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18 18F-Thymidine
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F-FLT PET:
Imaging Biomarkers
https://t.me/med1917
ofNeuroinammations: TSPO
Agents
AnnachiaraArnone andPierpaoloAlongi
19
19.1 Introduction
Neuroinammation is a biological mechanism
that constantly surveys the brain microenvironment by neutralizing and removing various
pathogen species [1]. This inammatory response
can preserve the brain homeostasis and provide
neuroprotective roles by promoting tissue repair
and removing cellular debris [2].
Derived from early myeloid progenitors that
migrate from the bone marrow into the central
nervous system (CNS) during the development,
microglia represent the resident immune population in the brain and along with the astrocytes
play a central role in the regulation of the inammatory state [3–5]. A range of phenotypes and
functional congurations is expressed by microglia cells. Different factors such as genetic mutations, protein aggregations, trauma, injuries and
infections could contribute in prolonging the
inammatory stimulation (through the secretion
of cytokines interleukin-1, interleukin-6, tumour
necrosis factor α, and chemokines) and inducing
neuronal damage [
dysregulate reactive microglia phenotype takes
A. Arnone
Nuclear Medicine Unit, Department of Experimental
and Clinical Biomedical Sciences “Mario Serio”,
University of Florence, Florence, Italy
P. Alongi (*)
Nuclear Medicine Unit, A.R.N.A.S.Ospedale Civico
Di Cristina Benfratelli, Palermo, Italy
2, 6–8]. Consequently, the
part in the development of neurodegenerative diseases and it is now considered a key element
together with the abnormal deposit of misfolded
proteins [
been explored among the neurodegenerative disorders [13]. Neuritic plaques, which represent an
Alzheimer’s disease (AD) pathological hallmark,
are surrounded by microglia [14]. HIV-dementia
is characterized by viral infection of microglia
[15]. In multiple sclerosis, areas of demyelination are rich in activated microglia [16].
Microglia activation in other neurodegenerative
diseases such as Parkinson’s disease (PD) [17],
Creutzfeldt–Jakob disease (CJD) [18], and amyotrophic lateral sclerosis (ALS) [19] is known but
less well characterized.
called peripheral benzodiazepine-binding site
(PBR), is a mitochondrial protein expressed by
immune competent cells (macrophages, microglia, astrocytes) and markedly increased in response
to cellular injuries [
oligomeric complex comprised of the voltagedependent anion channel and an adenine nucleotide
carrier determining the mitochondrial permeability transition pore (see Fig.19.1) [22, 23].
distinct from the central benzodiazepine receptor
(CBR) that is a part of the ionotropic GABA
receptor localized on the plasma membrane of
GABA-ergic neurons [24]. Outside the CNS,
9–12].
Various degrees of activated microglia have
The 18kDa translocator protein (TSPO), also
20, 21]. It is a part of a hetero-
PBR is structurally and pharmacologically
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
F. Calabria, O. Schillaci (eds.), Radiopharmaceuticals,
https://doi.org/10.1007/978-3-031-54196-4_19
309
310
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Fig. 19.1 TSPO/
peripheral
benzodiazepine-binding
site representation.
(From S.Venneti, B.J.
LoprestiC.A. Wiley,
《The peripheral
benzodiazepine
receptor (Translocator
protein 18kDa) in
microglia. From
pathology to imaging》,
Progress in
Neurobiology. 2006.
doi: 10.1016/j.
pneurobio.2006.10.002
23])
[
A. Arnone and P. Alongi
PBR is ubiquitously expressed, such as in the
adrenal glands, kidney, lung, heart, hormone
secreting tissue, and in glia cells, also having
high afnity for several 1,4-benzodiazepines
[25–27].
The endogenous ligands of PBR are not completely claried but some candidates have been
proposed, such as the diazepam-binding inhibitor
(DBI) and porphyrins. PBR is considered to be
related to various cellular activities, such as steroidogenesis and mitochondrial functioning [28].
Being a constituent of the mitochondrial permeability transition pore, PBR would represent a
sensor for cellular oxygen, also protecting neu-
rons against damage caused by reactive oxygen
species (ROS) and regulating the mitochondrial
permeability [21, 28].
Positron emission tomography (PET) imaging
allows the in vivo measurements of different
molecular targets, such as functional markers of
neurodegeneration (glucose metabolism), markers for pathological proteins (amyloid, tau, and
synuclein aggregates), and also neuroinammation, providing evidence for the pathophysiology
in neurodegenerative diseases.
