Efficient acid-catalyzed 18F/19F fluoride exchange of BODIPY dyes

Article abstract of DOI:10.1002/cmdc.201300506

Fluorine-containing fluorochromes are important validation agents for positron emission tomography imaging compounds, as they can be readily validated in cells by fluorescence imaging. In particular, the ¹⁸F-labeled BODIPY-FL fluorophore has emerged as an important platform, but little is known about alternative ¹⁸F-labeling strategies or labeling on red-shifted fluorophores. In this study we explore acid-catalyzed ¹⁸F/ ¹⁹F exchange on a range of commercially available N-hydroxysuccinimidyl ester and maleimide BODIPY fluorophores. We show this method to be a simple and efficient ¹⁸F-labeling strategy for a diverse span of fluorescent compounds, including a BODIPY-modified PARP-1 inhibitor, and amine- and thiol-reactive BODIPY fluorophores. A colorful exchange: In this study we explore acid-catalyzed ¹⁸F/¹⁹F exchange on a range of commercially available NHS ester and maleimide BODIPY fluorophores. We show this method to be a simple and efficient ¹⁸F-labeling strategy for a diverse range of fluorescent compounds, including a BODIPY-modified PARP-1 inhibitor, and amine- and thiol-reactive BODIPY fluorophores.

Full text of DOI:10.1002/cmdc.201300506

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DOI: 10.1002/cmdc.201300506
18
Efficient Acid-Catalyzed F/19F Fluoride Exchange of
BODIPY Dyes
Edmund J. Keliher,[a] Jenna A. Klubnick,[a] Thomas Reiner,[b] Ralph Mazitschek,[a] and
Ralph Weissleder*[a, c]
Fluorine-containing fluorochromes are important validation
agents for positron emission tomography imaging compounds,
as they can be readily validated in cells by fluorescence imag-
ing. In particular, the 18F-labeled BODIPY-FL fluorophore has
emerged as an important platform, but little is known about
alternative 18F-labeling strategies or labeling on red-shifted flu-
orophores. In this study we explore acid-catalyzed 18F/19F ex-
change on a range of commercially available N-hydroxysuccini-
midyl ester and maleimide BODIPY fluorophores. We show this
method to be a simple and efficient 18F-labeling strategy for
a diverse span of fluorescent compounds, including a BODIPY-
modified PARP-1 inhibitor, and amine- and thiol-reactive
BODIPY fluorophores.
the 18FÀ fluoride ion gives the chemically equivalent but iso-
topically distinct BODIPY (Scheme 1).
Scheme 1. Two-step fluoride-18 labeling of BODIPY dyes.
Earlier we reported the 18F-labeling of BODIPY dyes by
a modification of the procedure of Hudnall and Gabbai,[6] and
during the course of our studies found that acidic conditions
are required for the labeling of the reactive intermediate.[3]
Herein we describe and explore the relative reactivity of the
acid-catalyzed exchange of 19F with 18F of a number of com-
mercially available N-hydroxysuccinimidyl (NHS) ester and mal-
eimide (Mal) BODIPY fluorophores (Scheme 2). Additionally, we
show that the integrity of the NHS ester and Mal functional
groups is conserved by demonstrating subsequent reaction
with benzylamine and l-cysteine, respectively. Finally, by using
this method, we also describe the direct 18F-labeling small mol-
ecule, which is based on the PARP-1 inhibitor (PARPi) AZD2281
(Olaparib)[7] modified with BODIPY-FL. PARP-1 inhibition and
imaging have recently received significant attention for cancer
treatment.[8]
Fluorescence technology has revolutionized biological imaging
through the development of biocompatible fluorescent small
molecules, nanoparticles, and proteins.[1] Despite these advan-
ces, translation into the clinic has proven more difficult, and
clinical trials remain scarce. Conversely, several thousand posi-
tron emission tomography (PET) imaging agents have been
used for imaging in vivo in animals, but most of them have
not been validated at the cellular level, given the inherent spa-
tial resolution limitations of PET.[2] Chemically and biologically
equivalent bimodal PET/fluorescence imaging agents circum-
vent this problem by offering a number of advantages such as
rapid screening, direct cellular validation (via microscopy or
flow cytometry), and cost-effective testing of the stable isotope
compound prior to rapid precursor scale-up and labeling of
the optimized radiotracer.
