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.

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    • "Following the optimization of the quinoline derivative BF-170, three 18 F-labeled-tau PET tracers,[Harada et al., 2015a;Li et al., 2015;Okamura et al., 2014a;Okamura et al., 2013;Okamura et al., 2014b). The binding selectivity of these radiotracers to the PHF-tau was confirmed by the autoradiographic analyses of AD-brain sections (Harada et al., 2015a;Okamura et al., 2013).These radiotracers also showed a high binding affinity (Kd = 2.9 – 10.8 nM) to the AD-hippocampal brain homogenates containing a high density of the PHF-tau. "
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    • "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. "

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    • "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]. "
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