Efficient 11C-carbonylation of isolated aryl palladium complexes for PET: Application to challenging radiopharmaceutical synthesis

Article abstract of DOI:10.1021/ja511441u

We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric reagents in carbonylation reactions with ¹¹CO to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first ¹¹C-carbonyl labeling of an approved PET tracer, [¹¹C]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [¹¹C]olaparib and [¹¹C]JNJ 31020028, were efficiently labeled in this manner. The technique distinguishes itself from existing methods by the markedly improved purity profiles of the tracer molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to other ¹¹C-labeling strategies.

Full text of DOI:10.1021/ja511441u

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Article
Efficient 11C-Carbonylation of Isolated Aryl Palladium Complexes
for PET: Application to Challenging Radiopharmaceutical Synthesis
Thomas L. Andersen, Stig D. Friis, Hélène Audrain, Patrik Nordeman, Gunnar Antoni, and Troels Skrydstrup
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja511441u • Publication Date (Web): 08 Jan 2015
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Journal of the American Chemical Society
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Efficient 11C-Carbonylation of Isolated Aryl Palladium Complexes
for PET: Application to Challenging Radiopharmaceutical Synthesis
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Thomas L. Andersena, Stig D. Friisa, Hélène Audrainb, Patrik Nordemanc, Gunnar Antonic*, and Troels
Skrydstrupa*
a
The Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej
14, 8000 Aarhus, Denmark
b Department of Nuclear Medicine and PET Center, Aarhus University Hospital, 8000 Aarhus, Denmark
c Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden
ABSTRACT: We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric rea-
gents in carbonylation reactions with 11CO to produce structurally challenging, pharmaceutically relevant compounds. This method
enables the first 11C-carbonyl labeling of an approved PET tracer, [11C]raclopride, for the dopamine D2/D3 receptor by carbonyla-
tion with excellent radiochemical purity and yield. Two other molecules, [11C]olaparib and [11C]JNJ 31020028 were efficiently
labeled in this manner. The technique distinguishes itself from existing methods by markedly improved purity profiles of the tracer
molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to
other 11C-labeling strategies.
11C is routinely produced in high yielding reactions as ei-
Introduction
ther 11CH4 through proton bombardment of a N2/H2 target gas,
Positron Emission Tomography (PET) has established it-
or as 11CO2 generated by using a N2/O2 target gas. Through
self amongst the primary biomedical imaging techniques, and
online processes, these primary products can be transformed
serves today as a routine tool in disease diagnostics, drug
into a number of 11C-labeled building blocks. Thus, 11C-
development research, and molecular imaging in general.1,2
cyanations starting from H11CN, carboxylations employing
The field is expanding fast and combination techniques have
11CO2, and reactions with 11C-phosgene are common ways to
been developed, including PET-MR and PET-CT, to further
introduce
a
11C-label.3 However, the majority of 11C-
increase the resolution and information available from a scan.
Consequently, there is an ever-increasing demand for the
development of novel radiotracers and reliable labeling tech-
niques. Yet, considering this demand, 18F-labeled neuraceq; a
ligand for the estimation of ꢀ-amyloid neuritic density in the
brain of patients being evaluated for Alzheimer’s disease,
remain the only PET tracer which has been approved for clini-
cal use by the FDA in 2014. Altogether, only a handful of
approved PET-tracers exist. This discrepancy owes in part to a
continued need to develop new and improve existing labeling
techniques.
radiolabeling is confined to 11C-methylating agents (11CH3I,
11CH3OTf) because of their simplicity and efficiency as elec-
trophiles in nucleophilic substitution reactions with functional
groups such as alcohols, amines, and thiols.4 These methylat-
ing protocols are firmly established and include automated
tracer synthesis in one-pot procedures. On the downside, this
11C-carbon labeling technique necessitates that the parent
bioactive molecule displays a heteroatom-bound methyl
group. Hence, it would be useful to identify other general and
efficient protocols for 11C-carbon isotope labeling to increase
the breadth of potential tracers but also for investigations into
the importance of the positioning of the isotope-label on the
chemical structure of interest.5
18F remains the most widely used radionuclide for the la-
beling of tracer molecules for PET. This owes partly to a more
convenient half-life of 110 min, when compared to for exam-
ple 11C, being only 20 min. Nonetheless, from a future per-
spective, 11C remains an interesting radionuclide for PET
tracer production as all organic-based endogenous ligands of
protein receptors contain carbon but not necessarily fluorine.
Introduction of 18F to non-fluorine containing ligands could