Our research group and others have recently developed
methods for labeling boron dipyrromethene (BODIPY) fluoro-
chromes with the radionuclide fluorine-18.[3–5] Chemical remov-
al of 19F yields a stable intermediate, which when treated with
Scheme 2. Acid-catalyzed fluoride exchange of BODIPY dyes.
[a] Dr. E. J. Keliher,+ J. A. Klubnick,+ Dr. R. Mazitschek, Prof. R. Weissleder
Center for Systems Biology, Massachusetts General Hospital
Richard B. Simches Research Center
Following our previously published procedure,[3] 4,4-difluoro-
1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-propionic
succinimidyl ester (B493-NHS, 1) was electrophilically activated
with trimethylsilyl triflate, then treated with 2,6-lutidine to give
a stable but reactive intermediate. Addition of azeotropically
dried 18F to the stable intermediate in the presence of acid
gave the desired 18F-labeled BODIPY [18F]1 in high radiochemi-
cal yield in less than 2 min. We generated trifluoromethanesul-
fonic acid (TfOH) in situ by the addition of Tf2O with tBuOH to
the reaction mixture. These substances in the presence of re-
sidual water from 18F were sufficient to generate the acidic
185 Cambridge Street, Boston, MA 02114 (USA)
[b] Dr. T. Reiner
Department of Radiology, Memorial Sloan-Kettering Cancer Center
New York, New York 10065 (USA)
[c] Prof. R. Weissleder
Department of Systems Biology, Harvard Medical School
200 Longwood Avenue, Boston, MA 02115 (USA)
E-mail: rweissleder@mgh.harvard.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300506.
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pothesize that below this thresh-
old, the reaction mixture is too
basic for exchange to proceed.
In addition to the second-order
dependence on Tf2O/tBuOH, we
determined
that
there
is
a second-order dependence on
the concentration of the BODIPY
substrate, as shown in Figure 2B.
The BFL-NHS (2) concentrations
were varied (0.5, 1.0, and 2.0 mm
final reaction concentrations)
while all other reagent concen-
trations were held constant.
Linear regression of these ob-
served rate constants provided
a
second-order rate constant:
(4.19Æ0.15)ꢁ10À4 mÀ1 sÀ1.
We also tested TfOH and
methanesulfonic acid (MsOH) at
the same final reaction concen-
tration as the Tf2O/tBuOH mix-
ture (40 mm). TfOH showed
rapid 18F/19F exchange, but also
rapid decomposition of the fluo-
rophore and thus release of free
19FÀ into the reaction mixture,
decreasing the incorporation of
18F. The MsOH experiment shows
Figure 1. Chemical structures of B493-NHS (1), BFL-NHS (2), B530-NHS (3), BTMR-X-NHS (4), B630-X-NHS (5), BFL-
Mal (6), Bn-BFL (7), Cys-BFL (8), and PARPi (9).
conditions required for 18F fluorination of the stable intermedi-
ate. When these same conditions were applied to the labeling
of BFL-NHS (2), we found the rate of reaction significantly de-
creased. Upon further investigation, we found that structurally
different BODIPY dyes (BODIPYs 1–6, Figure 1) display signifi-
cant differences in their relative 18F/19F exchange rates.
Table 1. Observed and second-order rate constants for the acid-catalyzed
18F/19F exchange of BFL-NHS (2).
c [mm]
kobs [10À4
]
Æ3s [10À4
]
Error [%]
40
14
10
7.95
4.16
3.09
1.01
0.26
0.26
12.7
6.3
8.5
Tf2O/tBuOH
BFL-NHS (2)
Preliminary exchange experiments were conducted by treat-
ing NHS ester 2 with a mixture of Tf2O, tBuOH (40 mm final re-
action concentration) and azeotropically dried 18F at 508C.
Within minutes, radio-HPLC analysis showed 18F incorporation
into 2. When 2 was treated with Tf2O or tBuOH separately, only
1% exchange was observed after 2 h. With these observations
we proceeded to study the exchange of 18F for 19F in the gen-
eral BODIPY structure in greater detail by varying the reagent
concentrations, time, and temperature, as well as the starting
BODIPY fluorophore. The reaction rate was found to be depen-
dent on both Tf2O/tBuOH and BODIPY.
2.0
1.0
0.5
7.95
3.98
2.32
1.01
0.40
0.16
12.7
10.0
7.0
k [10À4 mÀ1 sÀ1
]
Error [10À4
0.10
]
Tf2O/tBuOH
BFL-NHS (2)
0.69
4.19
0.15
a significantly lower rate of 18F/19F exchange (Supporting Infor-
mation Figures S2A and S2B).