(R)-1-(2-chlorophenyl)-N-11C-methyl-N-(1methylpropyl)-3-isoquinoline carboxamide
([11C](R)-PK11195) was the rst TSPO PET
19 Imaging Biomarkers ofNeuroinammations: TSPO Agents
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311
radioligand developed to estimate neuroinammatory changes in several CNS disorders
[29, 30]. The rst evidence of increased TSPO
binding signal using [11C](R)-PK11195in AD
sensitive brain regions such as the entorhinal,
temporo-parietal, and cingulate cortices was
reported by Cagnin etal. [31]. However, this
study also evidenced high levels of [11C](R)PK11195 binding in regions not related to AD
pathology, such as the thalamus and the brainstem [31]. The authors have discussed these
ndings as a result of regional variations in the
constitutive PBR population, independently
from the pathology. Edison etal. assessed the
inverse correlation between Mini-Mental State
Examination (MMSE) score in AD subjects
and the levels of cortical microglial activation
[32]. The relationship between TSPO binding
and patients affected by mild cognitive impairment (MCI) seems to be less conclusive, since
some studies reported no specic increase or
only a slight increase in amyloid PET positive
compared to controls [33–35]. A signicant
correlation between increased microglia activation and reduced glucose metabolism was
also described in studies combining [11C](R)PK11195 and 18F-uorodeoxyglucose (FDG)
PET in AD patients. This nding suggested
that neuroinammation may dynamically act
with synaptic dysfunction and glucose hypometabolism throughout the AD pathogenetic
process [36, 37].
It is widely declared that TSPO PET signal
reveals reactive microglia, although a few studies
proposed a potential contribution of reactive
astrocytes [
very different roles, it remains essential to determine whether reactive astrocytes can also overexpress TSPO and lead to a detectable TSPO PET
signal in vivo [38]. Moreover, TSPO does not
discriminate between resting state, proinammatory and neuroprotective microglia subtypes [39]. New PET radiotracers which more
specically represent the status of microglial
cells are needed to better assess the role of neuroinammation in the development of neurodegenerative diseases.
38]. As astrocytes and microglia play
19.2 Synthesis
In accordance with Investigational New Drug
Application #101,908, the [11C](R)-PK11195
synthesis is based on labelling the precursor
N-Desmetil-(R)-PK11195 with 11C through
methylation agent (11CH3I). The methylation
agent is trapped in reactor, the nitrogen ow is
stopped, and the reaction is allowed to proceed
for a few minutes. The reaction proceeds by the
N-methylation of N-Desmetil-(R)-PK11195 with
a methyl group labelled with 11C via nucleophilic
substitution.
19.3 Pharmacokinetics
A well-known PET imaging advantage over other
modalities is the ability to extract quantitative
information regarding pathophysiological parameters that are relevant to a disease process.
Mathematical models can be applied to PET
image data in order to derive estimates from
observations of the kinetic behaviour of a radiotracer, which may be altered by various factors
such as perfusion, tissue clearance, peripheral
metabolism, and receptor binding phenomena.
The instability of [11C](R)-PK11195 in plasma
and its poor specic binding ratio (SBR) interfere
with the validation of a compartmental model to
describe the kinetic behaviour in the brain [40].
Consequently, other methods including the simplied reference tissue model (SRTM) proposed
by Lammertsma etal. have been considered [
This method consists of a simplication of the
model equations, assuming a specic underlying
model conguration and providing a distribution
volume ratio (DVR) or binding potential (BP)
estimation directly from the images by using a
reference tissue that could represent the arterial
input function [40]. Nevertheless, while BP
obtained from a plasma input model could contain a nonspecic component resulting in an
overestimation, a reference tissue containing a
low specic binding component would result in
an underestimation of reference tissue model
BP.In an effort to overcome these limits, an opti-
41].
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A. Arnone and P. Alongi
mal compartmental model of the brain kinetics of
[11C](R)-PK11195 has been proposed and validated by Kropholler etal. [42]. The authors considered several model congurations and based
on statistical criterion concluded that a reversible
two-tissue compartments model, using a metabolite corrected plasma input function, best
describes [11C](R)-PK11195 kinetics.
