Structure–Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease

Tago, Tetsuro; Furumoto, Shozo; Okamura, Nobuyuki; Harada, Ryuichi; Adachi, Hisanobu; Ishikawa, Yoichi; Yanai, Kazuhiko; Iwata, Ren; Kudo, Yoshihisa

doi:10.2967/jnumed.115.166652

Cited by 57 publications

(58 citation statements)

References 29 publications

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“…WM clearance was faster for THK-5351, in agreement with previously reported results showing slow in vivo WM clearance for THK-5317(19) and faster in vitro WM dissociation for THK-5351(13). Higher DVRs for THK-5351 in regions associated with tau pathology is likely attributed to a higher ligand-protein affinity for tau observed with THK-5351 in AD hippocampal homogenates(13,35,41). Though there was a systematic delay between THK-5351 and THK-5317 scans (THK-5351 always occurred after THK-5317), adjusting for time between scans did not change the relationship between tracer binding estimates, and on average THK-5351 GM signal was more than 3-fold higher than the highest annual rate of change reported in a longitudinal study(24).…”

Section: Discussionmentioning

confidence: 98%

In Vivo Comparison of Tau Radioligands ¹⁸F-THK-5351 and ¹⁸F-THK-5317

et al. 2016

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Purpose This study compared the in vivo imaging characteristics of tau positron emission tomography (PET) ligands 18F-THK-5351 and 18F-THK-5317 in the context of Alzheimer’s disease (AD). Additionally, reference tissue distribution volume ratio (DVR) estimation methods and standard uptake value ratio (SUVR) timing windows were evaluated to determine the optimal strategy for specific binding quantification. Methods Twenty-eight subjects (mean age 71±7yrs) underwent either dynamic 90-minute 18F-THK-5317 or 18F-THK-5351 PET scans. Bland-Altman plots were utilized to compare the simplified reference tissue method (SRTM), multilinear reference tissue method (MRTM2), and Logan reference tissue DVR estimates and to assess temporal stability of SUVR windows using cerebellar gray matter (GM) as a reference region. In vivo kinetics and DVR estimates were directly compared for 10 subjects that underwent both 18F-THK-5317 and 18F-THK-5351 PET scans. Results THK-5351 exhibited faster cerebellar GM clearance, faster cortical white matter (WM) clearance, and higher DVR estimates in AD tau-associated regions of interest (ROIs) compared to THK-5317. The MRTM2 method produced the most reliable DVR estimates for both tracers, particularly when scan duration was shortened to 60 minutes. SUVR stability was observed 50-70 minutes post injection for both tracers. Parametric images revealed differences between MRTM2, Logan and SUVR binding in WM regions for THK-5317. Conclusion THK-5317 and THK-5351 show promise for in vivo detection of AD tau. THK-5351 has more favorable pharmacokinetics and imaging characteristics compared to THK-5317.

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Section: Discussionmentioning

confidence: 98%

In Vivo Comparison of Tau Radioligands ¹⁸F-THK-5351 and ¹⁸F-THK-5317

et al. 2016

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“…THK-5351 standard and precursor were synthesized and supplied by Tohoku University (Tago et al, 2016). Bulk precursor was dissolved in anhydrous DMSO (Thermo Scientific), aliquoted, and stored at ~5°C.…”

Section: Methodsmentioning

confidence: 99%

“…The tC18 Sep-Pak Plus Light (Waters Corporation, tC18 light) and tC18 Sep-Pak Plus Short (Waters Corporation, tC18 short) cartridges were preconditioned with 5 mL of USP ethanol and rinsed with 10 mL of DI water (intermediate tC18 light) or SWI (formulation tC18 short) prior to use. Semi-preparative and analytical HPLC systems consisted of Waters 515 HPLC pump, Waters 2489 HPLC UV detector set at 360 nm absorbance (Tago et al, 2016), and in-line radioactivity detection (105-S, Carroll & Ramsey Associates). Semi-preparative HPLC purification used either an Inertsil ODS-4 (5μm, 10 × 250 mm, GL Sciences) or a Luna C18(2) (10μm, 10 × 250 mm, 100Å, Phenomenex) column.…”

Section: Methodsmentioning

confidence: 99%

“…Chemical synthesis of THK 2-arylquinoline compounds, including [ 18 F]THK-5351, has been reported in detail elsewhere (Harada et al, 2016b; Okamura et al, 2013; Tago et al, 2016). Briefly, [ 18 F]THK-5351 is synthesized through nucleophilic radiofluorination of the 2-tetrahydropyranyl-(OTHP-) protected tosylate precursor (S)-2-(2-methylaminopyrid-5-yl)-6-[[2-(tetrahydro-2H-pyran-2-yloxy)-3-tosyloxy]propoxy]quinoline (THK-5352), followed by acid hydrolysis and neutralization (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the radiosynthesis and purification of [18F]THK-5351, a PET ligand for neurofibrillary tau

Betthauser

Ellison

Murali

et al. 2017

Applied Radiation and Isotopes

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This work characterizes the radiochemical synthesis, purification, and formulation of [18F]THK-5351, a tau PET radioligand, and develops an automated radiosynthesis routine (ELIXYS, Sofie Biosciences). Nucleophilic radiofluorination reaction was complete by 7 minutes at 110°C with radiochemical yields proportional to precursor mass (0.1–0.5 mg). Optimized HPLC purification produced radiotracer product with no chemical impurities observed on analytical HPLC in formulation. Automated radiosynthesis (ELIXYS), HPLC purification and formulation was completed in 86 minutes producing formulated product suitable for human research use.

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“…Significant off-target binding was observed in the putamen and brain stem (193, 194). These agents were soon eclipsed by another 2-arylquinoline derivative, THK-5351, the S-enantiomer of a pyridine derivative of THK-5117 (195). 18 F-THK-5351 was shown to have improved signal-to-background characteristics and low white matter retention compared to 18 F-THK-5105 and 18 F-THK-5117, which the authors attributed to its optical purity and lower lipophilicity.…”

Section: Tau Imaging In Alzheimer’s Diseasementioning

confidence: 99%

Small-molecule PET Tracers for Imaging Proteinopathies

Mathis

Lopresti

Ikonomović

et al. 2017

Seminars in Nuclear Medicine

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In this chapter, we provide a review of the challenges and advances in developing successful positron emission tomography (PET) imaging agents for three major types of aggregated amyloid proteins – amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These three amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer’s disease, Lewy body dementias, multiple system atrophy, and frontal temporal dementias among others. In the Introduction, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts. Instead, the field has relied on largely serendipitous, trial and error methods to achieve useful and specific PET amyloid imaging tracers for Aβ, tau, and α-syn deposits. Because many of the proteopathies involve more than one amyloid protein, it is important to develop selective PET tracers for the different amyloids to help assess the relative contribution of each to total amyloid burden. We utilize Pittsburgh Compound B (PiB) to illustrate some of the critical steps in developing a potent and selective Aβ PET imaging agent. Other selective Aβ and tau PET imaging compounds have followed similar pathways in their developmental processes. Success for selective α-syn PET imaging agents has not been realized yet, but work is ongoing in multiple laboratories throughout the world. In the tau sections, we provide background regarding 3-repeat (3R) and 4-repeat (4R) tau proteins and how they can affect the binding of tau radioligands in different tauopathies. We review the ongoing efforts to assess the properties of tau ligands, which are useful in 3R, 4R or combined 3R/4R tauopathies. Finally, we describe in the α-syn sections recent attempts to develop selective tracers to image α-synucleinopathies.

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Structure–Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease

Cited by 57 publications

References 29 publications

In Vivo Comparison of Tau Radioligands ¹⁸F-THK-5351 and ¹⁸F-THK-5317

In Vivo Comparison of Tau Radioligands ¹⁸F-THK-5351 and ¹⁸F-THK-5317

Characterization of the radiosynthesis and purification of [18F]THK-5351, a PET ligand for neurofibrillary tau

Small-molecule PET Tracers for Imaging Proteinopathies

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Structure–Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease

Cited by 57 publications

References 29 publications

In Vivo Comparison of Tau Radioligands 18F-THK-5351 and 18F-THK-5317

In Vivo Comparison of Tau Radioligands 18F-THK-5351 and 18F-THK-5317

Characterization of the radiosynthesis and purification of [18F]THK-5351, a PET ligand for neurofibrillary tau

Small-molecule PET Tracers for Imaging Proteinopathies

Contact Info

Product

Resources

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In Vivo Comparison of Tau Radioligands ¹⁸F-THK-5351 and ¹⁸F-THK-5317

In Vivo Comparison of Tau Radioligands ¹⁸F-THK-5351 and ¹⁸F-THK-5317