Novel F-18-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Journal of Nuclear Medicine (Impact Factor: 6.16). 07/2013; 54(8). DOI: 10.2967/jnumed.112.117341
Source: PubMed


Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers.
(18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice.
In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-μM concentrations.
(18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

Full-text preview

Available from:
  • Source
    • "Development of non-invasive neuroimaging techniques such as amyloid PET and structural MRI including voxelbased morphometric MRI (VBM-MRI) facilitate early accurate diagnosis and help explain the underlying pathogenesis of MCI, AD, and dementia with Lewy bodies (DLB) [8] [9] [10] [11] [12] [13] [14] [15]. Very recently, the development of tau-PET, which allows the visualization of tau deposition directly in the brain, while exciting [16] [17] [18], will take a long time to be applied in our memory clinic. "

    Alzheimer's and Dementia 07/2014; 10(4):P717-P718. DOI:10.1016/j.jalz.2014.05.1327 · 12.41 Impact Factor
  • Source
    • "WM non-specific uptake reduces the diagnostic sensitivity of numerous imaging agents. To overcome this limitation, the second-generation of THK tracers, [18 F]THK5105 and [18 F]THK5117, were optimized for higher NFT cortical uptake and less WM retention [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypherphosphorylation of the tau protein leading to the formation of neurofibrillary tangles (NFTs) is a common feature in a wide range of neurodegenerative diseases known as tauopathies, which include Alzheimer's disease (AD) and the frontotemporal dementias (FTDs). Although heavily investigated, the mechanisms underlying the pathogenesis and progression of tauopathies has yet to be fully understood. In this context, several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology, aiming to achieve a better understanding of the link between tau and neurodegeneration. To date, behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid (CSF) sampling or post-mortem analysis. Recently, several novel positron emission tomography (PET) radiopharmaceuticals targeting tau tangles have been developed, allowing for non-invasive in vivo quantification of tau pathology. Combined with tau transgenic models and microPET, these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies. In this review, we briefly describe some of the most important insights for understanding the biological basis of tau pathology, and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models.
    Translational Neurodegeneration 03/2014; 3(1):6. DOI:10.1186/2047-9158-3-6
  • Source
    • "Hopefully in the near future we will refine techniques for non-invasive assessment of tau. Thereon, are extremely interesting attempts to generate PET markers for tau deposition in brain (48, 49) and we already have promising data regarding measurement of different forms of tau in blood cells (15, 29). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A cumulative number of approaches have been carried out to elucidate the pathogenesis of Alzheimer's disease (AD). Tangles formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. Most of recent studies share in common the observation that formation of tau oligomers and the subsequent pathological filaments arrays is a critical step in AD etiopathogenesis. Oligomeric tau species appear to be toxic for neuronal cells, and therefore appear as an appropriate target for the design of molecules that may control morphological and functional alterations leading to cognitive impairment. Thus, current therapeutic strategies are aimed at three major types of molecules: (1) inhibitors of protein kinases and phosphatases that modify tau and that may control neuronal degeneration, (2) methylene blue, and (3) natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. Only a few polyphenolic molecules have emerged to prevent tau aggregation. In this context, fulvic acid (FA), a humic substance, has potential protective activity cognitive impairment. In fact, formation of paired helical filaments in vitro, is inhibited by FA affecting the length of fibrils and their morphology.
    Frontiers in Neurology 10/2013; 4:167. DOI:10.3389/fneur.2013.00167
Show more