Figure 2A and Table 1 show the dependence of the rate on
the concentrations of Tf2O/tBuOH (10, 14, and 40 mm), while
all other concentrations were held constant. Linear regression
of the data from these kinetics experiments provided
a second-order rate constant with respect to the acid concen-
tration of (6.86Æ1.01)ꢁ10À5 mÀ1 sÀ1. Interestingly, we found
that there was no incorporation of 18F at Tf2O/tBuOH concen-
trations below the concentration of the alkaline tetra-n-buty-
lammonium bicarbonate (TBAB) phase-transfer catalyst. We hy-
While the above kinetics experiments were conducted at
508C, two other temperatures, 0 and 238C, were also explored
(Supporting Information Figure S2C). The observed reaction
rate at 508C (7.95Æ1.01)ꢁ10À4 sÀ1 was 11.7-fold higher than
that observed at 238C, (5.91Æ0.89)ꢁ10À5 sÀ1, and 33.1-fold
higher than that observed at 08C, (2.08Æ0.38)ꢁ10À5 sÀ1. In-
creasing the amount of starting activity (2.0, 16.5, and
34.5 mCi) added to the reaction, while maintaining a constant
starting BFL-NHS concentration (125 mmol at 10 mm) resulted
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marized in Figure 3 and Table 2.
The previously studied B493-
NHS (1) was the most reactive,
showing over 87% 18F exchange
within 15 min. Maleimide 6 and
NHS esters 2 and 4 were found
to be similar in reactivity, with
60, 64, and 65% 18F exchange at
30 min. NHS esters 3 and 5 were
considerably slower, with only
16 and 24% exchange after
30 min, respectively. For the spe-
cific activity, each reaction has
a
theoretical maximum, gov-
erned by the 18F activity incorpo-
rated and the amount of intact
radiolabeled plus cold BODIPY
dye after the reaction. The spe-
cific activities range from 1.9 to
12.8 mCimmolÀ1 (Table 2), corre-
lating with the radiochemical
yields, which range from 16.2 to
90.6% after 30 min reaction
time.
Following the labeling of
[18F]2 and [18F]6 after 45 min at
508C, these two compounds
were purified from unreacted
18FÀ by passage through a silica
Figure 2. Concentration-versus-time curves and linear-regression analysis of the observed rate constants for BFL-
NHS + 18F/Tf2O/tBuOH. A) Variation of [Tf2O/tBuOH] at 508C. B) Variation of [BFL-NHS] at 508C.
in a linear increase in specific activity of 6.5, 45.4, and
73.6 mCimmolÀ1, respectively.
In a series of separate experiments, individual exchange re-
actions on 2 were set up for each time point (15, 30, 60, 90,
and 120 min) in an effort to compare loss of activity due to
evaporation, presumably in the form of [18F]HF, while opening
and closing the reaction tube for serial analysis of a single re-
action. At each time point, the reaction activity was measured
before and after removal of the aliquot for analysis. These data
were decay corrected to the time of initial addition of activity
and compared. Less than 5% loss of radioactivity to evapora-
tion was observed during the course of running a single reac-
tion with multiple analyses, and less than 3% loss per reaction
when running multiple reactions in parallel with single analysis
per reaction.
Recognizing the potential utility of this method for the gen-
Figure 3. Concentration-versus-time curves for B493-NHS (1), BFL-Mal (6),
B630-X-NHS (5) and B530-NHS (3).
