TSPO 18 kDa (PBR) targeted photosensitizers for cancer imaging (PET) and PDT

Article abstract of DOI:10.1021/ml100211g

Translocator protein (TSPO) 18 kDa overexpression has been observed in a large variety of human cancers, especially breast cancers. PK 11195, an isoquinoline analogue, is one of the ligands of highest TSPO binding affinity. Due to the long biological half

Full text of DOI:10.1021/ml100211g

pubs.acs.org/acsmedchemlett
TSPO 18 kDa (PBR) Targeted Photosensitizers
for Cancer Imaging (PET) and PDT
Yihui Chen,*,†,‡ Munawwar Sajjad,*,‡ Yanfang Wang,†,§ Carrie Batt,† Hani A. Nabi,‡ and
Ravindra K. Pandey*,†
†PDT Center, Roswell Park Cancer Institute, Buffalo, New York 14263, United States, and ‡Department of Nuclear Medicine,
State University of New York, Buffalo, New York 14214, United States
ABSTRACT Translocator protein (TSPO) 18 kDa overexpression has been ob-
served in a large variety of human cancers, especially breast cancers. PK 11195, an
isoquinoline analogue, is one of the ligands of highest TSPO binding affinity. Due to the
long biological half life of our photosensitizers, there is a need to label them with a long
lived radioisotope, for example I-124. Our objectives are to find translocator protein
targeted photosensitizers for both tumor imaging (PET) and photodynamic therapy
(PDT). I-PK 11195 is conjugated with the tumor avid photosensitizer HPPH. We find that
those two tumor avid components complement each other and make the conjugate
molecule even more tumor avid; compared to the photosensitizer itself, the conjugate
is found to show improved PDTefficacy. It is concluded that I-PK 11195 can be a good
vehicle to deliver radionuclide and photosensitizer to TSPO overexpressed tumor
regions. Such conjugates could be useful for both tumor imaging (PET)and PDT.
KEYWORDS Photodynamic therapy (PDT), translocator protein (TSPO), peripheral
benzodiazepine receptor (PBR), positron emission tomography (PET), PK 11195,
cancer target specific
BR (peripheral benzodiazepine receptor) is suggested
to be named Translocator Protein (18 kDa) (TSPO 18
kDa) by Papadopoulos etal.1 based on its structure and
characteristics of the tumor while CT (computed tomography)
and MRI (magnetic resonance imaging) mainly assess the
tumor's anatomical and morphological features. 124I (t1/2
=
P
molecular function. TSPO is involved in numerous functions,2-4
including the role in steroidogenesis and mitochondrial respira-
tion5,6 and apoptosis regulation.7-9 A number of findings argue
in favor of the development of TSPO targeting approaches in the
treatment of human cancers. (i) TSPO overexpression has been
observed in a large variety of human cancers,10 especially in
breast cancers.11 (ii) TSPO is a component of the central regu-
latory complex of apoptosis;12 this suggests that TSPO targeting
could be of interest in combination with various antitumor
therapies. (iii) TSPO binding by high-affinity ligands enhances
apoptosis induction of numerous inducers; moreover, TSPO
ligands are able to reverse the Bcl-2 cytoprotective effect.13
For breast cancers, it was reported11 that TSPO expression and
TSPO-mediated cholesterol transport are involved in cell prolife-
ration and aggressive phenotype expression, thus participating
in the advancement of the disease. Altogether, these observa-
tions justify the use of TSPO ligands in combination with other
antitumor therapies for the diagnosis and treatment of breast
cancers. Although a number of wide varieties of endogenous
and synthetic molecules were reported to have high affinities for
TSPO,14 currently PK 11195 is still the most widely used TSPO
ligand and regarded as the gold standard.15
4.2 days) is a potential candidate for labeling compounds that
have slow clearance kinetics. Pentlow24 and our group25 have
shown that quantitative imaging with 124I is possible. We were
the first who labeled porphyrin by 124I to image cancers,25
although the PET imaging result of our 124I labeled porphyrin
photosensitizer was quite decent, we are still trying to find a more
breast cancer specific agent for tumor detection and therapy.
