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

Abstract

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. Methods: 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. Results: 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-mM concentrations. Conclusion: 18 Flabeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

[18F]AV‐1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation

“…Until recently it has only been feasible to examine the morphology, intensity, and distribution of tau pathology post‐mortem . Several radiolabeled compounds have been developed with evidence of binding to intracellular aggregates of tau,1, 2 allowing potential visualization and quantification of tau pathology using positron emission tomography (PET).…”

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

“…In this context, novel PET-tracers for tau-imaging may be of extraordinary importance. Fortunately, first successful experiments to establish such novel imaging biomarkers are currently on their way [288].…”

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

“…According to the previous methods (16), the inhibitory constant (K i ) and dissociation constant (K d ) were determined using the AD brain homogenates of temporal gray matter and hippocampus, respectively. Details are described in the supplemental data.…”