Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/μmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 μg (range, 0.16-8.27 μg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.

中文翻译：

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在人类首次研究中评价作为Tau PET显像剂的[18F] -N-甲基兰索拉唑。

在痴呆症研究领域中，开发能够定量化神经退行性疾病如阿尔茨海默氏病（AD）中的tau聚集体的正电子发射断层扫描（PET）成像剂非常重要。本研究的目的是使用潜在的新型tau显像剂[18F] N-甲基兰索拉唑（[18F] NML）进行首次人体成像研究。本文中，我们通过对相应的宝石-二氟烯醇醚前体进行放射性氟化来标记三氟甲基，从而报告了[18F] NML的临床合成验证。这是此方法首次用于临床生产PET放射性示踪剂，并证实可以在多个生产设施中轻松实施，以提供[18F] NML，并具有良好的未校正放射化学产率（3.4±1.5 GBq，4.6％±2.6％），以及摩尔活性（120。1±186.3 GBq /μmol），出色的放射化学纯度（> 97％）和适用于人类的用途（n = 15）。手持[18F] NML，我们在两个成像部位进行了啮齿动物生物分布，人体剂量估计和对[18F] NML的初步评估。健康对照（n = 4）和轻度认知障碍（MCI）AD患者（n = 6）接受[18F] NML（tau），[18F] AV1451（tau）和[18F] florbetaben或[18F] florbetapir（淀粉样蛋白） ）PET扫描。一名进行性核上性麻痹（PSP）患者也接受了[18F] NML和[18F] AV1451 PET扫描。[18F] NML在健康对照组中显示出良好的大脑摄取，合理的药代动力学和适当的影像学特征。[18F / 19F] NML的给药质量的平均±SD为2.01±2.17μg（范围为0.16-8.27μg），平均给药活性为350±62 MBq（范围为199-403 MBq）。在这11名受试者中，没有任何不良或临床上可检测到的药理作用，并且没有观察到生命体征的显着变化。然而，尽管在体外对tau的亲和力很高，但MCI / AD和PSP患者的大脑保留能力却很低，并且没有证据表明体内有与tau相对应的特定信号。尽管仍不清楚为什么放射性示踪剂的临床翻译不成功，但我们得出的结论是，目前尚无必要进一步开发[18F] NML作为tau PET显像剂。而且没有证据表明体内有与tau相对应的特定信号。尽管仍不清楚为什么放射性示踪剂的临床翻译不成功，但我们得出的结论是，目前尚无必要进一步开发[18F] NML作为tau PET显像剂。而且没有证据表明体内有与tau相对应的特定信号。尽管仍不清楚为什么放射性示踪剂的临床翻译不成功，但我们得出的结论是，目前尚无必要进一步开发[18F] NML作为tau PET显像剂。