A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation

Article abstract of DOI:10.1021/acs.jmedchem.7b00432

A suitable TSPO PET ligand may visualize and quantify neuroinflammation in a living brain. Herein we report a ¹⁸F-ligand, [¹⁸F]2 ([¹⁸F]FDPA), is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [¹⁸F]2 demonstrated saturable specific binding to TSPO, substantially elevated brain uptake, and slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alzheimer's disease).

Full text of DOI:10.1021/acs.jmedchem.7b00432

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Brief Article
18
A Facile Radiolabeling of [F]FDPA via Spirocyclic Iodonium Ylides:
Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation
Lu Wang, Ran Cheng, Masayuki Fujinaga, Jian Yang, Yiding Zhang, Akiko Hatori, Katsushi Kumata,
Jing Yang, Neil Vasdev, Yunfei Du, Chongzhao Ran, Ming-Rong Zhang, and Steven H Liang
J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2017
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A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium
Ylides: Preliminary PET Imaging Studies in Preclinical Models
of Neuroinflammation
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Lu Wang,†,§ Ran Cheng,†,¶,§ Masayuki Fujinaga,‡,§ Jian Yang,# Yiding Zhang,‡ Akiko Hatori,‡
Katsushi Kumata,‡ Jing Yang,# Neil Vasdev,† Yunfei Du,¶ Chongzhao Ran,# Ming-Rong Zhang*,‡
and Steven H. Liang*,†
† Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Harvard Medical School,
Boston, MA, USA.
‡ Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes
for Quantum and Radiological Science and Technology, Chiba, Japan.
¶ School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
#Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital & Harvard Medical School,
Boston, MA, USA.
ABSTRACT: A suitable TSPO PET ligand may visualize and quantify neuroinflammation in living brain. Herein we report
a
18F-ligand, [18F]2 ([18F]FDPA) is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium
ylide (SCIDY) strategy. [18F]2 demonstrated saturable specific binding to TSPO, substantially-elevated brain uptake and
slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alz-
heimer’s disease).
INTRODUCTION
The translocator protein 18 kDa (TSPO) is a five trans-
membrane domain protein and located with outer mito-
chondrial membrane. TSPO is expressed predominantly
in steroid-synthesizing endocrine organs including heart,
kidneys, adrenal cortex, testis or ovary.1 One of the most
well-characterized functions of TSPO is its involvement in
the translocation of cholesterol from the outer to the in-
ner mitochondrial membrane,2 which is critical to the
synthesis of steroids. In the central nervous system (CNS),
TSPO is dramatically upregulated in neuroinflammatory
conditions (activated microglial cells).3, 4 Abnormal over-
expression of TSPO has been found as a pivotal patholog-
ical signal in the progression of many other neurological
disorders. In particular, neuroinflammation occurs at the
pre-plaque stage5 of Alzheimer’s disease (AD) and serves
as a major driving force.6 Recent studies have also re-
vealed that the TSPO expression was closely associated
with infarction induced by ischemia.7 Therefore, TSPO is
a potential biomarker for detecting inflammation associ-
ated with brain disorders, and for monitoring treatment
response of anti-inflammatory therapies.
tional imaging tool to evaluate the status of neuroin-
flammation (activated microglia) in living brain.8,
9
[11C]PK11195 was the first extensively evaluated PET ligand
for TSPO; however, low signal-to-noise ratio and high
non-specific binding hampered its further advance.10 In-
tensive efforts therefore have been made to improve PET
imaging quality and quantitative process with the devel-
opment of a rich library of TSPO PET ligands.11-13 Particu-
larly a PET ligand [18F]1 ([18F]DPA-714; Figure 1), devel-
oped by James and Kassiou et al, has shown improved
bioavailability, lower nonspecific binding, and higher
15
non-displaceable binding potential (BPND).14,
Initial
evaluation of this radiopharmaceutical in healthy human
volunteers validated its biodistribution profile towards
TSPO.16 Clinical PET studies using [18F]1 were further
conducted on patients with amyotrophic lateral
sclerosis,17 post-stroke18 and AD,19 demonstrating this lig-
and may be useful in assessing the extent of neuroin-
flammation.
