Synthesis of [11C]bexarotene by cu-mediated [ 11C]carbon dioxide fixation and preliminary PET imaging

Article abstract of DOI:10.1021/ml500065q

Bexarotene (Targretin) is a retinoid X receptor (RXR) agonist that has applications for treatment of T cell lymphoma and proposed mechanisms of action in Alzheimer's disease that have been the subject of recent controversy. Carbon-11 labeled bexarotene ([

Full text of DOI:10.1021/ml500065q

Letter
pubs.acs.org/acsmedchemlett
Synthesis of [11C]Bexarotene by Cu-Mediated [11C]Carbon Dioxide
Fixation and Preliminary PET Imaging
Benjamin H. Rotstein,†,‡ Jacob M. Hooker,‡,§ Jiyeon Woo,† Thomas Lee Collier,†,‡,∥ Thomas J. Brady,†,‡
Steven H. Liang,*,†,‡ and Neil Vasdev*,†,‡
†Division of Nuclear Medicine and Molecular Imaging & Center for Advanced Medical Imaging Sciences, Massachusetts General
Hospital, Boston, Massachusetts 02114, United States
‡Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States
§Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United
States
∥Advion, Inc., Ithaca, New York 14850, United States
S
* Supporting Information
ABSTRACT: Bexarotene (Targretin) is a retinoid X receptor (RXR)
agonist that has applications for treatment of T cell lymphoma and
proposed mechanisms of action in Alzheimer’s disease that have been the
subject of recent controversy. Carbon-11 labeled bexarotene ([11C-
carbonyl]4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid)
was synthesized using a Cu-mediated cross-coupling reaction employing
an arylboronate precursor 1 and [11C]carbon dioxide under atmospheric
pressure in 15 2% uncorrected radiochemical yield (n = 3), based on
[11C]CO2. Judicious choice of solvents, catalysts, and additives, as well as
precursor concentration and purity of [11C]CO2, enabled the preparation
of this 11C-labeled carboxylic acid. Formulated [11C]bexarotene was
isolated (>37 mCi) with >99% radiochemical purity in 32 min.
Preliminary positron emission tomography−magnetic resonance imaging revealed rapid brain uptake in nonhuman primate in
the first 75 s following intravenous administration of the radiotracer (specific activity >0.3 Ci/μmol at time of injection), followed
by slow clearance (Δ = −43%) over 60 min. Modest uptake (SUVmax = 0.8) was observed in whole brain and regions with high
RXR expression.
KEYWORDS: Bexarotene, targretin, positron emission tomography, carbon-11, carbon dioxide fixation, retinoid X receptor,
Alzheimer’s disease
vivo studies also suggest that bexarotene is acting on RXRs, and
etinoid X receptors (RXRs) function as key transcription
Rfactors inasmuch as they are the heterodimeric partners not directly on β-amyloid or by compromising the blood−brain
barrier.6 A transgenic mouse model of AD (Tg2576) exhibited
for most nuclear receptors, including retinoic acid receptors
reversal of cognitive and behavioral degradation with the
administration of bexarotene.5 These findings have proven to
be controversial, however, as several laboratories have struggled
to reproduce both the scope and magnitude of the in vivo
results.7−11 An additional caveat to these results is that the
bexarotene dose used to achieve these effects with sufficient
brain penetration (100 mg/kg/day, po) translates to about
three times that of the clinical dose.12 It is noteworthy that the
brain permeability of bexarotene has only been evaluated in
mouse models. Nevertheless, in advance of clinical trials and in
the absence of effective treatments, off-label demand for
bexarotene among patients and families suffering from AD
poses an ethical quandary.13 To help guide drug repositioning,
(RARs), peroxisome proliferator-activated receptors (PPARs),
vitamin D receptor, and thyroid hormone receptor.1 Retinoid X
ligands (e.g., 9-cis retinoic acid, Figure 1) are small lipophilic