eration of dual PET–optical molecular imaging probes, we
sought to broaden the scope of this labeling method. There-
fore, we tested these conditions (125 nmol BODIPY and
2.5 mmol Tf2O/tBuOH, 2 and 40 mm final reaction concentra-
tions, respectively, at 508C) against a number of other com-
mercially available BODIPY fluorochromes (B493-NHS (1), B530-
NHS (3), BTMR-X-NHS (4), B630-X-NHS (5), and BFL-Mal (6)) as
well as a biologically relevant BODIPY-labeled small molecule
PARPi (9).[9] The structures of these compounds are shown in
Figure 1, and the results of the exchange experiments are sum-
gel cartridge. Once loaded onto the cartridge, elution with
CH2Cl2 and EtOAc secured the radiochemically pure [18F]2 and
[18F]6 in 75 and 66% radiochemical yield (non-decay-correct-
ed), respectively. Addition of benzylamine to [18F]2 in the pres-
ence of triethylamine and l-cysteine to [18F]6, provided [18F]7
and [18F]8, Figure 4A. Presence of the desired stable-isotope
conjugates was confirmed by detection of the correct mass by
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sults indicate that for compound 2, increasing the concentra-
tion of Tf2O/tBuOH increases the 18F/19F exchange rate. We an-
ticipate that the other compounds tested will follow this trend
to approach the exchange rate of 1. Both amine-reactive NHS
esters and thiol-reactive maleimides are well tolerated under
these reaction conditions and demonstrated reactivity in sub-
sequent conjugation reactions. To our knowledge, this is the
first example of a direct 18F-labeling of a maleimide. Other re-
ported 18F-labeling protocols require multiple steps to obtain
the desired thiol-reactive maleimide prosthetic group.[10–13]
As a general labeling strategy, this method does have a limi-
tation in specific activity due to the degeneracy of the starting
material and product, and therefore an inability to
chromatographically separate the desired labeled
product from starting material. To address this, we
have shown that increasing the amount of starting
activity will increase the specific activity and that the
relationship was found to be linear over the activity
range studied, 2–35 mCi (74–1295 MBq), shown in
Figure 5. Although the resulting activities of 70 mCim
molÀ1 (2590 MBqmmolÀ1) are lower than other com-
monly used radiotracers FES (2.5–5 CimmolÀ1),[14,15]
the specific activity generated is likely sufficient even
for clinical applications. For example, for a [18F]PARPi
scan, only 2 mmol would have to be injected (35 mCi,
70 mCimmolÀ1), which represents less than 0.1% of
a daily clinical dose of the parent compound, Olapar-
ib (based on a 300 mg (390 mmol) twice-daily oral
Table 2. Radiochemical yields and specific activity (SA) of 18F/19F ex-
change for 6 commercially available BODIPY fluorophores.[a]
Entry
BODIPY Dye
18FÀ Incorporation [%]
SA [mCimmolÀ1
]
1
2
3
4
5
6
B493-NHS
BFL-NHS
B530-NHS
BTMR-X-NHS
B630-X-NHS
BFL-Mal
86.2
63.8
16.2
65.1
24.3
60.4
12.8
6.5
1.9
8.5
2.6
4.0
[a] After 30 min reaction time at 508C (2.5 mmol Tf2O/tBuOH, 125 nmol
BODIPY); yields determined by HPLC (Method C).
administration,
ClinicalTrial.gov
identifier:
NCT01844986). We envision by varying the starting
quantity of 18F activity and/or starting material, the
radiochemical yield and specific activity may be opti-
mized for a particular application.
Figure 4. A) HPLC radio-chromatograms of the conjugation of [18F]6 with l-cysteine to
give [18F]8. B) HPLC UV and radio-chromatograms of [18F]PARPi ([18F]9).
LC–MS analysis, and the presence of radiolabeled conjugates
was verified by HPLC co-elution with the stable isotope 7 and
8.
A BODIPY conjugate previously prepared in our laboratory,
PARPi (9) was subjected to acid-catalyzed 18F/19F exchange
(conditions: 125 nmol PARPi, 2.5 mmol Tf2O/tBuOH, 408C) with
49% 18F incorporation observed after 30 min, Figure 4B. The
acid-catalyzed exchange of 19F for 18F on BODIPY fluorophores
was found to have second-order kinetics with respect to the
acid as well as the dye added. At 508C, the incorporation of
18F into BFL-NHS (2) achieved over 50% incorporation at
15 min and 64% at 30 min. The incorporation proceeded to
equilibrium over the next 1.5 h, reaching a maximum of ~85%
at 2 h total reaction time. An increase in the BODIPY concen-
Figure 5. Specific activity as a function of starting activity for the incorpora-
tration would not only increase the final concentration of the
18F-labeled species, but also the rate at which this equilibrium
would be achieved.
tion of 18FÀ in to BFL-NHS.
