), 4 with AD, and 8 with Parkinson's disease (PD). All participants underwent clinical assessments, 18 F-T807 tau PET, brain MRI, and plasma tau assay. Results: The global cortical standard uptake value ratio (SUVR) of 18 F-T807 PET was comparable between PD and control ( p = 0.088). The cortical SUVR was significantly higher in AD group ( p = 0.002) but was modestly increased in PSP group compared to the PD group ( p = 0.044), especially in parietal and pallidal regions. Asymmetric 18 F-T807 uptake at the pallidum was noted in patients with CBS and FTD. Cortical tau tracer uptake was associated with increased plasma total tau level ( p = 0.016), especially in frontal and parietal regions. Regional tracer uptake was correlated with cortical thinning in patients with CBS and PSP (CBS: r = −0.092, p = 0.025; PSP: r = −0.114, p = 0.015). Conclusions: The 18 F-T807 tau tracer uptake was only modestly increased in patients with PSP. Although the cortical tau tracer uptake correlated with regional cortical atrophy and plasma tau levels, a four-repeated tau-specific tracer is needed for future classifying tauopathy parkinsonism syndromes.

It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology. Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2. All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage. Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust.

Background [ 18 F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer’s disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [ 18 F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [ 18 F]AV1451 to use only 0.5 mg precursor, optimized the Boc-deprotection step and developed a simplified method for HPLC purification of the radiotracer. Results An optimized [ 18 F]AV1451 synthesis using a TRACERLab FX FN module led to high radiochemical yield (202 ± 57 mCi per synthesis) and doses with excellent radiochemical purity (98 ± 1%) and good specific activity (2521 ± 623 Ci/mmol). Conclusion An updated and operationally simple synthesis of [ 18 F]AV1451 has been developed that is fully automated and prepares radiotracer doses suitable for use in clinical tau PET studies.

Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance in vivo are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline 18FT807 and the pyridoindole 18FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of (N=5-7) P301S and wild-type (WT) mice at six and nine months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen’s d) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation ex vivo. Significantly elevated 18F-T807 binding in the brainstem of P301S mice was already evident at six months (+14%, p<0.01, d=1.64), and increased further at nine months (+23%, p<0.001, d=2.70). 18F-THK5117 indicated weaker increases and effect sizes at six months (+5%, p<0.05, d=1.07) and nine months (+10%, p<0.001, d=1.49). Regional similarity of binding of the two tracers was high (71%) at nine months. 18F-T807 was more sensitive than 18F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.