N,N-diethyl-2-(2-(4-[18F]fluorophenyl)-5,7-
dimethylpyrazolo[1,5-a]pyrimidine-3-yl)-acetamide [18F]2
([18F]FDPA), a fluoroaryl analog of [18F]1, in which the
fluorine atom is directly attached to terminal aromatic
ring, is another promising PET ligand (Figure 1). Its in-
trinsic structure (aryl-18F bond) offers an improved meta-
Positron emission tomography (PET) is a non-invasive
imaging technology that is capable of visualizing and
quantifying biochemical and pharmacological processes
in vivo. A TSPO-specific PET ligand is utilized as a transla-
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bolic profile via substantially-reduced formation of radio-
and direct radiolabeling via [18F]fluoride, demonstrating a
1
labeled metabolites in brain and plasma compared with
[18F]1 as observed by Solin and Dollé et al.20, 21 Several ra-
diofluorination reactions were reported to prepare [18F]2
via [18F]fluoride ion under various labeling conditions,
including nitroarene,
broad substrate scope for non-activated and/or sterically-
hindered (hetero)arenes. The operation is simple, metal-
free and suitable for routine and automated production.
Herein, we report an efficient radiosynthesis of [18F]2
based on SCIDY precursors from no-carrier added
[18F]fluoride and preliminary PET imaging evaluation in
preclinical models of ischemia and AD.
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RESULTS AND DISCUSSION
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Chemistry. As shown in Scheme 1, we developed an ef-
ficient route and improved the literature procedure30 to
obtain non-radioactive standard 10 (FDPA), and the key
intermediate 11 for our SCIDY strategy. Microwave-
assisted synthesis was utilized to assemble N,N-
diethylamide 6 with dramatically-reduced reaction time
(40 min) while maintaining a good yield (55%). The cy-
clization reaction triggered by hydrazine and acetic acid,
led to fluoroaminopyrazole 8 in 88% yield. Finally, con-
densation between 8 and acetylacetone afforded 10 as a
white crystalline solid in 75% yield. The key compound 11
was also prepared in an analogous synthetic route with an
overall yield of 41% in three steps from 3-(4-iodophenyl)-
3-oxopropanenitrile 4. We found that oxidation of 11 by
using Oxone in mixed solvents of CHCl3 and trifluoroace-
tic acid was critical for this type of transformation, lead-
ing to the corresponding iodo(III) intermediate 12 in ca.
60% conversion. The intermediate was used without fur-
ther purification in the subsequent coupling reactions
with spirocyclic auxiliaries (SPI5 and SPIAd)29 to afford
SCIDY precursors 13 (22%, two steps from 11) and 14 (34%,
two steps from 11), respectively.
Figure 1. Chemical structures of [18F]1 and [18F]2
aryltrimethylammonium salt and diaryliodomium salt as
precursors, that resulted in limited radiochemical conver-
sions (< 3%).22 Electrophilic fluorination starting with
carrier-added [18F]F2 to prepare [18F]Selectfluor as a label-
ing reagent was recently performed by Solin and co-
workers, to prepare [18F]2, and resulted in 15 ± 3% decay
corrected yields with a low specific activity of 7.8 ± 0.5
GBq/μmol (0.21 ± 0.01 Ci/μmol).23 However, because a
low-cold-mass PET ligand injection is critical to detect
inflammatory events,24, 25 there is an unmet and urgent
need for [18F]2 with high specific activity to evaluate the
potential of this radioligand in PET imaging of neuroin-
flammation.
On the basis of our previous work, precise radiofluori-
nation of non-activated aromatics can be achieved with
spirocyclic iodonium ylide (SCIDY) precursors.26-29 These
bench-stable precursors provide efficient, regiospecific
Scheme 1. Syntheses of 10, 11, and SCIDY Precursors 13 and 14a
aReagents and conditions: (a) NaOH, NaI, microwave, 80 ºC, 40 min, 80% EtOH in H2O, 55% for 6, 62% for 7; (b) hy-
drazine, AcOH, 80 ºC, 8 h, EtOH, 88% for 8, 83% for 9; (c) pentane-2,4-dione, 80 ºC, 4 h, EtOH, 75% for 10, 80% for 11;
(d) 11, Oxone, TFA/CHCl3 = 3/1, 23 ºC, 1 h; (e) SPI5, 10% Na2CO3 (aq.), rt, 70 min, EtOH, 22% for 13 over two steps from
11; (f) SPIAd, 10% Na2CO3 (aq.), rt, 70 min, EtOH, 34% for 14 over two steps from 11.