Experimental Section
Exchange reactions on other commercial BODIPY fluoro-
chromes (B493-NHS (1), B530-NHS (3), BTMR-X NHS (4), B630-
X-NHS (5), and BFL-Mal (6)) all demonstrated 18FÀ incorpora-
tion, although differences in reactivity were observed. Our re-
General: Unless otherwise noted, solvents and reagents were pur-
chased from Sigma–Aldrich (St. Louis, MO, USA) and used without
further purification. All NHS and maleimide BODIPY compounds
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were purchased from Invitrogen. Synthesis of 4-{[4-fluoro-3-(4-(5-
Conjugation reactions
oxopentanamide)piperazine-1-carbonyl)phenyl]methyl}-2H-phthala-
[18F]Benzyl-BFL ([18F]Bn-BFL, [18F]7): The crude [18F]BFL-NHS mix-
ture, prepared as described above in the acid-catalyzed exchange
reaction after 45 min at 508C, was loaded onto an SPE silica gel
cartridge (1.0 mCi) conditioned with pentane (500 mL). The car-
tridge was washed with pentane (2ꢁ150 mL), then the [18F]BFL-
NHS eluted with CH2Cl2 (3ꢁ150 mL) followed by DMSO (3ꢁ150 mL).
Activity collected in the elution fractions was as follows: 1.7 and
2.7 mCi for pentane fractions 1 and 2; 179.5, 273.0, and 14.3 mCi for
CH2Cl2 fractions 1, 2, and 3; 48.6, 192.1, and 14.3 mCi for DMSO
fractions 1, 2, and 3; and 229 mCi remaining on the silica cartridge.
To the combined CH2Cl2 fractions of [18F]BFL-NHS was added Et3N
(10 mL, 250 mm in CH2Cl2) and benzylamine (37.5 mL, 25 mm in
CH2Cl2) and stirred at room temperature for 40 min. HPLC analysis
(10 mL aliquot) demonstrated full conversion of [18F]BFL-NHS to
[18F]Bn-BFL. Bn-BFL (7) LC–ESIMS analysis found: 404.28 [M+Na]+,
362.18 [MÀFÀ]+, calculated: 404.17 [M+Na]+, 362.18 [M-FÀ]+.
[18F]Cysteine-BFL ([18F]Cys-BFL, [18F]8): The crude [18F]BFL-Mal mix-
ture, prepared as described above in the acid-catalyzed exchange
reaction after 45 min at 508C, was loaded onto an SPE silica gel
cartridge (1.0 mCi) conditioned with pentane (300 mL). The car-
tridge was washed with pentane (2ꢁ150 mL), then the labeled
compounds eluted with EtOAc (3ꢁ150 mL) and DMSO (3ꢁ150 mL).
Activity collected in the elution fractions was as follows: 2.6 and
2.5 mCi for pentane fractions 1 and 2; 198.9, 291.9, and 95.9 mCi for
EtOAc fractions 1, 2, and 3; 18.8, 30.5, and 5.6 mCi for DMSO frac-
tions 1, 2, and 3; and 317 mCi remaining on the silica cartridge. To
the combined EtOAc fractions of [18F]BFL-Mal was added Et3N
(10 mL, 250 mm in CH2Cl2) and l-cysteine (37.5 mL, 25 mm in CH2Cl2)
and stirred at room temperature for 40 min. HPLC analysis (10 mL
aliquot) demonstrated full conversion of [18F]BFL-Mal to [18F]Cys-
BFL. Cys-BFL (8) LC–ESIMS analysis found: 516.31 [MÀFÀ]+, 534.25
[MÀH+]À, calculated: 516.19 [MÀFÀ]+, 534.18 [MÀH+]+.
zin-1-one 9 was described earlier[9,16] 18FÀ ion (n.c.a.) in 18O-en-
.