hormones, which, when bound to a heterodimeric or a
homodimeric (i.e., RXR-RXR fusion) receptor, cause it to
bind a transcription complex on DNA and to promote
expression of target genes. RXRs are found ubiquitously and
differentially in mammalian cells, including in both glial and
neuronal brain tissue.2 Defective retinoid signaling and
deficiency of apolipoprotein E (ApoE) are closely associated
with Alzheimer’s disease (AD).3
Bexarotene (4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)-
ethenyl]benzoic acid, Figure 1), an FDA-approved selective
RXR agonist,4 has recently been demonstrated to induce
clearance of β-amyloid from the brains of murine AD models
through activation of the APOE gene, which is the most
indicative genetic risk factor for late-onset AD.5 In vitro and in
Received: February 10, 2014
Accepted: February 27, 2014
Published: February 27, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
Cyclotron generated carbon-11 is most commonly produced
in the form of [11C]carbon dioxide and is subsequently
converted to reactants such as [11C]methyl iodide or
[11C]methyl triflate. [11C]All-trans-retinoic acid has been
prepared using [11C]CH3I,16 and [11C]tamibarotene, another
retinoid-based therapeutic, has been prepared by a multistep
approach via [11C]CO (Figure 1).17 In the latter example,
methoxycarbonylation of arylboronates was achieved using a
Pd(0)-mediated reaction with [11C]CO, and the products were
subsequently hydrolyzed to generate [11C]carboxylic acids.17
This methodology requires both the conversion of cyclotron-
generated [11C]CO2 to [11C]CO prior to the labeling reaction
and cooling of the reaction mixture to −15 °C to improve
trapping of [11C]CO in organic solvents.
In contrast, we and others have been active in development
of new methodologies for direct fixation of [11C]CO2 in the
synthesis of complex radiolabeled molecules and tracers (for a
recent review see ref 18). Mild methodologies that rely on
organic bases to trap [11C]CO2 in solution prior to covalent
bond formation have been developed to access [11C]ureas,
[11C]carbamates, [11C]oxazolidinones, and [11C]carboxylic
acids.18 Carboxylation of Grignard or organolithium reagents
with [11C]CO2 represents a direct route to 11C-labeled
carboxylic acids. However, applications of this approach have
been limited to simple labeling precursors due to the high
reactivity of organometallic reagents. Rigorous exclusion of
atmospheric moisture and CO2 during storage and manipu-
lation is necessary to obtain labeled products with consistently
high radiochemical yields and specific activities. By way of
preparing [11C]carboxylic acids, a copper(I)-mediated carbox-
ylation of arylboronates using [11C]CO2 and KF/crypt-222
additives was recently reported.19
Figure 1. Top: Structures of RAR-selective agonists all-trans-retinoic
acid and tamibarotene (Am 80) (for carbon-11 isotopologues see refs
16 and 17). Bottom: Structures of RXR-selective agonists 9-cis-retinoic
acid and bexarotene.
there is an urgent need to evaluate the brain pharmacokinetics
of this pharmaceutical in higher species.
Carbon-11 (11C; t1/2 = 20.4 min) labeled radiotracers are
used extensively to study pharmacokinetics of drug compounds
in vivo via positron emission tomography (PET), a sensitive
and noninvasive molecular imaging modality.14,15 In the present
study, we describe an efficient synthesis of [11C]bexarotene by
rapid Cu-mediated [11C]CO2-fixation using an arylboronate
precursor, thereby preparing the isotopologue at the carbonyl
position of the corresponding carboxylic acid. We further
carried out a preliminary PET−magnetic resonance (PET−
MR) imaging study in a nonhuman primate with this
radiotracer to determine brain uptake and biodistribution of
this labeled drug.