excellent binding affinity (Ki: 2.0 ± 0.8 nM) which is con-
Pharmacology. In vitro binding affinity of 10 for TSPO
sistent with prior reports31 and comparable with that of
was measured from competitive binding of TSPO-
DPA-714 (Ki: 7.0 ± 0.4 nM).14 The selectivity of 10 towards
selective radioligand [3H]PK11195 (Figure S1). 10 showed
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activated arenes from no-carrier added [18F]fluoride,26, 29
central benzodiazepine receptor (CBR) binding was re-
1
ported as Ki > 1 mM,22 in comparison to that of DPA-714
(Ki > 10 µM).14 These results indicated that [18F]2 could be
utilized to study in vivo binding profiles for TSPO by PET.
Radiochemistry. Based on our prior reports of utiliz-
ing SCIDY precursors to enable radiofluorination on non-
we developed an efficient radiolabeling method from
SCIDY precursor 14 to produce [18F]2. Specifically, we car-
ried out comprehensive optimization of radiofluorination
conditions, including bases, solvents, reaction tempera-
tures and
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Figure 2. Radiolabeling optimization for [18F]2. [18F]fluoride (37-111 MBq; 1-3 mCi) was used in each reaction. (A) Precursor (2
mg), DMF (0.4 mL), 120 ºC, 5 min; (B) Precursor (2 mg), TEAClO4 or TBAOMs (12 mg), DMF (1.0 mL), 120 ºC; (C) Precursors
(2 mg), TBAOMs (12 mg), DMF (1.0 mL), heated for 15 min; (D) Precursors (2 mg), TBAOMs (12 mg), solvent (1.0 mL), 120 ºC,
15 min. Radiochemical conversion and product identity were assessed by radioTLC and radioHPLC, respectively.
precursor loadings (Figure 2). We first set out the radio-
fluorination with 14 using different types and loading
amounts of bases, including tetraethylammonium bicar-
bonate (TEAB) and K2CO3/K222 in DMF. Unfortunately,
under these conditions only trace amounts of [18F]2 were
detected. These fruitless results promoted us to study the
thermostability of SCIDY precursors. While compound 14
alone showed no decomposition when heating at 120 ºC
for 10 min, the addition of TEAB (1 mg) led to a rapid de-
composition even without heating, which indicates alter-
native milder bases/additives may be necessary to achieve
high radiolabeling efficiency (Figure S2). To our delight,
combination of K2C2O4/K222 gave the desired product
[18F]2 with >20% radiochemical conversion (RCC). Fur-
thermore two quaternary alkylammonium salts, namely,
tetrabutylammonium methanesulfonate (TBAOMs)32 and
tetraethylammonium perchlorate (TEAOCl4) were identi-
fied as the most promising additives (> 30% RCCs) for
further evaluation (Figure 2A & Figure S3). By optimizing
reaction time and temperature we found that TBAOMs
was superior to TEAOCl4, and RCCs reached to 40 ± 3% (n
= 3) at 120 ºC for 15 min (Figure 2B & 2C). Together with
solvent effect (Figure 2D) and the amounts of precursor
loading (Figure S4), we identified that the combination of
12 mg of TBAOMs, 1 mg of SCIDY precursor 14 in CH3CN
at 120 ºC for 15 min provided the highest RCC of 63 ± 5%
(n = 6). In addition, we also tested SPI5-based SCIDY pre-
cursor 13 under the optimal conditions (Figure S5), which
only provided 16 ± 3% RCC (n = 3). These results were
consistent with our prior observation that SPIAd precur-
sors were more efficient than SPI5 precursors under 18F-
labeling reactions.29 As a result, the radiosynthesis of
[18F]2 was achieved in 45 ± 8% decay-corrected yield with-
in 80 min with >99% radiochemical and chemical purity
and specific activity of 96 ± 22 GBq/μmol (2.6 ± 0.6
Ci/µmol; see experimental section). The identity of [18F]2
was confirmed by co-injection with 10 (Figure S6). No
radiolysis was observed up to 120 min after formulation.
