Synthesis of [11C]Am80 via novel Pd(0)-mediated rapid [ 11C]carbonylation using arylboronate and [11C]Carbon Monoxide

Article abstract of DOI:10.1021/ml300160w

¹¹C-labeled methylbenzoates [¹¹C]4a-d were synthesized using Pd(0)-mediated rapid cross-coupling reactions employing [ ¹¹C]carbon monoxide and arylboronic acid neopentyl glycol esters 3a-d under atmospheric pressure in methanol-dimethylformamide (MeOH-DMF), in radiochemical yields of 12 ± 5-26 ± 13% (decay-corrected based on [¹¹C]O). The reaction conditions were highly favorable for the synthesis of [¹¹C]Am80 ([¹¹C]2) and [¹¹C]methyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)benzoate ([¹¹C]2-Me) using 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-(5,5,8, 8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide (5), both of which produced a decay-corrected radiochemical yield (RCY) of 26 ± 13%, with >99% radiochemical purity and an average specific radioactivity of 44 GBq/μmol. The yields of [¹¹C]4a, [¹¹C]2-Me, and [ ¹¹C]2 were improved by the use of a 2-fold excess of the solvents and reagents under the same conditions to give respective yields of 66 ± 8, 65 ± 7, and 48 ± 2%.

Full text of DOI:10.1021/ml300160w

Letter
pubs.acs.org/acsmedchemlett
Synthesis of [11C]Am80 via Novel Pd(0)-Mediated Rapid [11C]
Carbonylation Using Arylboronate and [11C]Carbon Monoxide
Misato Takashima-Hirano, Hideki Ishii, and Masaaki Suzuki*
RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
S
* Supporting Information
ABSTRACT: 11C-labeled methylbenzoates [11C]4a−d were synthesized
using Pd(0)-mediated rapid cross-coupling reactions employing [11C]
carbon monoxide and arylboronic acid neopentyl glycol esters 3a−d under
atmospheric pressure in methanol−dimethylformamide (MeOH−DMF),
in radiochemical yields of 12 5−26 13% (decay-corrected based on
[11C]O). The reaction conditions were highly favorable for the synthesis of
[11C]Am80 ([11C]2) and [11C]methyl 4-((5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2-yl)carbamoyl)benzoate ([11C]2-Me) using 4-(5,5-
dimethyl-1,3,2-dioxaborinan-2-yl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahy-
dronaphthalen-2-yl)benzamide (5), both of which produced a decay-
corrected radiochemical yield (RCY) of 26
13%, with >99%
radiochemical purity and an average specific radioactivity of 44 GBq/
μmol. The yields of [11C]4a, [11C]2-Me, and [11C]2 were improved by the
use of a 2-fold excess of the solvents and reagents under the same conditions to give respective yields of 66 8, 65 7, and 48
2%.
KEYWORDS: Am80, tamibarotene, methoxycarbonylation, [11C]carbon monoxide
well-known as a useful drug for differentiation therapy for acute
ositron emission tomography (PET), which uses specific
Pprobes radiolabeled with short-lived positron-emitting promyelocytic leukemia (APL).4 The binding of ATRA to RAR
causes degradation of the promyelocytic leukemia protein
(PML)/RAR fusion protein, resulting in terminal differ-
entiation of APL.5 Although ATRA induces complete remission
(CR) in the majority of patients, relapse resulting from ATRA-
resistant cells has frequently been observed during maintenance
therapy with ATRA.6 The synthetic retinoid Am80 (2)7 is an
active agent for APL patients who have relapsed from ATRA-
induced CR8 and binds tightly to RAR-α but does not bind
with the RAR-γ receptor, which is the major RAR in the dermal
epithelium.9 Moreover, ATRA and Am80 induce strong
suppression of interleukin (IL)-6 production in IL-1-stimulated
synovial fibroblasts. Therefore, both of these drugs may be
applicable in therapies for psoriasis, multiple myeloma, and
rheumatoid arthritis, although their exact function is still
unknown.10 Accordingly, we have sought to synthesize 11C-
labeled Am80 and its ester derivative for comparison of the
biodistribution and pharmacodynamics of these compounds
with those of [11C]ATRA (1).