19.4 Physiological Distribution
In the normal healthy brain, TSPO is located in
ependymal cells lining the ventricles, the olfactory bulb, the choroid plexus, and glial cells,
including astrocytes and microglia [23, 43]. In
studies that have evaluated [11C](R)-PK11195BP
in healthy controls, a TSPO over-expression is
documented in the subcortical structures, such as
thalamus, midbrain, pons, and brainstem, with
midbrain and thalamus showing signicant
increase with age [30, 44, 45].
19.5 Acquisition Protocols
Given the multitude of TSPO PET tracers underdevelopment and not yet completely validated for
clinical practice, there is not one xed acquisition
protocol for all of them. However, regarding[11C]
(R)-PK11195, the tracers with the largest collective experience to date, a range dose of
244–481 MBq followed by a dynamic acquisition for a total duration of 60 minutes is most
commonly used in the research studies [
46].
19.6 Potential Clinical
Applications: Research
Outcomes
AD neurodegeneration is associated with a local
glial response within the brain parenchyma that
involves the activation of microglia cells. Recent
studies have implied an active role in the mediation between the amyloid deposits and the subsequent tissue damage via release of cytokines and
cytotoxic molecules. The in vivo detection of
11
increased [
Alzheimer-type dementia, including mild and
initial forms, has suggested that microglial activation could represent an early event in the pathogenesis of the disease [31].
Microglia activation has been also related to
other diseases such as dementia with Lewy bodies (DLB) and PD. These pathologies are both
associated with neuronal loss and α-synuclein
protein aggregated forms accumulation.
Oxidative damage, mitochondrial dysfunction,
and reactive microgliosis have been recently correlated to the pathogenesis and the progression of
neuronal damage in PD and DLB, contributing to
neuronal death. Neuroinammation occurs as a
local response driven by microglia in absence of
leukocyte inltration and may cause neuronal
damage through cytotoxic molecules such as proinammatory cytokines, proteinases, and reactive oxygen intermediates. Oxidative damage
induces protein alterations among which the carbonylation is the most common [47].
As well as for the histopathological correlates
of neuroinammation, post-mortem studies in
PD patients reported activated microglia in the
substantia nigra, putamen, cingulate cortex, and
medial temporal structures [17]. This ndings
have suggested that the pathogenic insult induces
a progressive inammatory/cytotoxic response,
starting likely near the sites of active brain pathology and going at distance, possibly as a consequence of disconnection processes. An
association between activated microglia and
α-synuclein aggregates has been also reported in
post-mortem DLB studies [
patients, the microglia-mediated inammatory
process seems to progressively surround degenerated neurons containing Lewy bodies
inclusions.
Neuroinammation has been also reported
using [11C](R)-PK11195 PET in PD and in
Parkinsonisms, such as corticobasal degeneration
(CBD)and progressive supranuclear palsy (PSP)
[49–51]. The previous PET studies of microglia
activation in PD showed different patterns of
inammation involving either selectively midbrain and putamen or more diffusely basal ganglia, pons and cortical regions [47].
C](R)-PK11195 binding in
48]. Thus, in these
z =
x = –8
z scores
19 Imaging Biomarkers ofNeuroinammations: TSPO Agents
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313
In a study of Gerhard etal., 18 PD patients
were examined by clinical evaluation, [11C](R)PK11195 and [18F]-DOPA PET. They showed
signicantly increased mean levels of [11C](R)PK11195 binding in the pons, basal ganglia and
in the frontal and temporal cortical regions.
Among them, eight patients were followed longitudinally, reporting a stable [11C](R)-PK11195
signal over 2years [51]. The levels of microglial
activation did not correlate with clinical severity
or putamen [18F]-DOPA uptake. The invivo ndings of this study have conrmed that widespread
microglial activation was associated with the
pathological process in PD, while the lack of signicant longitudinal changes has suggested that
microglia were activated early in the pathologic
process, and the levels then remained relatively
stable, possibly driving the downstream pathology via cytokine release (see Fig.19.2) [51].
