Evaluation of [¹⁸F]‑N‑Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies

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.