radionuclides, is one of the most powerful noninvasive tools
for modern clinical diagnosis of diseases such as cancer, heart
disease, and Alzheimer's disease.1 PET also allows for
microdose clinical assessment of drug distribution and action
at the molecular level in living systems. Because most biological
compounds contain carbon atoms, the development of
synthetic methods that enable 11C-radionuclide labeling is an
important requirement for PET probe synthesis. However, the
preparation of 11C-radiolabeled probes is hampered by certain
challenges because of the short half-life (t1/2 = 20.4 min) of 11C;
consequently, rapid and efficient methods remain necessary. In
this context, we have developed several Pd(0)-mediated rapid
11C-labeling reactions,2 which have recently been applied to the
synthesis of [11C]all-trans-retinoic acid3 ([11C]ATRA, 1)
(Figure 1). ATRA (1), a member of the retinoid family, is a
ligand for the retinoic acid receptors (RAR-α, -β, and -γ) and is
The straightforward synthesis of [11C]2 involves carbox-
ylation of the corresponding Am80 precursor at the 4′-
position.11 Classically, carboxylation of the corresponding
Grignard or organolithium reagents with [11C]carbon dioxide
([11C]O2) represents the simplest method. However, because
Received: June 20, 2012
Accepted: August 16, 2012
Published: August 16, 2012
Figure 1. Structures of ATRA (1), [11C]ATRA (1), Am80 (2), and
[11C]Am80 ([11C]2).
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
Table 1. Examination of Methoxy[11C]carbonylation
Reaction
of the high sensitivity of these organometallic reagents to traces
of moisture and the non-negligible contamination by
atmospheric carbon dioxide, maintaining a constant high
radiochemical yield and high specific radioactivity is generally
very difficult.12 On this basis, Pike et al. have very recently
reported [11C]carboxylation using the copper(I)-mediated
reaction of an arylboronate and [11C]O2 in the presence of
KF/Kryptofix 222.13 Alternatively, carbonylation using a
transition metal in conjunction with [11C]carbon monoxide
([11C]O) does not require such dry conditions and is applicable
even in the presence of a wide range of functional groups.
Moreover, the presence of [12C]O in the atmosphere is
generally negligible; thus, [11C]carbonyl compounds may be
obtained with high specific radioactivity.
However, as a result of the low solubility of CO in most
common solvents,14 carbonylation is still typically performed by
a general organic synthesis method using [12C]O with a Pd
catalyst under high pressure for long periods.15 Recently,
Yamamoto et al. elaborated the methoxycarbonylation of an
arylboronic acid or ester, which proceeds under atmospheric
pressure at ambient temperature for several hours, using a
catalytic amount of Pd(II) acetate/triphenylphosphine [Pd-
(OAc)2/PPh3] in the presence of p-benzoquinone (pbq) as a
stoichiometric oxidant in methanol (MeOH) solvent.16
temperature
a
entry
1
conditions
solvent
trap
reaction RCY (%)
1. CuCl,
K[Tp*],
THF
THF−MeOH−
DMF (10:1:4)
rt
rt
rt
rt
100 °C <1
2. Pd(PPh3)4,
PPh3
2
3
4
1. CuCl,
K[Tp*],
THF
THF−MeOH−
DMF (10:1:4)
100 °C <1
2. Pd(OAc)2,
P(o-tolyl)3
1. CuCl,
K[Tp*],
THF
THF−MeOH−
DMF (10:1:4)
rt
rt
<1
3
2. Pd(PPh3)4,
PPh3
1. CuCl,
K[Tp*],
THF
THF−MeOH−
DMF (10:1:4)
The incorporation of [11C]O via Pd(0)-mediated rapid cross-
coupling has been extensively developed over the last two
decades.12 To overcome the solubility problem, most of these
reactions have been conducted with the use of special
equipment such as high-pressure vessels,17 recirculation
systems,18 and microfluidic reactor systems19 to facilitate the
incorporation of [11C]O into the reaction. Chemical [11C]O-
fixation techniques have recently been developed as an
alternative, with the aim of increasing the concentration of
[11C]O in solution.20 The development of the advanced
technique of Pd(0)-mediated [11C]carbonylation has enabled
the execution of the reaction under atmospheric pressure using
xenon as a carrier gas, an aryl iodide as a substrate, and an
amine and an alcohol as trapping nucleophiles for the synthesis
of 11C-incorporated amides, ureas, and carbamates.21 Along a
similar line, we have made an attempt to explore a novel
reaction that is promoted under mild and advantageous
conditions (ambient temperature and atmospheric pressure)
and is adaptable to the synthesis of [11C]Am80 ([11C]2). In
this paper, we described the efficient syntheses of 11C-labeled 2
and its ester derivative via novel, rapid Pd(0)-mediated
methoxy[11C]carbonylation using arylboronate 5 and [11C]O
using conventional helium gas as a [11C]O carrier.