Microgliosis is also part of the immunobiology of CJD.Despite the rarity of the disease, a
study rst evaluated 11C-(R)-PK11195 PET
imaging invivo to measure TSPO expression, in
symptomatic CJD patients, followed by a postmortem neuropathology comparison [46]. The
study included genetic (gCJD), sporadic (sCJD),
and variant (vCJD) CJD forms. TSPO BPs were
estimated using clustering and parametric analyses of reference regions. Statistical comparisons
were run at the regional and at the voxel-wise levels. Post-mortem evaluation measured scrapie
prion protein (PrPSc) immunoreactivity, neuronal
Fig. 19.2 Transverse (z=4), coronal (y=−2), and sagit-
tal projections (x = −8) of statistical parametric maps
(SPM). Between-group comparison: volumes of signicant between-group differences in [
binding potential (BP) for the group of normal subjects
and patients with PD (cluster level p<0.05). The volumes
are superimposed on the standard single-subject MRI in
SPM99 in radiological orientation. The images show
4
11
C](R)-PK11195
y = –2
6
5
4
3
2
1
0
increase in BP in the striatum, thalamus, cerebellum, frontal and temporal cortex. (From Gerhard A, Pavese N,
Hotton G, Turkheimer F, Es M, Hammers A, Eggert K,
Oertel W, Banati RB, Brooks DJ. In vivo imaging of
microglial activation with [11C](R)-PK11195 PET in
idiopathic Parkinson’s disease. Neurobiol Dis. 2006
Feb;21(2):404–12. doi: 10.1016/j.nbd.2005.08.002. Epub
2005 Sep 21. PMID: 16182554 [
51])
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A. Arnone and P. Alongi
loss, spongiosis, astrogliosis, and microgliosis.
11
C-(R)-PK11195 PET showed a signicant
TSPO over-expression at the cortical level in the
two sCJD patients, as well as thalamic and cerebellar involvement; very limited parieto-occipital
activation in the gCJD case; and signicant
increases at the subcortical level in the thalamus,
basal ganglia, and midbrain and in the cerebellum in the vCJD brain. The study claried that
TSPO over-expression in microglia activation,
topography, and extent can vary in CJD subtypes,
possibly as a consequence of fast apoptotic processes, but reaches a large amount at the nal disease course [46].
19.7 Clinical Cases
A clinical series on TSPO PET imaging in MCI
suspected for AD is reported as follows (see
Fig.19.3), from the study: Tondo G, Boccalini C,
Caminiti SP, Presotto L, Filippi M, Magnani G,
Frisoni GB, Iannaccone S, Perani D. Brain
Metabolism and Microglia Activation in Mild
Cognitive Impairment: A Combined [18F]FDG
and [11C]-(R)-PK11195 PET Study. J
Alzheimer’s Dis. 2021;80(1):433–445. doi:
10.3233/JAD-201351. PMID: 33579848 [52].
MCI01 (Fig. 19.3): A 56-year-old male
received a diagnosis of amnestic MCI due to a
selective memory decit (MMSE: 25/30). FDG
SPM t-map revealed hypometabolism in
temporoposterior cingulate cortex, bilaterally, as in the
typical AD-like hypometabolism pattern, suggesting an underlying AD pathology [53–55].
Increased TSPO expression was widespread,
involving mainly the temporo-parietal and the
frontal cortex but also the occipital and the posterior cingulate cortex.
sented with difculties in naming and mild memory problems with normal global cognitive status
(MMSE: 27/30). FDG SPM t-map showed hypometabolism mainly involving the left superior,
middle, and inferior temporal gyri and the inferior and superior parietal lobules on the left side,
as a typical pattern of logopenic primary progres-
parietal cortex, in the precuneus and the
MCI02 (Fig. 19.3): A 75-year-old man pre-
sive aphasia [
56, 57]. [11C](R)-PK11195 PET
revealed left-lateralized microglia activation in
the temporal, parietal, and frontal regions.
MCI03 (Fig. 19.3): A 65-year-old man pre-
sented with impaired performances in tests evaluating memory and visuospatial abilities (MMSE:
28/30). FDG SPM t-map showed hypometabolism involving temporo-parietal and occipital
regions, as usually observed in posterior cortical
atrophy [58, 59]. [11C](R)-PK11195 BPs were
increased in occipital, temporal, and parietal
regions bilaterally, with signicant overlap with
hypometabolism in the posterior cortical regions.
MCI04 (Fig. 19.3): A 53-year-old man was
diagnosed as MCI showing memory decits,
executive and behavioural disturbances, including
apathy and irritability (MMSE: 27/30). CSF analysis revealed low amyloid and high p-tau and
t-tau levels, suggesting a diagnosis of MCI due to
AD [60]. FDG SPM t-map revealed diffuse hypometabolism involving the right frontal, the lateral
temporal, and parietal cortices but also the precuneus and the posterior cingulate cortex. [11C](R)PK11195 BPs map showed very limited microglia
activation, involving frontal and temporal medial
cortices and subcortical regions.
