Development of [11C]/[3H]THK-5351 – A potential novel carbon-11 tau imaging PET radioligand

Степанов, В. А.; Svedberg, Marie; Jia, Zhisheng; Красикова, Р. Н.; Lemoine, Laëtitia; Okamura, Nobujuki; Furumoto, Shozo; Mitsios, Nicholas; Mulder, Jan; Långström, Bengt; Nordberg, Agneta; Halldin, Christer

doi:10.1016/j.nucmedbio.2016.12.004

Cited by 17 publications

(36 citation statements)

References 20 publications

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“…All tracers were synthesized according to standard good manufacturing practice, as described previously [22–24]. The tracer THK5351, although originally developed as an 18 F tracer, was labelled with 11 C for the purposes of this project, to allow multitracer imaging on the same day as the 11 C-PBB3 acquisitions.…”

Section: Methodsmentioning

confidence: 99%

“…The 11 C-THK5351, 11 C-PBB3 and 11 C-AZD2184 PET measurements were acquired on a high-resolution research tomograph (HRRT; CTI/Siemens, Knoxville, TN, USA) in list mode, at the Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden. All tracers were synthesized according to standard good manufacturing practice, as described previously [ 22 – 24 ]. The tracer THK5351, although originally developed as an 18 F tracer, was labelled with 11 C for the purposes of this project, to allow multitracer imaging on the same day as the 11 C-PBB3 acquisitions.…”

Section: Methodsmentioning

confidence: 99%

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Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Chiotis

Stenkrona

Almkvist

et al. 2018

Eur J Nucl Med Mol Imaging

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PurposeSeveral tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design.MethodsNine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment.ResultsThe load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding.ConclusionThis research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.Electronic supplementary materialThe online version of this article (10.1007/s00259-018-4012-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Chiotis

Stenkrona

Almkvist

et al. 2018

Eur J Nucl Med Mol Imaging

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“…Over the past decade, several molecules have been suggested as potential tau PET tracers but many of those lacked sufficient specificity and selectivity [ 11 , 12 ]. Based on both in vitro and in vivo results, three families of radiotracers have to date shown promise as specific tau PET tracers: the aryquinoline derivatives THK5117 (and the ( S )-form THK5317) and THK5351, developed at Tohoku University, Japan [ 13 – 16 ]; the pyrido-indole derivative AV-1451 (also known as T807 and Flortaucipir), owned by Eli Lilly and originally developed by Siemens [ 17 , 18 ]; and the phenyl/pyridinyl-butadienyl-benzothiazole/benzothiazolium derivative PBB3 (Chiba, Japan), derived from the same tracer family as the Aβ ligand Pittsburgh Compound B (PIB) [ 19 , 20 ] (see Fig. 3 for chemical structures).…”

Section: Main Textmentioning

confidence: 99%

Tau PET imaging: present and future directions

Saint‐Aubert

Lemoine

Chiotis

et al. 2017

Mol Neurodegeneration

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Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3. These tracers are now available for clinical assessment in patients with various tauopathies, including Alzheimer’s disease, as well as in healthy subjects. Exploring the patterns of tau deposition in vivo for different pathologies will allow discrimination between neurodegenerative diseases, including different tauopathies, and monitoring of disease progression. The variety and complexity of the different types of tau deposits in the different diseases, however, has resulted in quite a challenge for the development of tau PET tracers. Extensive work remains in order to fully characterize the binding properties of the tau PET tracers, and to assess their usefulness as an early biomarker of the underlying pathology. In this review, we summarize recent findings on the most promising tau PET tracers to date, discuss what has been learnt from these findings, and offer some suggestions for the next steps that need to be achieved in a near future.

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“…Over the last few years, three classes of tau tracers have appeared as candidates to selectively measure neurofibrillary tangles in the living human brain: the derivative of pyrido-indole ([ 18 F]AV1451) [ 1 , 2 ], the derivatives of aryquinoline ([ 18 F]THK5117, [ 18 F]THK5317, and [ 18 F]THK5351) [ 3 , 4 ], and the derivative of phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazolium ([ 11 C]PBB3) [ 5 ]. Although these tracers have shown affinity to neurofibrillary tangles, compelling evidence suggests that off-target binding heavily influences the signal of some of them, even in cortical brain regions that are considered a target for AD.…”

Section: Introductionmentioning

confidence: 99%

In vivo quantification of neurofibrillary tangles with [18F]MK-6240

et al. 2018

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BackgroundImaging agents capable of quantifying the brain’s tau aggregates will allow a more precise staging of Alzheimer’s disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [18F]MK-6240.MethodsIn vitro properties of [18F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging.ResultsIn vitro [18F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time–activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates.ConclusionsThis evaluation shows an [18F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions.

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Development of [11C]/[3H]THK-5351 – A potential novel carbon-11 tau imaging PET radioligand

Cited by 17 publications

References 20 publications

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Tau PET imaging: present and future directions

In vivo quantification of neurofibrillary tangles with [18F]MK-6240

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