Imaging of neurofibrillary pathology in the brain helps in diagnosing dementia, tracking disease progression, and evaluating the therapeutic efficacy of antidementia drugs. The radiotracers used in this imaging must be highly sensitive and specific for tau protein fibrils in the human brain. We developed a novel tau PET tracer, ¹⁸F-THK5351, through compound optimization of arylquinoline derivatives. Methods: The in vitro binding properties, pharmacokinetics, and safety of ¹⁸F-THK5351 were investigated, and a clinical study on Alzheimer disease (AD) patients was performed. Results: ¹⁸F-THK5351 demonstrated higher binding affinity for hippocampal homogenates from AD brains and faster dissociation from white-matter tissue than did ¹⁸F-THK5117. The THK5351 binding amount correlated with the amount of tau deposits in human brain samples. Autoradiography of brain sections revealed that THK5351 bound to neurofibrillary tangles selectively and with a higher signal-to-background ratio than did THK5117. THK5351 exhibited favorable pharmacokinetics and no defluorination in mice. In first-in-human PET studies in AD patients, ¹⁸F-THK5351 demonstrated faster kinetics, higher contrast, and lower retention in subcortical white matter than¹⁸F-THK5117. Conclusion: ¹⁸F-THK5351 is a useful PET tracer for the early detection of neurofibrillary pathology in AD patients.

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of ¹⁸F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that ¹⁸F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid_1–42 fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of ¹⁸F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that ¹⁸F-THK523 fulfils ligand criteria for human imaging trials.

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 ¹⁸F-labeled THK-523 (¹⁸F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel ¹⁸F-labeled arylquinoline derivatives, ¹⁸F-THK-5105 and ¹⁸F-THK-5117, for use as tau imaging PET tracers. Methods: ¹⁸F-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 ¹¹C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than ¹⁸F-THK-523 and other reported ¹⁸F-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. Conclusion: ¹⁸F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

From pharmacological studies using histamine antagonists and agonists, it has been demonstrated that histamine modulates many physiological functions of the hypothalamus, such as arousal state, locomotor activity, feeding, and drinking. Three kinds of receptors (H ₁ , H ₂ , and H ₃ ) mediate these actions. To define the contribution of the histamine H ₁ receptors (H1R) to behavior, mutant mice lacking the H1R were generated by homologous recombination. In brains of homozygous mutant mice, no specific binding of [ ³ H]pyrilamine was seen. [ ³ H]Doxepin has two saturable binding sites with higher and lower affinities in brains of wild-type mice, but H1R-deficient mice showed only the weak labeling of [ ³ H]doxepin that corresponds to lower-affinity binding sites. Mutant mice develop normally, but absence of H1R significantly increased the ratio of ambulation during the light period to the total ambulation for 24 hr in an accustomed environment. In addition, mutant mice significantly reduced exploratory behavior of ambulation and rearings in a new environment. These results indicate that through H1R, histamine is involved in circadian rhythm of locomotor activity and exploratory behavior as a neurotransmitter.

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer’s disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer’s disease (three male and five females, 66–82 years) and eight healthy elderly controls (three male and five females, 63–76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90–100 min and 40–70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer’s disease compared with healthy control subjects. In patients with Alzheimer’s disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer’s disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer’s disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer’s disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer’s disease. * Abbreviations : CDR : clinical dementia rating MMSE : Mini-Mental State Examination PiB : Pittsburgh compound B SOB : sum of boxes SUV : standardized uptake value SUVR : ratio of regional SUV to cerebellar cortex SUV ratio