MCI05 (Fig.19.3): A 73-year-old female pre-
sented a pure amnestic syndrome without any
other objective decit (MMSE: 27/30). Structural
imaging showed atrophy of the medial temporal
lobe structures. FDG SPM t-map showed a selective hypometabolism involving the medial and
anterior temporal lobes and the posterior cingulate cortex. This metabolism pattern has been
associated with long-term clinical stability and
several possible underlying aetiologies, including primary age-related tauopathy, hippocampal
sclerosis, argyrophilic brain disease, and the
limbic-
predominant age-related TDP-43 encephalopathy [61–63]. [11C](R)-PK11195 BPs were
increased in temporal medial structures but also
in right temporal lateral cortex and to a lesser
degree in the orbitofrontal regions.
MCI06 (Fig. 19.3): A 62-year-old female
received a diagnosis of amnestic MCI due to
memory decit without impact on global cognitive status (MMSE: 29/30). FDG-PET scan was
unremarkable. When compared with controls,
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Fig. 19.3 Patterns of [18F]18F-FDG-PET brain hypome-
tabolism and [
single individuals. (From Tondo G, Boccalini C, Caminiti
SP, Presotto L, Filippi M, Magnani G, Frisoni GB,
Iannaccone S, Perani D.Brain Metabolism and Microglia
11
C](R)-PK11195 PET binding potentials in
[11C](R)-PK11195 PET analysis showed unremarkable microglia activation.
MCI07 (Fig. 19.3): A 71-year-old male was
diagnosed as MCI due to difculties in language
tasks which did not impact on his activities of
daily living (MMSE: 27/30). He also manifested
anxiety and depression. Structural imaging showed
a marked cortical atrophy mainly involving frontal
and parietal regions of the right hemisphere. FDG
SPM t-map revealed a signicant frontotemporal
hypometabolism with an extensive involvement of
the perisylvian cortex including the parietal opercula, bilaterally. Both MRI and 18F-FDGPET
were thus highly suggestive for corticobasal
degeneration [64, 65]. [11C](R)-PK11195 BPs map
revealed increased TSPO signal in temporo-pari-
Activation in Mild Cognitive Impairment: A Combined
[18F]FDG and [11C]-(R)-PK11195 PET Study. J
Alzheimer’s Dis. 2021;80(1):433–445. doi: 10.3233/JAD-
201351. PMID: 33579848 [52])
etal regions, amygdala, and in subcortical regions
including pallidum and putamen.
MCI08 (Fig. 19.3): A 56-year-old woman
presented anxiety, depression, and attentive disturbances (MMSE: 27/30). FDG SPM t-map
showed asymmetric hypometabolism in the dorsolateral frontal cortex, and in the lateral temporal and inferior parietal cortex, more evident in
the right hemisphere, suggesting a frontotemporal dementia-like pattern. [11C](R)-PK11195 PET
analysis showed microglia activation in the frontal cortex, lateral temporal, occipital, and parietal
cortex and, notably, prevalent on the right side.
About CJD, we report a case series from a study
published by Iaccarino etal. (see Fig.19.4) [46]. All
the patients were diagnosed following a standardized
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A. Arnone and P. Alongi
Fig. 19.4 Single-subject CJD 11C-(R)-PK11195
BPCDCA z-score maps. Single-subject z-score maps of
the CJD patients. Minimum z-score was set at z>2.58
(99% condence, i.e., p<0.01), to show only voxels with
values signicantly higher in the individual patient when
compared to the HC distribution. Multiple transaxial,
coronal, and sagittal views are shown. Warped
11C-(R)-PK11195 BPCDCA z-score maps are overlaid
on the standard SPM T1 template. gCJD genetic CJD,
protocol including EEG polygraphic recordings,
cerebral magnetic resonance imaging (MRI), CSF
examination for 14-3-3 and tau protein, and
sequencing of the open reading frame of the PRNP
gene, and all had post- mortem specimen assessment with pathology conrmation. The gCJD
sCJD1 sporadic CJD case 1, sCJD2 sporadic CJD case 2,
vCJD variant CJD. (Published in Iaccarino L, Moresco
RM, Presotto L, Bugiani O, Iannaccone S, Giaccone G,
Tagliavini F, Perani D.An In Vivo 11C-(R)-PK11195 PET
and In Vitro Pathology Study of Microglia Activation in
Creutzfeldt-Jakob Disease. Mol Neurobiol. 2018
Apr;55(4):2856–2868. doi: 10.1007/s12035-017-0522-6.
