Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers

Shah, Maliha; Catafau, Ana M.

doi:10.2967/jnumed.113.136069

Cited by 64 publications

(52 citation statements)

References 20 publications

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“…A second factor in our relatively low target-binding ratios might be related to the imperfect concordance of 18 F-THK5117 binding to the prevailing conformation of the tau deposits in frontotemporal dementia mice (22). Although the exact binding site of radiotracers to tau fibrils remains to be identified, the paired helical filaments described in postmortem AD material are more effectively targeted by 2-arylquinolines than is the tauopathy in frontotemporal dementia (23).…”

Section: Background/low Bindingmentioning

confidence: 98%

Small-Animal PET Imaging of Tau Pathology with ¹⁸F-THK5117 in 2 Transgenic Mouse Models

et al. 2016

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Abnormal accumulation of tau aggregates in the brain is one of the hallmarks of Alzheimer disease neuropathology. We visualized tau deposition in vivo with the previously developed 2-arylquinoline derivative 18 F-THK5117 using small-animal PET in conjunction with autoradiography and immunohistochemistry gold standard assessment in 2 transgenic mouse models expressing hyperphosphorylated tau. Small-animal PET recordings were obtained in groups of P301S (n 5 11) and biGT mice (n 5 16) of different ages, with agematched wild-type (WT) serving as controls. After intravenous administration of 16 ± 2 MBq of 18 F-THK5117, a dynamic 90-min emission recording was initiated for P301S mice and during 20-50 min after injection for biGT mice, followed by a 15-min transmission scan. After coregistration to the MRI atlas and scaling to the cerebellum, we performed volume-of-interest-based analysis (SUV ratio [SUVR]) and statistical parametric mapping. Small-animal PET results were compared with autoradiography ex vivo and in vitro and further validated with AT8 staining for neurofibrillary tangles. SUVRs calculated from static recordings during the interval of 20-50 min after tracer injection correlated highly with estimates of binding potential based on the entire dynamic emission recordings (R 5 0.85). SUVR increases were detected in the brain stem of aged P301S mice (111%; P , 0.001) and in entorhinal/amygdaloidal areas (115%; P , 0.001) of biGT mice when compared with WT, whereas aged WT mice did not show increased tracer uptake. Immunohistochemical tau loads correlated with small-animal PET SUVR for both P301S (R 5 0.8; P , 0.001) and biGT (R 5 0.7; P , 0.001) mice, and distribution patterns of AT8-positive neurons matched voxelwise statistical parametric mapping analysis. Saturable binding of the tracer was verified by autoradiographic blocking studies. In the first dedicated small-animal PET study in 2 different transgenic tauopathy mouse models using the tau tracer 18 F-THK5117, the temporal and spatial progression could be visualized in good correlation with gold standard assessments of tau accumulation. The serial small-animal PET method could afford the means for preclinical testing of novel therapeutic approaches by accommodating interanimal variability at baseline, while detection thresholds in young animals have to be considered. Al zheimer disease (AD) is the most frequent cause of dementia, with an exponentially increasing incidence as a function of age among the elderly. This epidemic is imposing an increasingly onerous burden on health care in societies with aging populations (1). There is an urgent need to find new biomarkers predictive of clinical course and also serving as outcome measures in clinical trials of innovative disease-modifying agents (2). The main neuropathologic features of AD, which include the accumulation of extracellular b-amyloid plaques and intracellular neurofibrillary tangles (3), are emulated in transgenic (TG) animal models (4-6). Small-animal PET has emerged as a useful tool for tr...

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Section: Background/low Bindingmentioning

confidence: 98%

Small-Animal PET Imaging of Tau Pathology with ¹⁸F-THK5117 in 2 Transgenic Mouse Models

et al. 2016

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“…To assess the specificity of the tracer binding to the tau pathology, self-blocking studies with the authentic reference compound JNJ311 and, in the AD case, also blocking studies with the structurally unrelated tau ligand AV680 and the specific b-amyloid ligand AV45 were performed. AV680 was used as the benchmark compound in this experiment, because of its higher selectivity for aggregated tau over b-amyloid and lower off-target binding than AV1451 (19). AV45 was used in the blocking studies to assess the specificity of JNJ311 for tau over b-amyloid.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of¹⁸F-JNJ64349311, a Novel PET Tracer for Tau Imaging

