Angewandte
Chemie
DOI: 10.1002/anie.201107957
Radiopharmaceuticals
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Synthesis of [ F]BODIPY: Bifunctional Reporter for Hybrid Optical/
Positron Emission Tomography Imaging**
J. Adam Hendricks, Edmund J. Keliher, Dongpeng Wan, Scott A. Hilderbrand,
Ralph Weissleder,* and Ralph Mazitschek*
Fluorescence-based intravital imaging approaches have been
essential for studying the function and distribution of
biologically active small molecules and their molecular
often relied on the use of distinct labels for each imaging
modality. For example, PET ligands and fluorochromes have
been used simultaneously on nanoparticles. However, these
methods result in chemically distinct compounds with non-
identical pharmacological properties.
[3]
[
1]
targets in vivo. While optical imaging enables visualization
over a broad scope of spatial resolution ranging from
subcellular to whole-body anatomical imaging, its application
is constrained by the optical transparency of tissues. Optical
imaging modalities are thus better suited for small-animal
Herein we introduce a generic and widely applicable
approach that enables a hybrid PET/fluorescence molecular
tomography (FMT) imaging agent, based on boron dipyrro-
methene (BODIPY), to be accessed through
[
2]
imaging rather than for translational applications. In con-
trast, positron emission tomography (PET) is used routinely
for clinical applications but its use is limited primarily to
macroscopic spatial and temporal imaging. A strategy that
would enable seamless switching between fluorescence and
PET imaging would thus be highly desirable for several
reasons. First, the ability to visualize PET probes at the
microscopic level would allow more rapid validation of the
former in vivo and consequently expedite the development of
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the F/ F exchange of one of the fluorides
within the canonical BF2 dipyrromethene
core 1, a motif that is shared by most
BODIPY dyes. This efficient method for
incorporating a PET tracer thus evades the above-mentioned
bottleneck in drug testing. We believe that this novel
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approach, which uses hybrid fluorescence/ F tags, will accel-
erate not only the development of imaging agents, but
perhaps also the screening of therapeutic molecules.
[3]
novel PET probes. Second, for macroscopic hybrid imaging,
it would be possible for optical and PET signals to be
superimposed onto structural information derived from
magnetic resonance imaging (MRI) or computed tomography
BODIPY dyes represent a unique class of fluorescent
small molecules, and have recently received recognition for
their extraordinary versatility as fluorescent tags in biological
[
4]
(
CT). Likewise, the ability to image in more than one or two
imaging applications. The most widely appreciated charac-
teristics of BODIPY dyes include their good photostability,
high brightness, compatibility with biological media, and their
broad tunable color range which covers the green to near-
channels would be useful for visualizing underlying physio-
logical events. Third, hits from microscopic screens of small-
molecule fluorochrome adducts could be more rapidly
translated into clinically relevant applications.
[
5]
infrared spectrum. One particular advantage of BODIPY
dyes over the majority of other commonly used fluorescent
dyes is the neutral nature of their scaffold. This feature is
critical for the efficient penetration of cell membranes, and as
such BODIPY dyes remain one of the few fluorophore classes
suited to intracellular imaging within living cells.
To date, the development of hybrid optical/PET probes
has been hindered by various methodological limitations. As
a result, a synthetic strategy that enables general access to
such compounds has yet to be established. For any approach
to be successful, however, two critical factors must be
considered: 1) the short half-lives of clinically relevant PET
These attractive features of the BODIPY dyes, combined
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radioisotopes, namely F (110 min) and C (20 min), both of
which (ideally) require the introduction of the nuclide during
the final synthetic steps; and 2) the pharmacodynamic
changes that result from addition of the imaging tag(s).
Because of these limiting factors, previous strategies have
with the presence of the canonical BF group within their
2
central core, highlighted this fluorochrome class as a promis-
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ing candidate for the development of hybrid F PET/FMT
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imaging agents through a F/ F exchange. This strategy
would not only allow the wide variety of analogues already
commercially available to be exploited, but also allows the
desirable characteristics of the BODIPY dyes to be retained.
Furthermore, this exchange system could potentially even
allow the seamless conversion of BODIPY-tagged small-
molecule probe compounds, already validated for fluorescent
imaging, into PET imaging probes.
[
+]
[+]
[
*] Dr. J. A. Hendricks, Dr. E. J. Keliher, D. Wan,
Dr. S. A. Hilderbrand, Prof. R. Weissleder, Prof. R. Mazitschek
Center for Systems Biology, Massachusetts General Hospital
Harvard Medical School, Boston, MA 02114 (USA)
E-mail: rweissleder@mgh.harvard.edu
Inspired by the recent report by Hudnall and Gabbaꢀ,
which described the development of a BODIPY-based
fluorogenic sensor for fluoride ions, we chose to explore the
use of a 4-dimethylaminopyridine (DMAP) BODIPY inter-
mediate (3; Scheme 1) as an activated reagent for the efficient
+
[
] These authors contributed equally to this work.
[
**] Financial support from the NCI (P50A086355, U24A092782, T32-
CA079443) is gratefully acknowledged.
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[6]
incorporation of F.
Angew. Chem. Int. Ed. 2012, 51, 4603 –4606
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4603