Epub 2017 Apr 28. PMID: 28455699 [
46])
patient presented aV210I mutation, which is the
most frequent PRNP mutation in Italy. The clinical
presentation of the four CJD patients was heterogeneous, including behavioural and personality
changes, motor and visual signs, somatosensory
decits, myoclonus, and cognitive decits [46].
19 Imaging Biomarkers ofNeuroinammations: TSPO Agents
https://t.me/med1917
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19.8 Variants andPitfalls
One peculiar aspect of [11C]-(R)-PK11195 studies in the brain is the very scarce presence of the
PBRs in the normal brain. This renders the modelling of this tracer particularly difcult because
effects of no interest such as tissue heterogeneity
and vascular signal become predominant,
whereas the abundant presence of the PBRs in
the periphery affects the availability of
[11C]-(R)-PK11195 for binding in the brain. This
problem affects the denition of a reference
region, a process that already must take into
account the unknown location of microglia activation. In the study of Turkheimer etal., using a
supervised clustering procedure, totally automatic, was possible to extract a grey matter reference region devoid of nuisance signal [66]. A
relevant nding of the study was the presence of
a slowly equilibrating kinetic component in the
tissue time–activity curves. Evidence from
immuno-histochemistry suggests that this signal
is specic for PBRs binding in the vasculature,
and its kinetic, although different from that of
specic binding to activated microglia, resembles
closely the [11C](R)-PK11195 kinetic in the heart
[29]. The presence of this additional component
introduced another level of complexity in the
kinetic modelling of ROI time–activity curves.
The effective extraction of a reference region
combined with parameter estimation through
RS-ESA could provide an excellent agreement
between plasma input and reference tissue
input2-derived BPs that were also highly correlated (r 5 0.811, P, 1025). This validates further
the use of reference region modelling for the
quantication of [
direct comparison with the plasma input counterpart. Finally, Turkheimer etal. investigated the
reliability of the new reference extraction when
BP parametric maps for [11C](R)-PK11195 are
produced on a test–retest dataset. In this application, given the generally low signal-to-noise ratio
in [11C](R)-PK11195 studies, SRTM was the
method of choice for kinetic analysis. Results
conrmed a substantial increase in the reliability
of the estimates with the new supervised approach
(mean ICC 5 0.878) compared with the unsuper-
11
C](R)-PK11195 and allows
vised approach (mean ICC 5 0.596) and low test–
retest variability (10.6%) [66].
19.9 Future Directions: New
Radiopharmaceuticals
Several second-generation TSPO radioligands
having lower lipophilicity than [11C](R)PK11195 and consequently higher specic to
nonspecic binding have been developed and
may be soon suitable for neuroinammation PET
imaging [67–69].The radioligand N-(2,5-11Cdimethoxybenzyl)-N-(5-fluoro-2phenoxyphenyl)acetamide ([11C]DAA1106) has
shown increased TSPO binding in AD and MCI
patients compared to healthy subjects [70, 71].
The 18F analogue of DAA1106, N-(5-uoro-2phenoxyphenyl)-N-(2-18F-fluoroethyl-5-methoxybenzyl)acetamide ([18F]FEDAA1106) has
not demonstrated signicant increase in TSPO
binding in AD patients in comparison with controls [72]. Other compounds that are still in preclinical stages of development include
deuterium-substituted analogues of
[18F]-FEDAA1106 that are less susceptible to
in vivo deuorination [73, 74], high-afnity
quinoline-carboxamides ([11C]-VC195), and
halogenated 2-quinolinecarboxamides that are
structurally similar to PK11195 [75, 76],
[11C]-vinpocetine [77], and pyrazolopyrimidine
[11C]-DPA-713 [78].
Moreover, in the complex process of the neuroinammations in which microglial activation
takes part, the development of invivo imaging
biomarkers that can evidence other pathways
of this mechanism is ongoing in the research
eld. The cannabinoid type 2 receptor (CB2R) is
expressed by microglia and 11c-NE40 has shown
an interesting lower CB2R binding in AD patients
compared to healthy subjects, without any relationship to Aβ load [
compound, a selective P2X7 receptor tracer
under the name of 11C-JNJ717 was tested both
in healthy people and PD patient. P2X7 receptor is an ATP-gated ion channel predominantly
expressed on activated microglia and is important
in neurodegenerative diseases including PD.The
79]. Another radiolabelled
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