ACS Pharmacology & Translational Science,
Год журнала:
2023,
Номер
6(11), С. 1616 - 1631
Опубликована: Окт. 11, 2023
Introduction
-
Several
11C-tracers
have
demonstrated
high
potential
in
early
diagnostic
PET
imaging
applications
of
neurodegenerative
diseases
including
Alzheimer's
and
Parkinson's
disease.
These
radiotracers
often
track
critical
biomarkers
disease
pathogenesis
such
as
tau
fibrils
([11C]PBB3)
or
β-amyloid
plaques
([11C]PiB)
associated
with
diseases.
Purpose
The
short
review
aims
to
serve
a
guideline
the
future
development
for
students,
postdocs
and/or
new
radiochemists
who
will
be
synthesizing
clinical
grade
novel
research
11C-tracers,
knowledge
regulatory
requirements.
We
aim
bridge
gap
between
established
11C-tracer
quality
control
(QC)
processes
through
exploring
design
process
requirements
11C-pharmaceuticals.
Methods
A
literature
survey
was
undertaken
identify
articles
detailed
description
QC
methodology
characterization
each
sections
review.
Overview
First
general
summary
production
presented;
this
used
establish
possible
places
contamination
assurances
sterile
final
product.
key
mandated
analyses
use
were
then
discussed.
Further,
we
assessed
methods
reviewed
routine
tests
preclinical
translational
validation
studies.
Therefore,
both
animal
studies
reviewed.
Last,
some
examples
optimization
automation
reviewed,
implications
practices
procedures
considered.
Conclusion
All
common
parameters
under
settings
(along
few
exceptions)
discussed
detail.
While
it
is
important
standard,
peer-reviewed
testing
protocols
entering
umbrella,
equal
importance
needed
on
address
credibility
repeatability
study.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(7), С. 6251 - 6251
Опубликована: Март 26, 2023
There
is
a
large
unmet
medical
need
to
develop
disease-modifying
treatment
options
for
individuals
with
age-related
degenerative
diseases
of
the
central
nervous
system.
The
sigma-2
receptor
(S2R),
encoded
by
TMEM97,
expressed
in
brain
and
retinal
cells,
regulates
cell
functions
via
its
co-receptor
progesterone
membrane
component
1
(PGRMC1),
through
other
protein–protein
interactions.
Studies
describing
S2R
involve
manipulation
expression
or
pharmacological
modulation
using
exogenous
small-molecule
ligands.
These
studies
demonstrate
that
modulates
key
pathways
involved
including
autophagy,
trafficking,
oxidative
stress,
amyloid-β
α-synuclein
toxicity.
Furthermore,
can
ameliorate
functional
deficits
cell-based
animal
models
disease.
This
review
summarizes
current
evidence-based
understanding
biology
function,
potential
as
therapeutic
target
system,
Alzheimer’s
disease,
α-synucleinopathies,
dry
macular
degeneration.
Pharmaceuticals,
Год журнала:
2023,
Номер
16(2), С. 317 - 317
Опубликована: Фев. 18, 2023
The
use
of
computer-aided
drug
design
(CADD)
for
the
identification
lead
compounds
in
radiotracer
development
is
steadily
increasing.
Traditional
CADD
methods,
such
as
structure-based
and
ligand-based
virtual
screening
optimization,
have
been
successfully
utilized
many
discovery
programs
are
highlighted
throughout
this
review.
First,
we
discuss
hit
at
beginning
programs.
This
followed
by
an
analysis
how
hits
derived
from
can
be
filtered
culled
to
highly
probable
candidates
test
vitro
assays.
We
then
illustrate
used
optimize
potency
experimentally
validated
positron
emission
tomography
(PET).
Finally,
conclude
with
a
survey
newest
techniques
employing
machine
learning
(ML).
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(15), С. 12025 - 12025
Опубликована: Июль 27, 2023
Sigma
(σ)
receptors
are
a
class
of
unique
proteins
with
two
subtypes:
the
sigma-1
(σ1)
receptor
which
is
situated
at
mitochondria-associated
endoplasmic
reticulum
(ER)
membrane
(MAM),
and
sigma-2
(σ2)
receptor,
located
in
ER-resident
membrane.
Increasing
evidence
indicates
involvement
both
σ1
σ2
pathogenesis
Alzheimer’s
disease
(AD),
thus
these
represent
potentially
effective
biomarkers
for
emerging
AD
therapies.
The
availability
optimal
radioligands
positron
emission
tomography
(PET)
neuroimaging
humans
will
provide
tools
to
monitor
progression
treatment
outcomes.
In
this
review,
we
first
summarize
significance
pathophysiology
highlight
therapeutic
strategies
related
receptors.
We
then
survey
potential
PET
radioligands,
an
emphasis
on
requirements
imaging
or
humans.
Finally,
discuss
current
challenges
development
receptors,
opportunities
elucidate
as
novel
early
diagnosis,
monitoring
drug
efficacy.
Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(17), С. 12185 - 12202
Опубликована: Авг. 31, 2023
Abnormal
α-synuclein
(α-syn)
aggregation
characterizes
α-synucleinopathies,
including
Parkinson's
disease
(PD)
and
multiple
system
atrophy
(MSA).
However,
no
suitable
positron
emission
tomography
(PET)
radiotracer
for
imaging
α-syn
in
PD
MSA
exists
currently.
Our
structure–activity
relationship
studies
identified
4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide
(4i)
as
a
PET
candidate
α-syn.