The synthesis of [11C]bexarotene was achieved by the
reaction of [11C]CO2 with boronic ester precursors 1 (Table
1), without intermediate chemical transformations. Pinacol
arylboronic ester 1a was synthesized in four steps (36% overall
yield) from toluene.20 [11C]CO2 was extracted from cyclotron
Table 1. Optimization of Reaction Conditions for the Synthesis of [11C]Bexarotene
a
b
entry
[B]
catalyst
additive
base
TMEDA
solvent
temp (°C)
conv (%)
1
2
Bpin (1a)
CuI
KF/crypt-222
KF/crypt-222
KF/crypt-222
KF/crypt-222
TBAT
DMF
DMF
DMF
DMF
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
100
100
100
100
100
100
100
100
120
90
9
NR
NR
22
1a
CuI
TMEDA, DBU
TMEDA, BEMP
TMEDA
3
1a
CuI
4
1a
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
5
1a
TMEDA
25
6
1a
TBAT
TMEDA
34
7
B(OH)2 (1b)
TBAT
TMEDA
NR
NR
8
8
BF3K (1c)
TBAT
TMEDA
9
1a
1a
1a
TBAT
TMEDA
10
TBAT
TMEDA
18
c
11
TBAT
TMEDA
100
100
100
39
d
12
1a
d
TBAT
TMEDA
86
e
13
1a
TBAT
TMEDA
88
a
b
Unless otherwise noted, precursor concentration was 0.03 M. Determined by radioHPLC integration of product peaks and unreacted [11C]CO2
c
d
e
complexes. No other radioactive products were observed. Reaction was heated for 10 min. Precursor concentration was 0.15 M. Added butylated
hydroxytoluene (BHT, 10 mol % relative 1a). Bpin, pinacolatoboron
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ACS Medicinal Chemistry Letters
Letter
target gas in a liquid N2-cooled trap and subsequently bubbled
into a reactor vial containing the labeling precursor 1, solvent,
catalyst, additives, and fixating base. Preliminary experiments
revealed that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2-
tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-dia-
zaphosphorine (BEMP), though efficient for trapping
[11C]CO2 in solution,21,22 were incompatible with the Cu-
mediated coupling (Table 1, entries 1−3). Using N,N,N′,N′-
tetramethylethylenediamine (TMEDA) as base and ligand for
the metal center, modest conversion was observed. We found
that the more soluble copper(I) thiophene-2-carboxylate
(CuTC) was an improvement over CuI, and replacing KF/
crypt-222 with crystalline and bench-stable tetrabutylammo-
nium difluorotriphenylsilicate (TBAT) led to more consistent
reaction outcomes (entry 5). To improve precursor and catalyst
solubility the solvent was changed from N,N-dimethylforma-
mide (DMF) to N-methylpyrrolidinone (NMP) (entry 6).
Radiochemical conversion remained suboptimal, however, so
we turned to alternative precursors to improve on the pinacol
ester 1a.
coincident with initiation of a 60 min dynamic brain PET
acquisition and followed by abdominal and thoracic static PET
scans to determine biodistribution. [11C]Bexarotene rapidly
crossed the BBB and reached a maximum whole brain activity
of 0.8 SUV (standardized uptake value) at approximately 90 s
post injection (Figure 2). A second, slightly lower peak was
To our dismay, boronic acid 1b and potassium trifluor-
oborate 1c, each prepared in a single step from 1a, were
unreactive in this context (entries 7 and 8). Higher temper-
atures were unable to afford greater conversion, and longer
reaction times did not prove to be fruitful (entries 9−11).
Significant improvements were realized by increasing the
concentration of precursor in the reaction mixture from 0.03
to 0.15 M, which led to high radiochemical conversion to
product (86% relative unreacted [11C]CO2 and solvates, entry
12). As the added precursor did not threaten to complicate
purification of [11C]bexarotene, we concluded that the optimal
conditions for radiolabeling were 1a (0.15 M), CuTC (0.015
M), TBAT (0.02 M), TMEDA (1.33 M), NMP, and [11C]CO2,
heated for 5 min at 100 °C at atmospheric pressure.
Figure 2. Nonhuman primate PET imaging: (A) Summed image 15−
60 min post tracer injection. (B) Time−activity curve for whole-brain
and selected brain regions. For ROI placement, see Supporting
Information. Occ Ctx, occipital cortex; Pu, putamen; Crb Ctx, cerebral
cortex; Th, thalamus; CGS, cingulate sulcus; SUV, standardized uptake
value.
As several oxidation states and mechanisms are available to
copper-catalyzed coupling reactions, we sought to gain insight
into the operative mode of reactivity. Reactions were run at our
optimized conditions for preparation of [11C]bexarotene with
the addition of radical inhibitor butylated hydroxytoluene
(BHT). At substoichiometric (10 mol % relative to precursor
1a) concentrations of BHT, little change in radiochemical
conversion (88%, Table 1, entry 13) was observed compared to
our optimized conditions. This evidence supports nonradical
mechanisms for synthesis of [11C]bexarotene by copper-
mediated [11C]CO2-fixation.