[18F]2 was stable in vitro in mouse serum at 37 ºC for 120
min. The efficient radiosynthesis with high specific activi-
ty, radiochemical purity and stability enabled the subse-
quent ex vivo biodistribution and preclinical in vivo PET
imaging studies.
Lipophilicity. Lipophilicity can be used, in part, as a
predictive value for assessing blood brain barrier (BBB)
permeability with an optimal range of 1.0-3.5.33 Using liq-
uid-liquid partition (“the shake flask method”), LogD7.4
value of [18F]2 was determined to be 2.34 ± 0.05 (n = 5),
which is comparable with several reported TSPO radiolig-
ands such as [18F]DPA-714 ([18F]1; LogD7.4 2.44)14 and
[18F]GE-180 (LogD7.4 2.95).31
Whole body biodistribution studies. The uptake,
distribution and clearance of [18F]2 were studied in mice
at three time points (2, 25 and 45 min) post injection
(Figure 3, Table S1 and S2). At 2 min p.i., high uptake (>5
%ID/g) was observed in the lungs, heart, liver, kidneys,
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pancreas and adrenal glands. After the initial phase the
activity curves of [18F]2 showed maximum uptake in the
1
radioactivity levels in most tissues decreased rapidly,
while the signals in the kidney, spleen and adrenal glands
continued to increase during the whole period. The radi-
ipsilateral side (ischemic site) reached a peak of 1.20 SUV
at 10 min. Blockade with PK11195 (3 mg/kg) decreased PET
signal by ca. 80%, indicating high in vivo specificity and
low non-specific binding. The SUV(2/40min) ratio of 2.9
showed a rapid washout rate of non-specific binding un-
der blocking conditions. In the contralateral side, [18F]2
showed limited peak brain uptake (0.54 SUV) and mar-
ginal changes between baseline and blocking conditions.
We also observed a rapid clearance of non-specific bind-
ing (SUV2/40min = 5.9) probably attributed to low expres-
sion of TSPO in normal brain.34 High ipsilateral to contra-
lateral ratios at 10 min and 90 min p.i. were determined as
5.41 ± 0.12 and 4.26 ± 0.34, respectively. Pretreatment with
PK11195 also substantially diminished heterogeneous radi-
oactive signals between ipsilateral and contralateral sides.
We also carried out a simplified reference-tissue model
(SRTM) analysis and determined BPND using the contrala-
teral side as the reference region.36 The BPND values in the
ipsilateral sides were determined to be 4.02 ± 1.32 (p <
0.05) for [18F]2, which was higher than [11C]PK11195 (1.59 ±
0.33, p < 0.05).36
Liu et al. demonstrated that TSPO was mainly ex-
pressed in activated microglia in APP/PS1 transgenic
mouse brains by immunofluorescence studies between
TSPO and Aβ as well as the association of Aβ deposition
and TSPO-positive microglia in human AD brain sec-
tions.37 Thus as proof of concept, we explored in vivo
binding profile of [18F]2 in a transgenic mouse model
(APP/PS1) of AD. [18F]2 rapidly crossed the BBB and in-
creased to 1.50 ± 0.13 SUV at 3 min p.i., demonstrating 1.6-
fold higher peak brain uptake and slow washout (possibly
attributed to increased specific and non-specific binding)
in APP/PS1 brain compared with age-matched control
(Figure 5).
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Figure 3. Ex vivo biodistribution of [18F]2 in mice. Data
are expressed as %ID/g (mean ± SD, n = 3).
oligand was efficiently cleared from blood (2 min/45 min
ratio >10), and high uptake of [18F]2 in the liver, kidney
and small intestine indicated urinary and hepatobiliary
excretion, as well as possible intestinal re-uptake. The
uptake of [18F]2 in the present study is consistent with the
distribution of TSPO in mice, as high expression in the
lungs, heart, kidneys and adrenal glands has been previ-
ously observed.1 In particular, since TSPO expression in
microglia cells of normal brain has been found to be in a
low level,34 brain uptake of [18F]2 was moderate with 3.69
%ID/g at 2 min p.i., and the radioactivity washout was
reasonable with 1.15 %ID/g at 45 min time point (2 min/45
min ratio 3.2). In addition, negligible bone uptake was
detected (<1 %ID/g), showing little or no defluorination
occurred in vivo, which was also confirmed by PET imag-
ing studies (Figure S7). Based on these results, we further
evaluated if [18F]2 is a suitable PET ligand targeting TSPO
in preclinical models of neuroinflammatory brain.