2. Pd(OAc)2,
PPh3, pbq
5
6
Pd(OAc)2,
PPh3, pbq
MeOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2
Pd(OAc)2,
PPh3, pbq
MeOH−DMSO
(1:1)
<1
7
Pd(OAc)2,
PPh3, pbq
MeOH−THF
(1:1)
<1
8
Pd(OAc)2,
PPh3, pbq
MeOH−DMF
(1:1)
25
9
Pd(OAc)2,
PPh3, pbq
MeOH−DMF
(1:1)
−15 °C
−15 °C
−15 °C
−15 °C
26 13,
b
66
8
10
11
12
Pd(OAc)2,
PPh3
MeOH−DMF
(1:1)
20 10
Pd(OAc)2,
PPh3, CsF
MeOH−DMF
(1:1)
<5
4
Pd2(dba)3,
P(o-tolyl)3
MeOH−DMF
(1:1)
a
Isolated RCY based on trapped [11C]O after purging. Mean value
b
range for n = 3, determined by isolated yield. Two-fold excesses of
solvents and reagents were used.
Yamamoto's methoxycarbonylation conditions16 were then
introduced, in combination with the [11C]O-fixation, to shorten
the reaction time. However, unexpectedly, the cross-coupling
product was also obtained in only very low yield (Table 1, entry
4). Performing the reaction under Yamamoto's original
methoxycarbonylation conditions (the use of only MeOH
solution) also gave a similarly poor result (Table 1, entry 5). A
solvent mixture containing dimethyl sulfoxide (DMSO) or
tetrahydrofuran (THF) with MeOH was also ineffective as a
reaction medium. Here, it was surprisingly found that rapid
methoxy[11C]carbonylation was facilitated simply by using the
combination of MeOH and dimethylformamide (DMF), giving
the product [11C]4a in 25% decay-corrected radiochemical
yield (RCY) (Table 1, entry 8). Furthermore, [11C]O trapping
was more efficient at lower temperature (−15 °C), furnishing
[11C]4a in 26 13% RCY (Table 1, entry 9). The use of a 2-
fold excess of the solvents and reagents under the same
conditions greatly improved the RCY, up to 65 7% (Table 1,
The synthesis of [11C]benzoic acid methyl ester ([11C]4a)
was undertaken, using the reaction of phenylboronic acid 2,2-
dimethylpropane-1,3-diol ester (3a) and [11C]O as a model
reaction (Table 1). First, the [11C]O-fixation method20 was
conducted in the presence of MeOH at 100 °C. The desired
product was obtained in very low yield (Table 1, entry 1).
Changing the phosphine ligand of the Pd complex to the bulky
arylphosphine group with the objective of enhancing the
reactivity also gave the same poor yield (Table 1, entry 2).
Under these [11C]O-fixation reaction conditions, it was found
that as soon as the reaction temperature increased to 100 °C,
[11C]O gas was vigorously emitted from the reaction vessel.