In order to find TSPO targeted bifunctional (PDT and PET)
agents, we started from the synthesis of iodo-PK 11195 (3). The
iodo-PK 11195 (3; Scheme 1) was synthesized following the
method reported by Gildersleeve et al.26 Briefly, 2-(2-iodophe-
nyl)-4-benzylidene-5(4H)-oxazolone, which was in turn pro-
duced by reacting 2-iodohippuric acid with benzaldehyde, was
converted into iodo-PK 11195 carboxylic acid (2) under acidic
conditions. It was then treated with ethylchloroformate before
reacting with N-methyl-sec-butylamine; the desired isoquinoline
analogue (3) was obtained in overall 40% yield. In order to
convert cold PK 11195 into 124I-PK 11195, we abandoned the
isotope exchange approach26 due to its hard reaction conditions
and low yield; instead, we first converted the I-PK 11195 into its
stannic derivatives. In an initial experiment, I-PK 11195 (3) was
Photodynamic therapy (PDT) is a unique approach that uses
low energy light to kill cancer cells;16-20 more selective and
potent sensitizers need to be developed. PET (positron emis-
sion tomography)21-23 assesses the functional or metabolic
Received Date: September 12, 2010
Accepted Date: November 16, 2010
Published on Web Date: November 23, 2010
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Scheme 1. Structures and Syntheses of 1-22a
a Reagents: (a) Sn2(CH3)6 or Sn2(C4H9)6; (b) PdCl2(PPh3)2; (c) N-chlorosuccinimide; (d) Na124I; (e) (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP); (f) hexamethylene diamine; (g) N-Boc-ethylenediamine; (h) HBr in acetic acid and then hexanol.
converted into the trimethylstannyl analogue (4a) in 60% yield
by reacting 3 with hexamethylditin with the catalysis of trans-
dichlorobis(triphenylphosphine)palladium(II). Due to the ap-
proximately same retention times of 3 and the corresponding
trimethylstannyl analogue (4a), the separation of these two
compounds by HPLC was very difficult. However, replacing the
trimethylstannyl group with a tributylstannyl substituent, 4b
(Scheme 1) produced significantly longer HPLC retention time,
and we were able to separate both compounds easily by HPLC.
4b was then converted into 124I-PK 11195 (5) by reacting with
Na124I in the presence of N-chlorosuccinimide, in 60% yield and
with >95% radioactive specificity. 124I-PK 11195 (5) was
purified by HPLC (column: C18, 5 μm, 150 mm ꢀ 4.6 mm
Adsorborsphere; eluting solvent: 58% MeOH/42% H2O; flow
rate: 1.0 mL/min). The HPLC process was monitored by both
UV (328 nm) and radiodetectors. The specific activity of the
desired labeled analogue 5 was >1 Ci/μmol.
Methylpheophorbide-a (6), obtained from Spirulina Pacifica,
was converted into pyropheoporbide-a carboxylic acid (8) by
following the methodology improved in our laboratory.25 Upon
reaction with BOP [(benzotriazol-1-yloxy)tris(dimethylamino)-
phosphonium hexafluorophosphate] and hexamethylene di-
amine, 8 was converted into amide 9 in 60% yield. By following
a similar approach, after reacting with N-Boc-ethylenediamine, 8
was converted to 10 in 90% yield. Deprotection of 10 by trifluo-
roacetic acid produced desired 11 in almost quantitative yield.
Compounds 9 and 11 were converted to the conjugate mole-
cules 13 and 12, respectively, in approximately 70% yield by
the reaction with BOP and 2. 12 and 13 were converted into 14
and 15, respectively, by reacting with sodium hydride and then
methyl iodide in 30% yield. Following the procedure described
for the synthesis of 5, compound 13 was converted into the
radiolabeled analogue 17. Similarly, following the procedure
described for the synthesis of 13, compound 20, the conjugate
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Figure 1. (A) Displacement of 3H-PK 11195 with various compounds; (B) IC50 value of various compounds;the concentration of
competitor at which 50% of 3H-PK 11195 binding was inhibited; (C and D) microPETemission imaging (coronal view) of Balb/c mice bearing
colon-26 (C) and EMT-6 tumors (D) at 24 h p.i. of 124I-3; 124I-3 possesses obvious tumor imaging ability.
of iodo-PK 11195 carboxylic acid (2) with 18 (HPPH, 3-[10-
hexyloxyethyl]-3-devinyl pyropheophorbide-a), was also pre-
pared in moderate yield. HPPH is a tumor-avid photosensitizer
currently in phase II clinical trials. Following the procedure
described for the synthesis of 17, 124I-labeled 20, i.e. 22, was
also successfully prepared in a decent yield (Scheme 1). Both17
and 22 were purified by HPLC (symmetry C18 column; eluting
solvent: 95% MeOH/5% H2O; flow rate: 1.0 mL/min); the
specific activity for them was larger than 1 Ci/μmol.