PET imaging studies in preclinical models of neu-
roinflammatory brain. Due to the low TSPO expression
in normal brain,34 we utilized a focal cerebral ischemic rat
model (see section 10 in SI) in which TSPO expression
was up-regulated with activated microglia35 while the
blood-brain barrier was intact or not seriously
disrupted.36 As shown in Figure 4, PET images and time-
Figure 5. PET Imaging studies in APP/PS1 mouse models
for [18F]2 uptake. (A) Representative PET images (summed
0-30 min) between age-matched wild type and APP/PS1
mouse models; (B) time-activity curves (n = 2).
In vitro autoradiography. The binding specificity of
[18F]2 to TSPO was further confirmed by autoradiography
studies in ischemia and AD brains. The ipsilateral side of
ischemic rat brain showed substantially increased signal
levels than that of contralateral side (ratio 7:1; Figure 6).
The difference in radioactivity levels between the ipsilat-
eral and contralateral sides was diminished by co-
incubation with PK11195 (Figure 6B), leaing to a dramatic
reduction (>98%) of ipsilateral binding (Figure 6C). We
also noted increased whole brain uptake in APP/PS1
Figure 4. PET images (summed 0-90 min) (A,B) and time
activity curves (C,D) for baseline and blocking with
PK11195.
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mouse brain slices compared with age-matched controls
(Figure S8). These in vitro findings are consistent with the
in vivo binding specificity of [18F]2 by PET studies.
A solution of TBAOMs (12.0 mg) in CH3CN / H2O (v/v, 1/1,
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1.0 mL) was used to elute [18F]fluoride into a V-shaped vial
sealed with a Teflon-lined septum. The vial was heated to
110 °C while nitrogen gas was passed through a P2O5-
Drierite™ column into the vented vial. When no liquid
was visible, it was removed from heat, anhydrous CH3CN
(1 mL) was added, then the heating was resumed until
dryness. This step was repeated three times. The vial was
then cooled to room temperature under nitrogen flow. A
solution of precursor 14 (1.0 mg) in anhydrous CH3CN (1
mL) was added into the reaction vial and heated at 120 ºC
for 12 min. CH3CN / H2O (v/v, 1/1, 2.0 mL) was added to
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the mixture, which was then injected to
a semi-
preparative HPLC system. HPLC purification was com-
pleted on a semi-preparative Phenomenex Luna C18 col-
umn (250 x 10 mm, 5 µm) eluting with CH3CN/ 0.1 M
NH4•HCO2(aq) (v/v, 1/1) at a flowrate of 5 mL/min. The
retention time for [18F]2 was 17.5 min. The radioactive
fraction corresponding to the desired product was col-
lected and diluted with 23 mL H2O. The mixture was then
loaded onto a C18 SPE cartridge (pre-activated with 5 mL
EtOH followed by 10 mL of H2O). The cartridge was
washed with 20 mL of H2O and dried by nitrogen gas for 5
min. The product [18F]2 was then eluted with 1.5 mL of
CH3OH, and collected in a sterile flask, evaporated to
dryness by nitrogen gas at 60 °C for 20 min, and reformu-
lated in a saline solution (3 mL) containing 100 µL of 25%
ascorbic acid in H2O and 100 µL of 20% Tween® 80 in eth-
anol. The synthesis time was ca. 80 min from end-of-
bombardment. Radiochemical and chemical purity were
measured by analytical HPLC (Phenomenex Luna C18, 250
x 4.6 mm, 5 µm, UV at 254 nm; CH3CN / 0.1 M
NH4•HCO2(aq) (v/v, 7/3) at a flowrate of 1.0 mL/min). The
identity of [18F]2 was confirmed by the co-injection with
unlabeled 10. Radiochemical yield was 45 ± 8% (decay-
corrected) with >99% radiochemical purity and 96 ± 22
GBq/μmol (2.6 ± 0.6 Ci/μmol) specific activity.
Figure 6. In vitro autoradiography of [18F]2 in ischemic rat
brains. Representative autoradiogram of [18F]2 alone (A) or
with PK11195 (B). Arrows indicate ipsilateral side. Quantita-
tive effects of PK11195 blocking (C).
