F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.

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-[ 18 F]fluoro-2hydroxy)propoxy]quinoline, ( 18 F-SMBT-1), was successfully developed via lead optimization from firstgeneration tau positron-emission tomography (PET) tracer 18 F-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 18 F-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 18 F-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 (K D = 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 18 F-SMBT-1 binding in the Alzheimer's disease (AD) brain sections than in the control brain sections. 18 F-SMBT-1 binding was completely displaced with reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of 18 F-SMBT-1 for MAO-B. Furthermore, 18 F-SMBT-1 showed a high uptake by brain, rapid washout, and no 4 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: 18 F-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.

Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN accumulation in the endosomal compartment, presumably due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments using human αSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN in fly head but also induced dopaminergic neurodegeneration, rough eye phenotype and age-dependent locomotor impairment. Together, these findings suggest that DNAJC13 mutation perturbs multi-directional endosomal trafficking, resulting in the aberrant endosomal retention of αSYN, which might predispose to the neurodegenerative process that leads to PD.

Background and purpose Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18F‐THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease‐related pathology in the brains of patients with CBS using positron emission tomography with 18F‐THK5351. Methods Baseline and 1‐year follow‐up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18F‐THK5351 in 10 subjects: five patients with CBS and five age‐matched normal controls (NCs). Results The 1‐year follow‐up scan images revealed that 18F‐THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18F‐THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18F‐THK5351 retention in the NCs. Conclusions Longitudinal increases in 18F‐THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.

The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α‐synuclein (α‐SYN)‐positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α‐SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)‐1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up‐regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α‐SYN can potentiate FLOT1–dopamine transporter (DAT) binding and pre‐endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down‐regulating its transporter activity. Moreover, we demonstrated that α‐SYN itself exploited the DAT endocytic process to enter dopaminergic neuron‐like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α‐SYN on cellular trafficking of DAT and may provide a rationale for the cell type‐specific, functional, and pathologic alterations in PD.—Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α‐synuclein enters dopaminergic cells by modulating flotillin‐1–assisted dopamine transporter endocytosis. FASEB J. 33, 10240–10256 (2019). http://www.fasebj.org