18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18F-THK5351 brain uptake using PET and autoradiography. Eight participants (five mild cognitive impairment, two Alzheimer’s disease, and one progressive supranuclear palsy) had baseline 18F-AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18F-THK5351 scan 9–28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline. At baseline, 18F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9–28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18F-THK5351 uptake. These results indicate that the interpretation of 18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18F-THK5351 scans using reference region methods.

Clinical PET studies using ¹⁸F-THK5351 have demonstrated significant tracer retention in sites susceptible to tau burden in Alzheimer disease (AD). However, the in vivo PET signal to reflect tau aggregates remains controversial. Methods: We examined the spatial pattern of tracer binding, amyloid-β, tau, and gliosis in an autopsy-confirmed AD patient who underwent ¹⁸F-THK5351 and ¹¹C-Pittsburgh compound B PET before death. Results: Regional in vivo ¹⁸F-THK5351 retention was significantly correlated with the density of tau aggregates in the neocortex and monoamine oxidase-B in the whole brain, but not correlated with that of insoluble amyloid-β. Furthermore, significant association was observed between the density of tau aggregates, monoamine oxidase-B, and glial fibrillary acidic protein, suggesting that neocortical tau would strongly influence the formation of reactive astrocytes. Conclusion: ¹⁸F-THK5351 PET may have limited utility as a biomarker of tau pathology in AD; however, it could be used to monitor the neuroinflammatory processes in the living brain.

Tau deposition is one of the neuropathological hallmarks in Alzheimer’s disease as well as in other neurodegenerative disorders called tauopathies. Recent efforts to develop selective tau radiopharmaceuticals have allowed the visualization of tau deposits in vivo. In vivo tau imaging allows the assessment of the regional distribution of tau deposits in a single human subject over time for determining the pathophysiology of tau accumulation in aging and neurodegenerative conditions as well as for application in drug discovery of anti-dementia drugs as surrogate markers. However, tau deposits show complicated characteristics because of different isoform composition, histopathology, and ultrastructure in various neurodegenerative conditions. In addition, since tau radiopharmaceuticals possess different chemotype classes, they may show different binding characteristics with heterogeneous tau deposits. In this review, we describe the characteristics of tau deposits and their ligands that have β-sheet binding properties, and the status of tau imaging in clinical studies.

Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, (S)-(2-methylpyrid-5-yl)-6-[(3-[¹⁸F]fluoro-2-hydroxy)propoxy]quinoline, (¹⁸F-SMBT-1), was successfully developed via lead optimization from first-generation tau positron-emission tomography (PET) tracer ¹⁸F-THK-5351. Methods: SMBT-1 was radiolabeled with fluorine-18 using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of ¹⁸F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics (PK) and metabolism were assessed in normal mice after intravenous administration of ¹⁸F-SMBT-1. A 14-day toxicity study following the intravenous administration of SMBT-1 was performed using rats and mice. Results: In vitro binding assays demonstrated a high binding affinity of SMBT-1 to MAO-B (KD = 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-β and tau fibrils. Autoradiographic analysis showed higher amounts of ¹⁸F-SMBT-1 binding in the Alzheimer’s disease (AD) brain sections than in the control brain sections. ¹⁸F-SMBT-1 binding was completely displaced with reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of ¹⁸F-SMBT-1 for MAO-B. Furthermore, ¹⁸F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. SMBT-1 showed no significant binding to various receptors, ion channels, and transporters, and no toxic effects related to its administration were observed in mice and rats. Conclusion: ¹⁸F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.

Introduction: The introduction of tau imaging agents such as ¹⁸F-THK523 offers new hope for the in vivo assessment of tau deposition in tauopathies such as Alzheimer’s disease (AD), where preliminary ¹⁸F-THK523-PET studies have demonstrated significantly higher cortical retention of ¹⁸F-THK523 in AD compared to age-matched healthy individuals. In addition to AD, tau imaging with PET may also be of value in assessing non-AD tauopathies, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick’s disease (PiD). Methods: To further investigate the ability of THK523 to recognize tau lesions, we undertook immunohistochemical and fluorescence studies in serial brain sections taken from individuals with AD (n = 3), CBD (n = 2), PSP (n = 1), PiD (n = 2) and Parkinson’s disease (PD; n = 2). In addition to the neuropathological analysis, one PSP patient had undergone a ¹⁸F-THK523 PET scan 5 months before death. Results: Although THK523 labelled tau-containing lesions such as neurofibrillary tangles and neuropil threads in the hippocampus and frontal regions of AD brains, it failed to label tau-containing lesions in non-AD tauopathies. Furthermore, though THK523 faintly labelled dense-cored amyloid-β plaques in the AD frontal cortex, it failed to label α-synuclein-containing Lewy bodies in PD brain sections. Conclusion: The results of this study suggest that ¹⁸F-THK523 selectively binds to paired helical filament tau in AD brains but does not bind to tau lesions in non-AD tauopathies, or to α-synuclein in PD brains.