10.1021/acschemneuro.9b00639.s001
Vasko Kramer
Vasko
Kramer
Allen F. Brooks
Allen F.
Brooks
Arlette Haeger
Arlette
Haeger
Rodrigo O. Kuljis
Rodrigo O.
Kuljis
Waqas Rafique
Waqas
Rafique
Robert A. Koeppe
Robert A.
Koeppe
David M. Raffel
David M.
Raffel
Kirk A. Frey
Kirk A.
Frey
Horacio Amaral
Horacio
Amaral
Peter J. H. Scott
Peter J. H.
Scott
Patrick J. Riss
Patrick J.
Riss
Evaluation of [<sup>18</sup>F]‑<i>N</i>‑Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human
Studies
American Chemical Society
2020
PET radiotracers
difluoro enol ether precursor
quantifying tau aggregates
conduct first-in-man imaging studies
novel tau imaging agent
report validation
tau PET imaging agent
First-in-Human Studies Development
Healthy controls
imaging characteristics
supranuclear palsy
rodent biodistribution
imaging sites
positron emission tomography
Tau PET Imaging Agent
brain retention
production facilities
PET scans
AD patients
SD
brain uptake
dementia research
pharmacologic effects
imaging agents
neurodegenerative disorders
PSP patients
18 F
noncorrected radiochemical
MCI
trifluoromethyl group
11 subjects
2020-01-14 23:13:31
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Evaluation_of_sup_18_sup_F_i_N_i_Methyl_lansoprazole_as_a_Tau_PET_Imaging_Agent_in_First-in-Human_Studies/11608383
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 [<sup>18</sup>F]<i>N</i>-methyl lansoprazole
([<sup>18</sup>F]NML). Herein we report validation of the synthesis
of [<sup>18</sup>F]NML for clinical use by labeling the trifluoromethyl
group via radiofluorination of the corresponding <i>gem</i>-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
[<sup>18</sup>F]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 (<i>n</i> = 15). With [<sup>18</sup>F]NML in hand, we conducted rodent biodistribution, estimates of
human dosimetry, and preliminary evaluation of [<sup>18</sup>F]NML
in human subjects at two imaging sites. Healthy controls (<i>n</i> = 4) and mildly cognitively impaired (MCI) AD patients
(<i>n</i> = 6) received [<sup>18</sup>F]NML (tau), [<sup>18</sup>F]AV1451 (tau), and [<sup>18</sup>F]florbetaben or [<sup>18</sup>F]florbetapir (amyloid) PET scans. A single progressive supranuclear
palsy (PSP) patient also received [<sup>18</sup>F]NML and [<sup>18</sup>F]AV1451 PET scans. [<sup>18</sup>F]NML showed good brain uptake,
reasonable pharmacokinetics, and appropriate imaging characteristics
in healthy controls. The mean ± SD of the administered mass of
[<sup>18</sup>F/<sup>19</sup>F]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 <i>in vitro</i>, brain retention
in MCI/AD and PSP patients was low, and there was no evidence of specific
signals <i>in vivo</i> that corresponded to tau. Although
it is still unclear why clinical translation of the radiotracer was
unsuccessful, we nevertheless conclude that further development of
[<sup>18</sup>F]NML as a tau PET imaging agent is not warranted at
this time.