et al. 2017

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In this study, we have synthesized and evaluated 18 F-JNJ64349311, a tracer with high affinity for aggregated tau (inhibition constant value, 8 nM) and high ($500·) in vitro selectivity for tau over b-amyloid, in comparison with the benchmark compound 18 F-AV1451 ( 18 F-T807) in mice, rats, and a rhesus monkey. Methods: In vitro binding characteristics were determined for Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration patient brain tissue slices using autoradiography studies. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in the brain and plasma of mice and in the plasma of a rhesus monkey using high-performance liquid chromatography. Dynamic small-animal PET studies were performed in rats and a rhesus monkey to evaluate tracer pharmacokinetics in the brain. Results: Mouse biodistribution studies showed moderate initial brain uptake and rapid brain washout. Radiometabolite analyses after injection of 18 F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in the brain. Semiquantitative autoradiography studies on postmortem tissue sections of human Alzheimer's disease brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human progressive supranuclear palsy and corticobasal degeneration brain slices. Small-animal PET scans of Wistar rats revealed moderate initial brain uptake (SUV, ;1.5 at 1 min after injection) and rapid brain washout. Gradual bone uptake was, however, also observed. Blocking and displacement did not affect brain time-activity curves, suggesting no off-target specific binding of the tracer in the healthy rat brain. A small-animal PET scan of a rhesus monkey revealed moderate initial brain uptake (SUV, 1.9 at 1 min after injection) with a rapid washout. In the monkey, no bone uptake was detected during the 120-min scan. Conclusion: This biologic evaluation suggests that 18 F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with 18 F-AV1451.

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“…1) (5,6). 18 F-AV-1451 ( 18 F-T807) was the first PET tracer to show promise for quantifying NFT pathology in AD patients (7) and is currently the most widely studied NFT PET tracer.…”

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confidence: 99%

Preclinical Characterization of ¹⁸F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles

Hostetler¹,

Abbas

Zeng³

et al. 2016

J Nucl Med

234

214

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A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18 F-MK-6240. Methods: In vitro binding studies were conducted with 3 H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3 H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18 F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18 F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. Results: The 3 H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3 H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. 3 H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18 F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18 F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. Conclusion: 18 F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients. Cur rently, the clinical evaluation of disease-modifying therapies for Alzheimer disease (AD) requires large, resourceintensive clinical trials focused on measuring cognitive endpoints, which are highly variable. A biomarker that could be used early in clinical development to build confidence in the ability of a therapeutic mechanism to modify disease progression would provide a valuable bridge to investment in a large efficacy study once adequate pharmacokinetics, safety, and tolerability have been established. Biomarkers currently in use (e.g., volumetric MRI, amyloid plaque PET, cerebrospinal fluid measures of amyloid-b and tau) either do not directly inform on modification of disease pathology (volumetric MRI) or do not correlate strongly enough with cognitive decline to measure therapeutic response (amyloid plaque PET and cerebrospinal fluid measures) (1,2). Therefore, there is an unmet need for sensitive biomarkers that quantify early pathologic changes and correlate closely to disease progression and clinical outcomes.Histologic analysis of brains from human autopsy cases have shown that the density and distribution of neurofibrillary tangles (NFTs) correlate with cognitive decline ...

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Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers

Cited by 64 publications

References 20 publications

Small-Animal PET Imaging of Tau Pathology with ¹⁸F-THK5117 in 2 Transgenic Mouse Models

Small-Animal PET Imaging of Tau Pathology with ¹⁸F-THK5117 in 2 Transgenic Mouse Models

Preclinical Evaluation of¹⁸F-JNJ64349311, a Novel PET Tracer for Tau Imaging

Preclinical Characterization of ¹⁸F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles

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Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers

Cited by 64 publications

References 20 publications

Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 Transgenic Mouse Models

Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 Transgenic Mouse Models

Preclinical Evaluation of18F-JNJ64349311, a Novel PET Tracer for Tau Imaging

Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles

Contact Info

Product

Resources

About

Small-Animal PET Imaging of Tau Pathology with ¹⁸F-THK5117 in 2 Transgenic Mouse Models

Small-Animal PET Imaging of Tau Pathology with ¹⁸F-THK5117 in 2 Transgenic Mouse Models

Preclinical Evaluation of¹⁸F-JNJ64349311, a Novel PET Tracer for Tau Imaging

Preclinical Characterization of ¹⁸F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles