Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease

Lerdsirisuk, Pradith; Harada, Ryuichi; Hayakawa, Yoshimi; Shimizu, Yuki; Ishikawa, Yoichi; Iwata, Ren; Kudo, Yoshihisa; Okamura, Nobuyuki; Furumoto, Shozo

doi:10.1016/j.nucmedbio.2020.10.002

Cited by 9 publications

(17 citation statements)

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“…[ 18 F]Fluoroethyl harmol ([ 18 F]FEH) was prepared using the corresponding precursor via the adoption of microscale (50 μL) radiosynthesis methods, as per methods previously described. 37 (S)-[ 18 F]6, (R)-[ 18 F]6, and [ 18 F]FEH were produced in >99% radiochemical purity. The decay-corrected radiochemical yields of (S)-[ 18 F]6 and (R)-[ 18 F]6 were 29% and 41%, respectively.…”

Section: ■ Methodssupporting

confidence: 91%

“…The product was extracted from a collected HPLC fraction with a Sep-Pak tC18 light cartridge and solubilized in saline with polysorbate 80 (<0.1%). [ 18 F]Fluoroethyl harmol ([ 18 F]FEH) was prepared using the corresponding precursor via the adoption of microscale (50 μL) radiosynthesis methods, as per methods previously described . ( S )-[ 18 F] 6 , ( R )-[ 18 F] 6 , and [ 18 F]FEH were produced in >99% radiochemical purity.…”

Section: Methodsmentioning

confidence: 99%

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The Role of Chirality of [¹⁸F]SMBT-1 in Imaging of Monoamine Oxidase-B

Harada

Shimizu

et al. 2022

ACS Chem. Neurosci.

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(S)-(2-Methylpyrid-5-yl)-6-[(3-[18F]fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B (MAO-B) tracers for in vivo imaging of reactive astrogliosis via positron emission tomography. To investigate the effect of the chirality of [18F]SMBT-1 on tracer performance, we synthesized (S)-[18F]6 ([18F]SMBT-1) and (R)-[18F]6 and compared their binding properties, pharmacokinetics, and metabolism. (S)-6 showed higher binding affinity to MAO-B and lower binding affinity to MAO-A than (R)-6, demonstrating a higher selectivity ratio (MAO-B/MAO-A). A pharmacokinetic study in mice demonstrated that both (S)-[18F]6 and (R)-[18F]6 showed sufficient initial brain uptake. However, (S)-[18F]6 was cleared significantly faster from the body. An abundant sulfoconjugate metabolite M2 was observed in plasma for (S)-[18F]6 but not for (R)-[18F]6. In vitro sulfation assays confirmed that (S)-6 was more reactive than (R)-6, consistent with the in vivo findings. Mefenamic acid, a selective sulfotransferase 1A1 (SULT1A1) inhibitor, strongly inhibited the in vitro sulfation of (S)-6 by mouse liver fractions, human liver cytosol fractions, and human recombinant SULT1A1 enzyme. Genetic polymorphisms of SULT1A1 did not affect the sulfation of (S)-6 in vitro. In conclusion, (S)-[18F]6 had a more favorable binding affinity and binding selectivity for MAO-B than (R)-[18F]6. Additionally, (S)-[18F]6 also possessed better pharmacological and metabolic properties than (R)-[18F]6. These results suggest that (S)-[18F]6 ([18F]SMBT-1) is a promising candidate for application in the imaging of MAO-B in vivo.

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Section: ■ Methodssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

The Role of Chirality of [¹⁸F]SMBT-1 in Imaging of Monoamine Oxidase-B

Harada

Shimizu

et al. 2022

ACS Chem. Neurosci.