In
vitro
assays
revealed
high
binding
of
4i
to
recombinant
fibrils
(inhibition
constant
(Ki)
=
6.1
nM)
low
affinity
amyloid
beta
(Aβ)
Alzheimer's
(AD)
homogenates.
[3H]4i
also
exhibited
specific
AD,
progressive
supranuclear
palsy,
corticobasal
degeneration
tissues
well
tissues,
suggesting
notable
tau.
Nevertheless,
the
pathologic
aggregates
post-mortem
brain
was
significantly
higher
than
tissues.
This
finding
demonstrated
potential
use
[11C]4i
tracer
patients.
Nonhuman
primate
confirmed
good
uptake
rapid
washout
[11C]4i.
ACS Pharmacology & Translational Science,
Год журнала:
2025,
Номер
8(4), С. 951 - 977
Опубликована: Март 7, 2025
Cancer
ranks
among
the
top
triumvirate
leading
causes
of
human
deaths
worldwide.
The
pathological
mechanisms
are
notably
intricate,
demonstrating
proliferative
and
metastatic
capabilities,
which
complicate
therapeutic
interventions.
sigma-1
receptor
(σ1R)
plays
a
crucial
role
in
tumor
survival
migration,
while
sigma-2
(σ2R)
is
intimately
associated
with
proliferation.
This
review
encapsulated
investigation
concerning
σ1R
σ2R
neoplasms
rigorously
summarized
ligands
radio-ligands
development
their
applications,
such
as
antitumor
cell
proliferation
PET/SPECT
imaging
tumors.
A
comprehensive
classification
discussion
was
undertaken
regarding
chemical
structures
emphasized
possibility
dual/multitargeted
ligands.
Ultimately,
we
discussed
effects
chiral
pharmacological
characteristics
on
affinity
pharmacokinetic
features
vivo,
particularly
radiopharmaceuticals.
functions
beneficial
resource,
fostering
ligand
deployment
stimulating
generation
innovative
ideas
for
developing
Molecules,
Год журнала:
2022,
Номер
27(11), С. 3617 - 3617
Опубликована: Июнь 4, 2022
Sigma
receptors
modulate
nociception,
offering
a
potential
therapeutic
target
to
treat
pain,
but
relatively
little
is
known
regarding
the
role
of
sigma-2
(S2R)
in
nociception.
The
purpose
this
study
was
investigate
vivo
analgesic
and
anti-allodynic
activity
liabilities
novel
S2R
selective
ligand,
1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one
(CM-398).
inhibition
thermal,
induced
chemical,
or
inflammatory
pain
as
well
allodynia
resulting
from
chronic
nerve
constriction
injury
(CCI)
model
neuropathic
were
assessed
male
mice.
CM-398
dose-dependently
(10-45
mg/kg
i.p.)
reduced
mechanical
CCI
model,
equivalent
at
higher
dose
effect
control
gabapentin
(50
i.p.).
Likewise,
pretreatment
(i.p.)
with
produced
antinociception
acetic
acid
writhing
test
(ED50
(and
95%
C.I.)
=
14.7
(10.6-20)
mg/kg,
formalin
assay
0.86
(0.44-1.81)
without
55
°C
warm-water
tail-withdrawal
assay.
A
high
(45
exhibited
modest
locomotor
impairment
rotarod
conditioned
place
aversion,
potentially
complicating
interpretation
nociceptive
testing.
However,
an
operant
resistant
these
confounds,
mice
experiencing
treated
demonstrated
robust
preference.
Overall,
results
demonstrate
antagonist
produces
anti-allodynia
fewer
than
established
therapeutics,
adding
emerging
data
suggesting
possible
mediation
nociception
by
S2R,
development
ligands
treatments
for
pain.
International Journal of Molecular Sciences,
Год журнала:
2022,
Номер
23(15), С. 8259 - 8259
Опубликована: Июль 27, 2022
A
series
of
σ2R
compounds
containing
benzimidazolone
and
diazacycloalkane
cores
was
synthesized
evaluated
in
radioligand
binding
assays.
Replacing
the
piperazine
moiety
a
lead
compound
with
diazaspiroalkanes
fused
octahydropyrrolo[3,4-b]
pyrrole
ring
system
resulted
loss
affinity
for
σ2R.
On
other
hand,
bridged
2,5-diazabicyclo[2.2.1]heptane,
1,4-diazepine,
3-aminoazetidine
analog
possessed
nanomolar
affinities
Computational
chemistry
studies
were
also
conducted
recently
published
crystal
structure
σ2R/TMEM97
revealed
that
hydrogen
bond
interactions
ASP29
π-stacking
TYR150
largely
responsible
high
small
molecules
to
this
protein.
Molecular Pharmaceutics,
Год журнала:
2023,
Номер
21(1), С. 194 - 200
Опубликована: Ноя. 28, 2023
The
sigma-2
receptor
(σ2R),
recently
identified
as
transmembrane
protein
97,
is
expressed
in
many
cell
types
and
mediates
important
functions
both
the
peripheral
central
nervous
systems.
Over
years,
σ2R
has
emerged
a
potential
therapeutic
target
for
cancer
neurological
disorders
such
Alzheimer’s
disease
(AD).
currently
available
radiotracers
have
been
developed
primarily
imaging
with
limited
brain
uptake.
Here,
we
report
evaluation
of
first
penetrant
18F-labeled
radiotracer
suitable
positron
emission
tomography
(PET)
nonhuman
primate
brain.