CONCLUSION
The SCIDY-based methodology provides a high-yield
and high-specific-activity radiosynthesis of [18F]2 that
enabled preliminary PET studies in preclinical models of
focal cerebral ischemia and Alzheimer’s disease. These
proof-of-concept results not only warrant [18F]2 as a
promising imaging biomarker to elucidate the involve-
ment of microglia activity in preclinical models of ische-
mia and AD, but also provide the basis for designing new
pyrazolo[1,5-a]pyrimidine based TSPO PET ligands. Fur-
ther validation including immunofluorescent staining,
radiometabolite analysis, PET imaging studies in higher
species among different polymorphism are outlined to
evaluate the suitability of [18F]2 as a potential imaging
tool for clinical translation.
ASSOCIATED CONTENT
EXPERIMENTAL SECTION
Supporting Information
Preparation of SPIAd precursor 14. To a solution of
11 (50 mg, 0.11 mmol) in trifluoroacetic acid (0.39 mL) and
chloroform (0.13 mL) was added Oxone (100mg, 0.165
mmol) under stirring. The mixture was stirred at room
temperature for 60 min, then concentrated in vacuo. To
the crude was added EtOH (0.8 mL), then a solution of
SPIAd (25.3 mg, 0.11 mmol) in 10% Na2CO3 (0.5 mL), fol-
lowed by additional 10% Na2CO3 (0.3 mL) to adjust to pH
9. The mixture was stirred at room temperature for 70
min, then diluted with H2O (5 mL), extracted with CH2Cl2
(5 mL × 3). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (0-10%
MeOH in EtOAc) to afford ylide precursor 14 as a white
solid (26.1 mg, 34% yield).
Synthetic and analytical results for all compounds; animal
models and imaging methods; supplemental figures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +81 43 382 3709. Fax: +81 43 206 3261. E-mail:
zhang.ming-rong@qst.go.jp.
*Tel: +1 617 726 6106. Fax: +1 617 726 6107. E-mail:
liang.steven@mgh.harvard.edu.
Author Contributions
§L.W., R. C. and M. F. contributed equally to this work.
Radiolabeling of [18F]2. [18F]Fluoride solution (0.74-
1.48 GBq; 20-40 mCi) was delivered and trapped on a Wa-
ters Sep-Pak light QMA cartridge (pretreated with 1 mL of
8.3% aqueous NaHCO3 and 20 mL H2O) by nitrogen gas.
ACKNOWLEDGEMENT
We thank the National Institute of Mental Health's Psycho-
active Drug Screening Program for the compound screening.
R.C. is supported by China Scholarship Council
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tomography. Biochem. Soc. Trans. 2015, 43, 586-592.
(201506250036). S.H.L. is a recipient of an NIH career devel-
opment award (DA038000).
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13. Albrecht, D. S.; Granziera, C.; Hooker, J. M.; Loggia, M. L. In
vivo imaging of human neuroinflammation. ACS Chem. Neurosci.
2016, 7, 470-483.
14. James, M. L.; Fulton, R. R.; Vercoullie, J.; Henderson, D. J.;
Garreau, L.; Chalon, S.; Dolle, F.; Costa, B.; Guilloteau, D.; Kassiou,
M. DPA-714, a new translocator protein-specific ligand: synthesis,
radiofluorination, and pharmacologic characterization. J. Nucl.
Med. 2008, 49, 814-822.
ABBREVIATIONS
PET, positron emission tomography; TSPO, translocator pro-
tein;
FDPA,
N,N-diethyl-2-(2-(4-fluorophenyl)-5,7-
SUV,
dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide;
standardized uptake value, BPND, non-displaceable binding
potential; SRTM, simplified reference-tissue model; TAC,
time-activity curve; %ID/g, percentage of injected dose per
gram of wet tissue.
15. Chauveau, F.; Van Camp, N.; Dolle, F.; Kuhnast, B.; Hinnen, F.;
Damont, A.; Boutin, H.; James, M.; Kassiou, M.; Tavitian, B.
Comparative evaluation of the translocator protein radioligands
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11C-DPA-713, 18F-DPA-714, and C-PK11195 in a rat model of acute
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