Therefore, further trials of the reaction were performed at a
lower temperature. At ambient temperature, the original
[11C]O-fixation reaction20 yielded the desired product in very
low yield (Table 1, entry 3). With this information in mind,
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ACS Medicinal Chemistry Letters
Letter
Scheme 1. One-Pot Synthesis of [11C]Am80 ([11C]2)
entry 9). In contrast, the removal of pbq greatly decreased the
yield (Table 1, entry 10). Interestingly, the addition of CsF
instead of pbq, with the aim of activating the carbon−boron
bond, retarded the reaction strongly (Table 1, entry 11). The
use of the bulky arylphosphine was also not effective in the
reaction (Table 1, entry 11). Thus, it was concluded that the
reaction was effectively promoted by a combination of the
[11C]O trap at −15 °C, followed by reaction at ambient
temperature under atmospheric pressure using conventional
helium carrier gas.21 To confirm the generality of the reaction,
we further examined the methoxy[11C]carbonylation reaction
using several p-substituted neopentyl glycol arylboronic acid
esters ([11C]4b−d); the results are summarized in Table 2.
Table 2. Generality of the Methoxy[11C]carbonylation
Conditions
rate, 1 mL/min; UV detection, 254 nm; and retention time, 8.2
min). The radiochemical purity was greater than 99%. The use
of 2-fold excesses of solvents and reagents under the same
conditions outlined above improved the yield of [11C]2 to 48
2% (n = 3) RCY with 99% radiochemical purity.
In summary, Pd(0)-mediated rapid methoxy-[11C]-
carbonylation was successfully achieved under mild conditions
using a phenylboronic acid neopentyl ester as a model
precursor, and the reaction conditions were highly applicable
to the synthesis of [11C]esters([11C]4a−d) and [11C]Am80
methyl ester ([11C]2-Me) and, eventually, the corresponding
acid 2 by subsequent rapid hydrolysis. The novel PET probe 2
and its methyl ester will be used as specific PET probes for
investigating the receptor functions involved in serious diseases
such as APL in in vivo vital systems.22 The rapid methoxy-
[11C]carbonylation should be applicable not only to the
synthesis of [11C]2 but also to a variety of biologically
important [11C]carboxylic acids and their methyl esters.
Furthermore, this first example of a simple methoxy[11C]-
carbonylation method at ambient temperature and under
atmospheric pressure should be highly attractive to organic
chemists who desire to synthesize [11C]carbonyl compounds
such as 11C-labeled amides, ureas, isocyanates, oxazoles, and
carbamates directly.23
a
entry
R
pbq
RCY (%)
b
1
2
H (3a)
1
0
1
0
1
0
1
0
1
0
26 13, 66
20 10
8
H (3a)
3
OMe (3b)
OMe (3b)
F (3c)
27
3
5
3
7
4
4
6
5
25
6
6
F (3c)
7
COOEt (3d)
COOEt (3d)
CONHR2 (5)
CONHR2 (5)
12
<1
8
b
9
27 10, 65
<1
7
([11C]2-Me)
10
a
Isolated RCY based on trapped [11C]O after purging. Mean value
range for n = 3, determined by isolated yield. Two-fold excess
b
amounts of solvents and reagents were used.
In all cases, the methoxy[11C]carbonylation proceeded with
moderate yields without any effects of electron-withdrawing
(Table 2, entries 5 and 7) or electron-donating groups (Table
2, entry 3). In these reactions, pbq greatly influenced the
reaction efficiency, and its absence resulted in much lower
yields of the product. The improved conditions shown in Table
1, entry 9, were also effective for the reaction of 5, as shown in
Table 2, entry 9. It is likely that the reaction efficiency of entries
3, 5, and 7 could also be enhanced by using the same improved
conditions. Finally, the conditions shown in Table 2, entry 9,
were applied to the synthesis of [11C]Am80 ([11C]2). The
synthesis was conducted in a one-pot manner without isolation
of [11C]2-Me. Thus, after methoxy[11C]carbonylation of
boronate precursor 5, [11C]2-Me underwent rapid hydrolysis
with potassium hydroxide at 80 °C over 2 min to afford the
desired acid [11C]2 in 26 13% radiochemical yield based on
[11C]O (Scheme 1). The total synthesis time for formulation of
[11C]2 was 36 min. The isolated radioactivity was as high as 1.4
GBq at the end of the synthesis, and the specific radioactivity
was up to 44 GBq/μmol. The chemical identity of [11C]Am80
was confirmed via coinjection analytical high-performance
liquid chromatography (HPLC) using an authentic Am80
(column: Waters XBridge, 4.6 mm i.d. × 150 mm, 5 mm;
mobile phase, CH3CN:0.2% HCOOH in water = 60:40; flow
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental methods for the preparation of 5, generation of
[11C]O, standard procedure for rapid methoxy[11C]-
carbonylation, and synthesis of [11C]Am80 ([11C]2). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +81-78-304-7130. E-mail: suzuki.masaaki@riken.jp.