Based on the optimized conditions described above, the
reaction was scaled and [11C]bexarotene was isolated and
formulated for preclinical imaging studies. Briefly, after
bubbling [11C]CO2 into the reaction mixture, the vial was
sealed and heated to 100 °C for 5 min, after which the reaction
was quenched with HPLC mobile phase (80% CH3CN, 20%
0.1 M NH4·HCO2(aq)) and purified by semipreparative HPLC.
Reformulation of the product HPLC fraction into ethanolic
saline and sterile filtration provided [11C]bexarotene in
injectable form. The non-decay-corrected isolated radio-
chemical yield (RCY) based on [11C]CO2 was 15 2%, after
32 3 min synthesis time (n = 3). Radiochemical purity was
>99% for each synthesis.
reached near 8 min postinjection. Regional brain distribution
was fairly uniform, with greater uptake in the occipital cortex,
putamen, and thalamus. Likewise, RXR distribution is known to
be enriched in the rhombencephalon and the basal ganglia.2
The logD7.4 of [11C]bexarotene was measured to be 3.68.23
which likely accounts for the slow clearance (Δ = −43%)
observed over 60 min. Abdominal and thoracic PET data
revealed high activity in the heart (>35 SUV), gall bladder (>20
SUV), and small intestine (>50 SUV) and accumulation in the
liver, consistent with high levels of RXR expression in the heart
and liver, as well as biliary metabolism and excretion.24,25 To
our knowledge this work represents the first [11C]carboxylic
acid radiotracer synthesized from [11C]CO2 suitable for use in
PET imaging studies without using organometallic precursors.
In summary, we have optimized a copper-mediated
[11C]CO2-fixation reaction for the synthesis of [11C]-
bexarotene. Cu-mediated [11C]carboxylation of arylboronates
is an efficient and direct route to [11C]carboxylic acids that
obviates the need for preformed and unstable organometallic
reagents or multistep synthetic strategies, and should be
broadly applicable toward the synthesis of 11C-labeled
carboxylic acids and retinoid-based imaging agents. Preclinical
PET imaging using [11C]bexarotene demonstrated a reasonable
brain uptake in nonhuman primate and shows regional
distribution in line with known RXR distribution. [11C]-
Bexarotene has potential to be used for pharmacokinetic and
dose response studies and warrants further imaging studies that
could facilitate clinical translation.
To determine the in vivo distribution and brain permeability
of [11C]bexarotene, we performed PET imaging in an
isoflurane-anesthetized baboon (3 y.o., 16.4 kg, female).
Bolus iv administration of [11C]bexarotene (4.14 mCi; with
specific activity of 310 mCi/μmol at time of injection) was
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ACS Medicinal Chemistry Letters
Letter
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EXPERIMENTAL PROCEDURES
■
Radiosynthesis of [11C]Bexarotene. Prior to end-of-bombard-
ment, a septum-sealed vial was charged with pinacol arylboronate 1a
(12.9 mg), CuTC (1.0 mg), TBAT (2.7 mg), TMEDA (60 μL), and
NMP (300 μL) and agitated to ensure complete solubility of its
contents. Cyclotron-generated [11C]CO2 was trapped in a short metal
coil, cooled in a liquid N2 bath, and then bubbled into the reaction
mixture with He(g) at 10 mL/min. When radioactivity had peaked, gas
flow was halted, and the vial was sealed and heated to 100 °C for 5
min. The reaction mixture was then quenched with 1 mL of HPLC
mobile phase (80% CH3CN, 20% 0.1 M NH4·HCO2(aq)) and purified
by semipreparative HPLC.
(7) Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R.
Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid
and Reverse Deficits in AD Mouse Models”. Science 2013, 340, 924−
924.
(8) Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt,
D. R.; Golde, T. E.; Felsenstein, K. M. Comment on “ApoE-Directed
Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD
Mouse Models”. Science 2013, 340, 924−924.
ASSOCIATED CONTENT
* Supporting Information
Full experimental details and characterization data for organic
and radiochemical procedures, PET imaging studies, and logD
determination. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(9) Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck,
B.; Borgers, M.; Gijsen, H.; Moechars, D.; Mercken, M.; Kemp, J.;
D’Hooge, R.; De Strooper, B. Comment on “ApoE-Directed
Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD
Mouse Models”. Science 2013, 340, 924−924.