focused on breast cancer models; breast cancer is one of the
deadliest diseases.28
The utility of 11 C-PK 11195 as PET imaging agent has been
reported by Pappata,29 unfortunately due to a veryshort half-
life of carbon-11 (20 min), it is impractical to use 11 C-PK 11195
as the imaging agent for tumors because the drug accumulation
needs at least several hours circulation. Tritium labeled PK
11195 is another radiodetectable form of this molecule; how-
ever, tritium decays into helium-3 by emission of a low energy
β particle, not a positron, so that 3H-PK 11195 cannot be used
for PET imaging. In contrast, 124I-PK 11195's longer half-life
(4.2 days) enables us to image tumors. Although there are some
publications that report using ligands of TSPO to image brain,
for example, Chalon et al.30 reported use of iodinated PK 11195
as an ex vivo marker of neuronal injury in the lesioned rat brain,
we are the first to use 124I-PK 11195 as the imaging agent for
cancers here. In our approach to develop a bifunctional agent
for both tumor imaging and phototherapy, we are interested in
conjugating I-PK 11195 with photosensitizers. For photosensiti-
zers of low tumor affinity, the idea was to use I-PK 11195 as a
vehicle to deliver the photosensitizers to the tumor site; for
photosensitizer of high tumor affinity (for example, 18 HPPH),
we assume this photosensitizer will facilitate the tumor-target-
ing of conjugate molecules in some areas of low TSPO expres-
sion. Tumors are heterogeneous and mutable and may not
have a uniform or consistent expression of a particular receptor,
such as TSPO. For the preparation of the desired conjugate, the
photosensitizer was linked with PK 11195 by following the reac-
tion sequence illustrated in Scheme 1. In fact, after intensive
literature research and analyzing our own experimental results
of previous work, we found the structural requirements of PK
11195 analogues for ideal TSPO binding affinity (Scheme 1). In
brief they are (a) the long-range electrostatic interactions pro-
viding the amide bond in position 3; (b) the bicyclic aromatic
system needed to preserve the dihedral angle (Φ); (c) the
halogen atom in position 12 that plays some role in the TSPO
binding affinity; and (d) the phenyl group needed to preserve
the angle (ψ) between the bicyclic system and the phenyl
substituent. The TSPO binding affinity data of the conjugates
12, 13, 14, and 15 and intermediates 9 and 11 are summarized
in Figure 1A and 1B. It was found that their TSPO binding
After the preparation of the iodinated PK 11195 3, we
compared its TSPO binding affinity with that of the parent
molecule 1. As can be seen from Figure 1A and B, replacing the
chloro-substituent with an iodo-substituent did not inhibit the
TSPO binding affinity. We also investigated the possibility of
using 124I-3 as a tumor imaging agent. As discussed previously,
TSPO overexpression has been reported for both colon and
breast cancers; therefore, we selected Balb/c mice bearing
Colon-26 (colon adenocarcinoma) and EMT6 (well-character-
ized, undifferentiated mouse breast cancer) tumors. As can be
clearly seen from Figure 1 C and D, for both of those tumors, at
24 h postinjection, the tumor sites are clearly defined. Our
imaging results were furtherconfirmed by biodistribution study.
As can be seen in Figure 2, at early time points, 1 and 2 h
postinjection (Figure 2A for Colon-26 tumor) or 4 h postinjec-
tion (Figure 2C for EMT6 tumor), tumor uptake of 3 was not
conspicuous compared to the cases of other organs; however, at
24 h postinjection, the tumor uptake was just lower than that of
liver and stomach (Figure 2B for Colon-26 tumor) or gut
(Figure 2D for EMT6 tumor), and it was much higher than that
of any other organ. This is obviously due to much a higher drug
clearance rate from organs than tumor. To test the 124I - P K 111 9 5
imaging potential for brain cancers, we also investigated the
imaging potential of 124I-3 for nude mouse bearing U87 tumor;
U87 cells are glioblastoma cells. Even at 24 h postinjection, we
found the tumor uptake was not conspicuous compared to the
cases of other organs (Figure 2D). This may be due to the lower
TSPO expression in U87 tumor27 compared to Colon-26 and
EMT-6 tumors. Therefore, we concluded that I-PK 11195 is an
effective TSPO targeting agent, and it can be used as a vehicle to
deliver photosensitizers to the tumor site of specific cancers
of high TSPO expression. In the following work, we mainly
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Figure 2. Biodistribution of (124I-labeled) compound 3. (A and B) Colon-26 tumors (Balb/c mice); (C and D) EMT6 tumors (Balb/c mice) or
U87 tumors (nude mice). For Colon-26 tumor, the drug uptakes at 1 h and 2 h postinjection are not conspicuous (A)while the uptake at 24 h
postinjection is conspicuous (B); similarly, for EMT6 tumor, the drug uptake at 4 h postinjection is not conspicuous (C) while the uptake at
24 h postinjection is conspicuous (D). For U87 tumor, even at 24 h postinjection, the drug uptake is not conspicuous (D). Standard deviations
are presented in error bars.