riched water was purchased from PETNET (Woburn, MA, USA) and
dried by azeotropic distillation of water with MeCN in the presence
of tetra-n-butylammonium bicarbonate (TBAB; ABX) using a Synthra
RN Plus automated synthesizer (Synthra GmbH, Hamburg, Germa-
ny) operated by SynthraView software. The dried 18F/TBAB was re-
constituted in MeCN, collected in a 2 mL vial, and diluted to ach-
ieve a 12 mm TBAB solution. For non-radioactive compounds, LC–
ESIMS analysis and HPLC purifications were performed on a Waters
(Milford, MA, USA) LC–MS system. For LC–ESIMS analyses, a Waters
XTerra C18 (4.6ꢁ50 mm, 5 mm) column was used (Method A: elu-
ents 0.1% formic acid (v/v) in H2O (A) and MeCN (B); gradient: 0–
1.5 min, 5–100% B; 1.5–2.0 min 100% B; 5 mLminÀ1). Preparative
HPLC runs for synthetic intermediates involved an Atlantis Prep T3
OBD (19ꢁ50 mm, 5 mm) column (Method B: eluents 0.1% TFA (v/v)
in H2O (A) and MeCN (B); gradient: 0–1.5 min, 5–100% B; 1.5–
2.0 min 100% B; 30 mLminÀ1). Analytical HPLC of radiolabeled
compounds was performed with an Agilent 1200 Series HPLC and
a
Poroshell 120 EC-C18 (4.6ꢁ50 mm, 2.7 mm) reversed-phase
column (Method C: eluents 0.1% TFA (v/v) in H2O (A) and MeCN
(B); gradient: 0–0.3 min, 5% B; 0.3–7.5 min, 5–100% B; 7.5–10 min,
100% B; 2.5 mLminÀ1) with a multichannel-wavelength UV/Vis de-
tector, fluorescence detector, and a flow-through g detector con-
nected in series. Solid-phase extraction cartridges used were Oasis
C18 3-cc cartridge (60 mg, 30 mm particle size, Waters, MA, USA)
and Sep-Pak Silica 3-cc Vac cartridge (500 mg, 55–105 mm particle
size, (Waters)). The two-step, one-pot 18FÀ labeling procedure em-
ploying TMS-OTf was described previously.[3]
Isotope exchange reactions: To azeotropically dried 18F/TBAB
(30 mL, 12 mm TBAB in MeCN) in a 1.5 mL centrifuge tube, triflic an-
hydride (Tf2O; 10 mL, 250 mm in MeCN), tert-butanol (tBuOH; 10 mL,
250 mm in MeCN) and the BODIPY dye (12.5 mL, 10 mm in 1.5:1
CH2Cl2/MeCN, B493-NHS (1), BFL-NHS (2), B530-NHS (3), BTMR-X-
NHS (4), B630-X-NHS (5), BFL-Mal (6), or PARPi (9)) were added se-
quentially in 2 min intervals. The radioactivity of the reaction tube
was measured in a well counter then placed in 508C shaker. At 15,
30, 60, 90, 120, and 150 min (with exception of 1, only 15 and
30 min data points were obtained), the tubes were removed from
heat, cooled in an ice bath for 20 s, and the activity of the reaction
tube measured. An aliquot (1–3 mL) was removed from the reaction
tube, radioactivity measured in a well counter and analyzed by
HPLC (Method C). Radioactivity of the reaction tube was measured
and then returned to the heated shaker. Kinetic data points were
obtained from the area of the HPLC radio-chromatograms and
plotted as a percent fraction. Observed rate constants were gener-
ated from the data by the program KINETIC of Dr. R. Fink, a gift
from the late Prof. William von Eggars Doering, which handles ki-
netic schemes containing up to seven components, and incorpo-
rates a calculation of Marquardt that generates error limits in the
rate constants at the 95% confidence level.[17,18] Second-order rate
constants were calculated using GraphPad Prism 4.0c (GraphPad
Software, Inc., San Diego, CA, USA). Exchange experiments were re-
peated for 2 in the same manner as described above by varying
starting concentrations of 2 (final reaction concentrations of 1.0
and 0.5 mm) or Tf2O/tBuOH (final reaction concentrations of 14, 10,
and 7 mm) while maintaining a constant final reaction volume. Ad-
ditional experiments were conducted for 2 at 0 and 238C.
Acknowledgements
This work was supported by National Institutes of Health grants
P50CA86355 and RO1EB010011, and the Department of Energy
Training grant DE-SC0001781PO1.
Keywords: fluorine-18 · BODIPY · fluorescence · molecular
imaging · positron emission tomography
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Received: December 5, 2013
Revised: February 13, 2014
Published online on && &&, 0000
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A colorful exchange: In this study we
explore acid-catalyzed 18F/19F exchange
on a range of commercially available
NHS ester and maleimide BODIPY fluo-
rophores. We show this method to be
a simple and efficient 18F-labeling strat-
egy for a diverse range of fluorescent
compounds, including a BODIPY-modi-
fied PARP-1 inhibitor, and amine- and
thiol-reactive BODIPY fluorophores.
E. J. Keliher, J. A. Klubnick, T. Reiner,
R. Mazitschek, R. Weissleder*
&& – &&
Efficient Acid-Catalyzed 18F/19F
Fluoride Exchange of BODIPY Dyes
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 6
&
7
&
ÞÞ
These are not the final page numbers!