■
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
PET, positron emission tomography; ATRA, all-trans-retinoic
acid; CR, complete remission; PML, promyelocytic leukemia
protein; MeOH, methanol; DMF, dimethylformamide; RAR,
retinoic acid receptors; APL, acute promyelocytic leukemia;
DMSO, dimethyl sulfoxide; THF, tetrahydrofuran; [11C]O2,
[11C]carbon dioxide; [11C]O, [11C]carbon monoxide; pbq, p-
benzoquinone; RCY, decay-corrected radiochemical yield
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ACS Medicinal Chemistry Letters
Letter
Emission Tomography 11C-Radiolabeling. Angew. Chem., Int. Ed. 2007,
46, 2875−2878.
(20) Kealey, S.; Plisson, C.; Collier, T. L.; Long Nicholas, J.;
Husbands, S. M.; Martarello, L.; Gee, A. D. Microfluidic reactions
using [11C]carbon monoxide solutions for the synthesis of a positron
emission tomography radiotracer. Org. Biomol. Chem. 2011, 9, 3313−
3319 and references therein.
(21) Eriksson, J.; Johan, H.; Windhorst, A. D. Transition metal
mediated synthesis using [11C]CO at low pressureA simplified
method for 11C-carbonylation. J. Labelled Compd. Radiopharm. 2012,
55, 223−228.
(22) Both acid and its ester would be usefyl as PET probes,
particularly for the study of a behavior in the brain because of the
different permeability through the blood−brain barrier (BBB). See the
following reference Takashima-Hirano, M.; Shukuri, M.; Takashima,
T.; Goto, M.; Wada, Y.; Watanabe, Y.; Onoe, H.; Doi, H.; Suzuki, M.
General method for the (11)C-labeling of 2-arylpropionic acids and
their esters: Construction of a PET tracer library for a study of
biological events involved in COXs expression. Chem.Eur. J. 2010,
16, 4250−4258.
REFERENCES
■
(1) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular imaging
with PET. Chem. Rev. 2008, 108, 1501−1516 and references therein.
(2) Hosoya, T.; Sumi, K.; Doi, H.; Wakao, M.; Suzuki, M. Rapid
methylation on carbon frameworks useful for the synthesis of 11CH3-
incorporated PET tracers: Pd(0)-mediated rapid coupling of methyl
iodide with an alkenyltributylstannane leading to a 1-methylalkene.
Org. Biomol. Chem. 2006, 4, 410−415 and references therein.
(3) 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.
(4) Breitman, D. R.; Selonick, S. E.; Collins, S. J. Different
mechanisms account for the relative resistance of KG-1 and HL-60
cell lines to retrovirus infection. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
2936−2940.
(5) He, L. Z.; Tribiloli, C.; Ribi, R.; Peruzzi, D.; Pelicci, P. G.;
Soaresn, V.; Cattoretti, G.; Pandolfi, P. P. Acute leukemia with
promyelocytic features in PML/RARα transgenic mice. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 5302−5307.
(6) Ohno, R.; Yoshida, H.; Fuutami, H. Multi-institutional study of
all-trans-retinoic acid as a differentiation therapy of refractory acute
promyelocytic leukemia. Leukemia 1993, 7, 1722−1727.
(23) Recently, azidocarbonylation has been reported, which is
applicable for the synthesis of isocyanates, amides, and oxazoles:
Miloserdov, F. M.; Grushin, V. V. Palladium-Catalyzed Aromatic
Azidocarbonylation. Angew. Chem., Int. Ed. 2012, 51, 3668−3672.