affinity decreases in this order: 15 ≈13>14>12>11>9. Itwas
found that after 9 and 11 were conjugated with 2 (produc-
ing 13 and 12, respectively), their TSPO binding affinities were
greatly enhanced; methylation of 12 (producing 14) enhanced
its TSPO binding affinity. In addition, the TSPO binding affinity
data of 12 and 13 also indicate that the length of the linkers
joining the PK 11195 with the photosensitizer plays a key role in
TSPO binding affinity; it is obvious that the six-carbon long
linker was more effective than the two-carbon one; maybe this is
because that there is no interference to PK 11195's TSPO binding
when it is conjugated with photosensitizer by a six-carbon long
linker. Considering that the preparation of 15 takes one more
step of low yield (30%),and13 has similar TSPO binding affinity
to 15, we chose the conjugate 13 for further investigations. The
dissociation constant (Kd) of 13 binding with TSPO is 40 nM.
Conjugate 13 not only showed efficient TSPO binding affinities
but also produced a significant tumor avidity determined by
124I-positron emission tomography in both EMT-6 (in Balb-c
mice) and MDA-MB-231 (in SCID mice) tumors. We selected
MDA-MB-231 (also known as MDA-231) cells, because it was
reported31 that the very aggressive human breast cancer cell line
has the highest TSPO expression. Furthermore, it was found
that, compared with nonconjugated molecules 9, 13 produced
significantly (P < 0.001) higher in vivo PDTefficacy in MDA-MB-
231 tumors (at 5.0 μmol/kg, 20% tumor-free for 13 versus 0%
for 9 at day 60); 8 possesses similar in vivo PDTefficacy to 9 (for
detailed data, see Supporting Information S-Table 2).
was added. It was found that the cellular uptake of 13 was ap-
proximately reduced by half, while the uptake of 9 was retained
unchanged. This result strongly confirms the TSPO target-speci-
ficity of 13. In vitro PDTefficacy itself is a very important indicator
for the potential of a photosensitizer; furthermore, investigation
of comparative in vitro PDT efficacy for the conjugated and non-
conjugated photosensitizers is conducive to understanding target
specificity. When 13 was added (at a concentration of 0.03 μM)
in the presence of 3(at 2.5 μM, about 85 times the concentration
of 13), inhibition effects were observed at both 24 J/cm2 and
48 J/cm2 (Figure 3B). The difficulties for this inhibition experiment
are if the concentration of 13 is too low (lower than 0.03 μM),
no PDTefficacy can be observed; on the other hand, if the con-
centration of 3 is too high (higher than 2.5 μM), it will produce
toxicity. If just comparing the in vitro PDTefficacy, the conjugate
molecule 13 produced higher PDTefficacy than the correspond-
ing nonconjugate photosensitizer 9 (Figure 3C). At 1.0 μM, the
IC50 light doses for 13 and 9 are 0.17 and 0.93 J/cm2, respec-
tively. Contrarily to the results of EMT-6 and MDA-MB-231
cells, for the TSPO negative Jurkat cells,27 the cellular drug
uptakes of 9 and 13 are similar; no inhibition effect for the
in vitro efficacy of 13 was observed. In summary, all these
results strongly confirm the TSPO target-specificity of 13.
In order to find photosensitizers of higher PDTefficacy, the
conjugate of HPPH 20 was prepared. It was found that 20
possesses similar TSPO binding affinity to 13. As can be seen
from Figure 4A-D, 124I-20 possesses strong imaging ability.