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“…The PET radioligand, 18 F-THK5351, binds to both monoamine oxidase B (MAO-B) and tau aggregates 1–3 . However, because the binding affinity of 18 F-THK5351 toward MAO-B is higher than that toward tau aggregates, 1,2,4 18 F-THK5351 PET is recognized for estimating regional MAO-B concentrations, specifically in cases that are irrelevant to tau pathology, such as in young subjects, patients without tauopathy, or regions where tau protein does not usually accumulate.…”

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confidence: 99%

Distribution Pattern of the Monoamine Oxidase B Ligand, 18F-THK5351, in the Healthy Brain

et al. 2022

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Background18F-THK5351 PET estimates the concentrations of monoamine oxidase B (MAO-B) that are preferentially located in astrocytes and can be used to visualize and quantify ongoing astrogliosis. To study images of astrogliosis in neurological disorders, it is essential to understand the detailed binding sites of 18F-THK5351 as the MAO-B ligand under normal conditions. In this study, we examined the detailed distribution pattern of 18F-THK5351 in the healthy brain by comparing 18F-THK5351 uptake between subjects taking and not taking the MAO-B inhibitor.MethodsTen healthy controls (HCs: 67.4 [SD, 15.1] years) and 4 patients with Parkinson disease taking the MAO-B inhibitor underwent 18F-THK5351 PET. The uptake ratio index (URI) was defined to quantify 18F-THK5351 uptake, using the cerebellum as a reference region. The cerebellar URI was set to zero.ResultsFor HCs, regions with URI ≥1 were preferentially observed in the following order: the striatum, globus pallidus, thalamus, hypothalamus, amygdala, periaqueductal gray, substantia nigra, medulla, hippocampus, and pons. The peak URI values in the corresponding regions were 2.93, 2.47, 2.12, 2.04, 1.84, 1.68, 1.67, 1.37, 1.20, and 1.11, respectively. For all patients with Parkinson disease taking the MAO-B inhibitor, the URI values in all these regions were significantly decreased (Z score >2) and were reduced from 60.4% to 99.9%, compared with HCs.ConclusionsThis study presented the detailed distribution pattern of 18F-THK5351 in HCs and suggests that 18F-THK5351 uptake largely reflects MAO-B concentrations under normal conditions.

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“…Although this may be interpreted as a limitation for selective detection of tau pathology, our results indicate that it provides a strong correlation between tau-related pathology, clinical changes, and imaging. In addition, other tau PET imaging probes, such as 2-pyrrolopyridinylquinoline derivatives, have been recently developed to selectively target tau aggregates in an effort to reduce this off-target binding [38]. Therefore, the use of 18 F-THK5351 in the clinic still can provide information about tauopathies onset and development, helping to discriminate from other non-tau-related neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study

et al. 2021

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Several common and debilitating neurodegenerative disorders are characterized by the intracellular accumulation of neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. In Alzheimer’s disease (AD), NFTs are accompanied by extracellular amyloid-beta (Aβ), but primary tauopathy disorders are marked by the accumulation of tau protein alone, including forms of frontotemporal dementia (FTD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), among others. 18F-THK5351 has been reported to bind pathological tau as well as associated reactive astrogliosis. The goal of this study was to validate the ability of the PET tracer 18F-THK5351 to detect early changes in tau-related pathology and its relation to other pathological hallmarks. We demonstrated elevated in vivo 18F-THK5351 PET signaling over time in transgenic P301S tau mice from 8 months that had a positive correlation with histological and biochemical tau changes, as well as motor, memory, and learning impairment. This study indicates that 18F-THK5351 may help fill a critical need to develop PET imaging tracers that detect aberrant tau aggregation and related neuropathology in order to diagnose the onset of tauopathies, gain insights into their underlying pathophysiologies, and to have a reliable biomarker to follow during treatment trials.

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Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease

Cited by 9 publications

References 28 publications

The Role of Chirality of [¹⁸F]SMBT-1 in Imaging of Monoamine Oxidase-B

The Role of Chirality of [¹⁸F]SMBT-1 in Imaging of Monoamine Oxidase-B

Distribution Pattern of the Monoamine Oxidase B Ligand, 18F-THK5351, in the Healthy Brain

Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study

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Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease

Cited by 9 publications

References 28 publications

The Role of Chirality of [18F]SMBT-1 in Imaging of Monoamine Oxidase-B

The Role of Chirality of [18F]SMBT-1 in Imaging of Monoamine Oxidase-B

Distribution Pattern of the Monoamine Oxidase B Ligand, 18F-THK5351, in the Healthy Brain

Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study

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The Role of Chirality of [¹⁸F]SMBT-1 in Imaging of Monoamine Oxidase-B

The Role of Chirality of [¹⁸F]SMBT-1 in Imaging of Monoamine Oxidase-B