AUTHOR INFORMATION
Corresponding Author
*Tel: +1 617 643 4736. Fax: +1 617 726 6165. E-mail: liang.
steven@mgh.harvard.edu and vasdev.neil@mgh.harvard.edu.
■
(10) Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.;
Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; Tanzi, R.
E.; Vassar, R.; Sisodia, S. S. Comment on “ApoE-Directed
Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD
Mouse Models”. Science 2013, 340, 924−924.
Funding
B.H.R. is a Natural Sciences and Engineering Research Council
of Canada (NSERC) Postdoctoral Fellow.
Notes
The authors declare no competing financial interest.
(11) Landreth, G. E.; Cramer, P. E.; Lakner, M. M.; Cirrito, J. R.;
Wesson, D. W.; Brunden, K. R.; Wilson, D. A. Response to Comments
on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and
Reverse Deficits in AD Mouse Models”. Science 2013, 340, 924−924.
(12) Corbett, A.; Pickett, J.; Burns, A.; Corcoran, J.; Dunnett, S. B.;
Edison, P.; Hagan, J. J.; Holmes, C.; Jones, E.; Katona, C. Drug
Repositioning for Alzheimer’s Disease. Nat. Rev. Drug Discovery 2012,
11, 833−846.
ACKNOWLEDGMENTS
■
We thank David F. Lee, Jr., Dr. Ronald Moore, Nathan
Schauer, and Ehimen Aisaborhale for assistance with radio-
isotope production and Dr. Ronald Borra, Shirley Hsu, Grae
Arabasz, and Helen Deng for assistance with PET-MR imaging
experiments.
(13) Lowenthal, J.; Hull, S. C.; Pearson, S. D. The Ethics of Early
EvidencePreparing for a Possible Breakthrough in Alzheimer’s
Disease. N. Engl. J. Med. 2012, 367, 488−490.
DEDICATION
■
(14) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular
Imaging with PET. Chem. Rev. 2008, 108, 1501−1516.
This article is dedicated to Professor James H. Thrall on the
occasion of his retirement as Chair of Radiology, Massachusetts
General Hospital and Harvard Medical School.
(15) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Synthesis of 11C,
18F, 15O, and 13N Radiolabels for Positron Emission Tomography.
Angew. Chem., Int. Ed. 2008, 47, 8998−9033.
ABBREVIATIONS
■
(16) Suzuki, M.; Takashima-Hirano, M.; Watanabe, C.; Ishii, H.;
Sumi, K.; Koyama, H.; Doi, H. Synthesis of [11C]all-trans-Retinoic
Acid via an Alkenylboron Precursor by Pd(0)-Mediated Rapid C-
[11C]methylation. J. Labelled Compd. Radiopharm. 2011, 54, S92.
(17) Takashima-Hirano, M.; Ishii, H.; Suzuki, M. Synthesis of
[11C]Am80 via Novel Pd(0)-Mediated Rapid [11C]Carbonylation
Using Arylboronate and [11C]Carbon Monoxide. ACS Med. Chem.
Lett. 2012, 3, 804−807.
ApoE, apolipoprotein E; BBB, blood−brain barrier; CNS,
central nervous system; CuTC, copper thiophene-2-carbox-
ylate; crypt-222, 2.2.2-cryptand; DMF, N,N-dimethylforma-
mide; NMP, N-methyl-2-pyrolidinone; PET, positron emission
tomography; PPAR, peroxisome proliferator-activated receptor;
RAR, retinoic acid receptor; RXR, retinoid X receptor; SUV,
standardized uptake value; TBAT, tetrabutylammonium
triphenyldifluorosilicate; TMEDA, N,N,N′,N′-tetramethylethy-
lenediamine
(18) Rotstein, B. H.; Liang, S. H.; Holland, J. P.; Collier, T. L.;
Hooker, J. M.; Wilson, A. A.; Vasdev, N. 11CO2 Fixation: A
Renaissance in PET Radiochemistry. Chem. Commun. 2013, 49,
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Convenient Entry to 11C-Labeled Carboxylic Acids, Esters, and
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