It was also found that 20 did bear stronger tumor affinity
than 13, because the %ID/g value of 20 was higher than that
of 13 at every time point; for example, at 24 h postinjection,
the %ID/g value for 20 and 13 was 3.87 and 3.28, respec-
tively. The best tumor images for 124I-20 were obtained at
48, 72, and 96 h postinjection. The long time circulation of
compound 20 also further rationalizes the necessity to use
I-124 (t1/2 4.2days) rather than F-18 (t1/2 110 min) for the PET
imaging. Biodistribution results show that the tumor has
In order to further confirm the target specificity of con-
jugate molecule 13, the cellular uptake of 13 and the corre-
sponding nonconjugate 9 were determined by fluorescence
spectroscopy. The compounds were excited at 412 nm, and
emission was measured over the range 550-750 nm. The
maximum emission was at 678 nm. We found that cellular up-
take of 13 was more than 2-fold as high as that of 9 (Figure 3A).
To further confirm the target specificity of conjugate 13,
I-PK 11195 3 (at 10 μM, 100 times the concentration of 13 and 9)
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Figure 3. (A) Comparative cellular uptake for 9 and 13 with and without 3; the presence of 3 decreases the uptake of 13 while it has little
effect on the uptake of 9; (B) in vitro PDTefficacy of 13 (0.03 μM) with and without 3 (2.5 μM) on MDA-MB-231 cells; the presence of an
∼85 times larger concentration of 3 inhibits the PDTefficacy of 13; (C) 13 produces better PDTefficacy than 9 (1.0 μM) on MDA-MB-231 cells.
Standard deviations are presented in error bars. For EMT6 cells, similar results were obtained.
Figure 4. For MDA-231 tumors bearing Scid mice, 22 possesses strong tumor imaging capability. MicroPETemission imaging (coronal view) at
24 h (A), 48 h (B), 72 h (C), and 96 h (D) postinjection of 22 (i.e., 124I-20) (dose: 50 μCi (∼40 ng)/mouse). (E) Kaplan-Meier plot for the in vivo PDT
efficacyof compounds HPPH 18 and 20 at 0.4 μmol/kg dose. Light dose: 135 J/cm2, 75mW/cm2, ten mice foreach group. 20 produces significantly
better in vivo PDTefficacy than 18 (P < 0.0001).
SUPPORTING INFORMATION AVAILABLE Synthesis, NMR
spectra, elemental analysis of new compounds, experimental pro-
cedures of TSPO binding, and in vitro and in vivo PDT efficacy
investigations. This information is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *Yihui Chen, PDT Center, Cell Stress
Biology Department, Roswell Park Cancer Institute, Buffalo, NY
14263. Phone: 716-845-1245. E-mail: yihui.chen@roswellpark.
org. Ravindra K. Pandey, PDT Center, Cell Stress Biology Depart-
ment, Roswell Park Cancer Institute, Buffalo, NY 14263. E-mail:
ravindra.pandey@roswellpark.org. Munawwar Sajjad, Department
of Nuclear Medicine, State University of New York, Buffalo, NY
14214. E-mail: msajjad@buffalo.edu.
Figure 5. Biodistribution of 22 for MDA-231 tumor bearing Scid
mice; tumor has much higher uptake for 22 than any other organs
except liver at 48, 72, and 96 h postinjection; three mice for each
group. Standard deviations are presented in error bars.
much higher 20 uptake than any other organs except liver at
48, 72, and 96 h postinjection (Figure 5).
Author Contributions: § Y.W. is on temporary leave from Tongji
University, Shanghai, People's Republic of China.
Comparative in vivo PDT efficacy experiments were also per-
formed in Scid mice bearing MDA-231 tumors (10 mice/group)
for 20 and its nonconjugate counterpart 18 HPPH. 20 was found
to show much higher efficacy than 18 (P < 0.0001) (Figure 4E).
Inspiringly, it was also found that, compared to HPPH 18, 20
produces less skin phototoxicity, which is a major drawback for
clinical PDT. The TSPO target-specificity of 20 was also further
confirmed by similar experiments described in Figure 3.
In summary, the preliminary results indicate that conjugat-
ing the iodo-PK 11195 with PDT agent enhances its target
specificity and the PDT efficacy. Currently the study to investi-
gate the synergetic (PDTand chemotherapy) treatment effect
for primary and metastatic cancers is in progress.
Funding Sources: We thank the National Institutes of Health
(1RO1CA127369-O1A1, CA109914) for financial support of this work.
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DOI: 10.1021/ml100211g ACS Med. Chem. Lett. 2011, 2, 136–141
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