(7) Hashimoto, Y.; Kagechika, H.; Shudo, K. Expression of Retinoic
Acid Receptor Genes and the Ligand-Bind Selectivity of Retinoic Acid
Receptors. Biochem. Biophys. Res. Commun. 1990, 166, 1300.
(8) Tobita, T.; Takeshita, A.; Kitamura, K.; Ohnishi, K.; Yanagi, M.;
Hiraoka, A.; Karasuno, T.; Takeuchi, M.; Miyawaki, S.; Ueda, R.;
Naoe, T.; Ohno, R. Treatment with a new synthetic retinoid, Am80, of
acute promyelocytic leukemia relapsed from complete remission
induced by all-trans retinoic acid. Blood 1997, 90, 967−973.
(9) Zelent, A.; Krust, A.; Petkovich, M.; Kastner, P.; Chambon, P.
Cloning of murine α and β retinoic acid receptors and a novel receptor
gamma predominantly expressed in skin. Nature 1989, 339, 714−717.
(10) Fukasawa, H.; Kagechika, H.; Shudo, K. Retinoid therapy for
autoimmune diseases. Jpn. J. Clin. Immunol. 2006, 29, 114−126.
(11) Hashimoto, S.; Mizobuchi, M.; Kuroda, T.; Okabe, H.; Mizojiri,
K.; Takahashi, S.; Kikuchi, J.; Terui, Y. Biotransformation of a new
synthetic retinoid, 4-[(5,6,7, 8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl)carbamoyl] benzoic acid (Am-80), in the rat. Structure
elucidation of the metabolites by mass and nmr spectrometry.
Xenobiotica 1994, 24, 1177−1193.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper published ASAP on August 27, 2012 with
typographical errors in the title and keywords. The corrected
version was reposted on August 31, 2012.
(12) Langstrom, B.; Itsenko, O.; Rahman, O. [11C]Carbon
̊
̈
monoxide, a versatile and useful precursor in labelling chemistry for
PET-ligand development. J. Labelled Compd. Radiopharm. 2007, 50,
794−810 and references therein.
(13) Riss, R. J.; Lu, S.; Telu, S.; Aigbirhio, F. I.; Pike, V. W. CuI-
Catalyzed 11C Carboxylation of Boronic Acid Esters: A Rapid and
Convenient Entry to 11C-Labeled Carboxylic Acids, Esters, and
Amides. Angew. Chem., Int. Ed. 2012, 51, 2698−2702.
(14) Fogg, P. G. T.; Gerrard, W. Solubility of Gases in Liquids: A
Critical Evaluation of Gas/Liquid Systems in Theory and Practice; J.
Wiley: Chichester; New York, 1991.
(15) Tsuji, J. Transition Metal Reagetns and Catalysts: Innovations in
Organic Synthesis; John Wiley & Sons: Chichester, United Kingdom,
2000; pp 85−92.
(16) Yamamoto, Y. The First General and Selective Palladium(II)-
Catalyzed Alkoxycarbonylation of Arylboronates: Interplay among
Benzoquinone-Ligated Palladium(0) Complex, Organoboron, and
Alcohol Solvent. Adv. Synth. Catal. 2010, 352, 478−492.
(17) Itsenko, O.; Kihlberg, T.; Langstrom, B. Labeling of aliphatic
̊
̈
carboxylic acids using [11C]carbon monoxide. Nat. Protoc. 2006, 1,
798−802.
(18) Lidstrom, P.; Kihlberg, T.; Langstrom, B. [11C]Carbon
̈
̊
̈
monoxide in the palladium-mediated synthesis of 11C-labelled ketones.
J. Chem. Soc., Perkin Trans. 1 1997, 2701−2706.
(19) Miller, P. W.; Long, N. J.; de Mello, A. J.; Vilar, R.; Audrain, H.;
Bender, D.; Passchier, J.; Gee, A. Rapid Multiphase Carbonylation
Reactions by Using a Microtube Reactor: Applications in Positron
807
dx.doi.org/10.1021/ml300160w | ACS Med. Chem. Lett. 2012, 3, 804−807