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.

No abstract

No abstract

Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer N-(4-[ 18 F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([ 18 F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [ 18 F]SNFT-1 using a head-to-head comparison with other reported 18 F-labeled tau tracers. Methods: The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of 18 F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [ 18 F]SNFT-1. Results: In vitro binding assays demonstrated that [ 18 F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [ 18 F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, a-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [ 18 F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [ 18 F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. Conclusion: These preclinical data suggest that [ 18 F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain.

Background [18F]THK‐5351, which was originally designed to detect tau aggregates, bound to monoamine oxidase B (MAO‐B) with high affinity. Lead optimization toward selective binding profiles to tau has resulted in the development of novel selective tau PET tracer named [18F]SNFT‐1 (THK‐5562). Here we present the preclinical characteristics of this tracer. Method In vitro competitive binding assays against MAO‐A, MAO‐B, amyloid, and tau were performed. In vitro autoradiography of the human brain tissues of various neurodegenerative diseases was performed. Receptor panel screen was performed to confirm the binding selectivity of this compound. Biodistribution study was performed in mice. In addition, an acute toxicity with intravenous administration of a single dose of this compound in mice was also investigated. Result SNFT‐1 showed high affinity (K d = 0.47 nM) and selectivity for tau aggregates over other misfolding proteins as well as MAO enzymes. In vitro autoradiography demonstrated the intense laminar binding of [18F]SNFT‐1 to tau pathology in AD and less off‐target binding than currently available tau PET tracers. No remarkable binding inhibition on various receptors ion channels, and transporters was observed at 1 μM concentration. [18F]SNFT‐1 showed good initial brain uptake and rapid washout without defluorination and troublesome radiolabeled metabolites in mice. In acute toxicity study, no drug‐related changes were noted after intravenous administration of this compound in mice. Conclusion [18F]SNFT‐1 is highly selective tau PET tracer, which will enable accurate monitoring of abnormal tau pathology in AD brain.

No abstract

Objective: Intratumoral heterogeneity is associated with poor outcomes in head and neck cancer (HNC) patients owing to chemoradiotherapy resistance.[ 18 F]-FDG positron emission tomography (PET) / Magnetic Resonance Imaging (MRI) provides spatial information about tumor mass, allowing intratumor heterogeneity assessment through histogram analysis. However, variability in quantitative PET/MRI parameter measurements could influence their reliability in assessing patient prognosis. Therefore, to use standardized uptake value (SUV) and apparent diffusion coefficient (ADC) parameters for assessing tumor response, this study aimed to measure SUV and ADC's variability and assess their relationship in HNC. Methods: First, ADC variability was measured in an in-house diffusion phantom and in five healthy volunteers. The SUV variability was only measured with the NEMA phantom using a clinical imaging protocol. Furthermore, simultaneous PET/MRI data of 11 HNC patients were retrospectively collected from the National Cyclotron and PET center in Chulabhorn Hospital. Tumor contours were manually drawn from PET images by an experienced nuclear medicine radiologist before tumor volume segmentation. Next, SUV and ADC's histogram were used to extract statistic variables of ADC and SUV: mean, median, min, max, skewness, kurtosis, and 5 th , 10 th , 25 th , 50 th , 75 th , 90 th , and 95 th percentiles. Finally,the correlation between the statistic variables of ADC and SUV,as well as Metabolic Tumor volume and Total Lesion Glycolysis parameters was assessed using Pearson's correlation. Results: This pilot study showed that both parameters' maximum coefficient of variation was 13.9% and 9.8% in the phantom and in vivo, respectively. Furthermore, we found a strong and negative correlation between SUV max and ADV med (r = −0.75, P = 0.01). Conclusion:The SUV and ADC obtained by simultaneous PET/MRI can be potentially used as an imaging biomarker for assessing intratumoral heterogeneity in patients with HNC. The low variability and relationship between SUV and ADC could allow multimodal prediction of tumor response in future studies.

Tau is one of the characteristic deposits in Alzheimer's Disease which occurs in neurofibrillary tangles within neurons. Positron-emission tomography (PET) is a nuclear imaging technique, making it possible to detect tau aggregation in AD in vivo, thereby helping to pre-diagnose and trace disease progression. Up to now, many tau tracers have been developed. For example, the first generation tau tracer [ 18 F]AV-1451 and [ 18 F]THK-5351 developed by our group displayed strong uptake in patients' brains. Although they were promising, considerable off-target binding has been observed, especially to MAO-B and other non-tau protein deposits. This led to the optimization of binding characteristics and discovery of novel tau tracers. More than 200 candidates synthesized by our group were screened through binding assay for tau, amyloid β, monoamine oxidase A and B. Among these compounds, [ 18 F]THK-5562 was identified with high affinity and selectivity for tau aggregation without off target bindings, followed by further evaluation. As a result, [ 18 F]THK-5562 displayed excellent in vivo pharmacokinetics characteristics in mice. Besides, [ 18 F]THK-5562 seemed to be specific for 3R/4R tau in AD by autoradiography and immunohistochemistry. In conclusion, preclinical validation suggested the potential usefulness of [ 18 F]THK-5562 in imaging tau aggregation in Alzheimer's disease.