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Evaluation of [18F]‑N‑Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies
journal contribution
posted on 2020-01-14, 23:13 authored by Vasko Kramer, Allen F. Brooks, Arlette Haeger, Rodrigo O. Kuljis, Waqas Rafique, Robert A. Koeppe, David M. Raffel, Kirk A. Frey, Horacio Amaral, Peter J. H. Scott, Patrick J. RissDevelopment
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.
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Keywords
PET radiotracersdifluoro enol ether precursorquantifying tau aggregatesconduct first-in-man imaging studiesnovel tau imaging agentreport validationtau PET imaging agentFirst-in-Human Studies DevelopmentHealthy controlsimaging characteristicssupranuclear palsyrodent biodistributionimaging sitespositron emission tomographyTau PET Imaging Agentbrain retentionproduction facilitiesPET scansAD patientsSDbrain uptakedementia researchpharmacologic effectsimaging agentsneurodegenerative disordersPSP patients18 Fnoncorrected radiochemicalMCItrifluoromethyl group11 subjects
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