lead to changes in biological properties, such as binding effi-
ciency and receptor selectivity. Only in isolated cases can the
incorporation of a fluorine atom be expected to directly benefit
the biological properties of the ligands. Moreover, if marketed
pharmaceuticals can be labeled as their parent structures, little
additional efforts are necessary for approval of the 11C-labeled
structure for PET applications, thus reducing the development
costs of the tracers.
Over the last decade, a rising interest in the use of 11CO as
a C1-building block in labeling strategies has emerged. The
advantages of this strategy include i) the facile production of
11CO from 11CO2, ii) a diverse array of developed carbonyla-
tion reactions,6-13 iii) high selectivity of the labeling position,
iv) the general high functional group tolerance and v) the high
specific activity of the labeled tracers as very low contamina-
tion with 12CO2 is usually observed. Furthermore, the possibil-
ity of labeling both known and novel radiotracers and pharma-
ceuticals at an internal position, for example the carbonyl
group of an amide, could be useful for shedding light on the
metabolic fate of such molecules. Finally, where it is applica-
ble, future work to develop new tracer molecules will not be
complicated by the requirement of installing certain functional
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Page 2 of 9
groups in the target molecule for late stage radiolabeling, for (Scheme 1). To circumvent this difficulty, we envisioned the
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example free hydroxyl groups or primary/secondary amines.
The quantities of 11CO2, and thereby the 11CO produced by
the cyclotron amounts to only pico- to nanomoles. Further-
more, reaction times must be kept short in order to produce
useful amounts of the radiotracer at the end of synthesis.
These features differentiate 11C-carbonylation from ordinary
transition metal-catalyzed carbonylation reactions considera-
bly, and direct
utilization of pregenerated (Aryl)Pd(X)Ln oxidative addition
complexes as a potential solution. These complexes would
already have undergone the potentially challenging oxidative
addition prior to their employment in carbonylative 11C-
labeling. Additionally, the steps involved for the formation of
a phosphine ligated, catalytically active palladium complex
would also be eliminated, thereby effectively eliminating two
potentially slow reaction steps. The use of transition metal
complexes as PET-labeling mediators has recently been ele-
gantly illustrated on several occasions in late stage 18F-
fluorinations by the Doyle and Ritter groups.26–28 On a similar
note, the general notion of employing preformed aryl palladi-
um complexes to mediate challenging couplings has previous-
ly been investigated by the Myers group.29 The use of Pd-
complexes for the detection of CO in living cells has also
recently been demonstrated.30 No similar initiative has so far
been reported with regards to 11C-carbon labeling.
9
Scheme 1. Advantages of Using Aryl Palladium Complexes
in 11C-Radiolabeling.
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Herein, we wish to report on the finding, that the use of
pregenerated aryl palladium complexes in 11C-carbonylation
reactions greatly improves the radiochemical purity and yield
in the preparation of 11C-labeled pharmaceutically relevant
molecules. Furthermore, this strategy significantly broadens
the scope of 11C-carbonylations, exemplified by the production
of three synthetically challenging molecules, [11C]raclopride,
[11C]olaparib, and the neuropeptide Y Y2 receptor antagonist,
[11C]JNJ-31020028, in good to excellent purities and all in
synthetically useful yields.
Results and discussion
Initial work was undertaken to assess the ability of phos-
phine ligated aryl palladium complexes to absorb CO from the
gas phase. This property is essential, considering the minute
amount of 11CO, which is available during radiolabeling. In
order to investigate the effect which the halide counter ion
exerts on the CO-uptake ability of phosphine ligated aryl
palladium complexes, oxidative addition complexes of iodo-
and bromobenzene were prepared with triphenylphosphine as
the supporting ligand. These complexes were then treated with
2.05 equivalents of 13CO at room temperature applying a two-
chamber system setup. 13CO was generated in the other cham-
ber from 13C-labeled methyldiphenylsilacarboxylic acid by
treatment with KF.31,32 The bromobenzene complex 1 was first
subjected to these conditions for 60 min in CDCl3. Subsequent
1H-, 13C-, and 31P-NMR spectroscopy indicated full conversion
of the oxidative addition complex into the corresponding 13C-
labeled acyl complex 13CO-1 (Table 1, entry 1). Shortening the
reaction time to 20 min led to only 59% conversion to the acyl
complex 13CO-1 (entry 2). Reaction of complex 2 under simi-
lar conditions led to full conversion into the acyl complex,
thereby demonstrating an enhanced ability of iodide-
coordinated complexes towards CO capture (entry 3). By
reducing the reaction time to 8 min only a 50% conversion of
the oxidative addition complex 2 was observed (entry 4). This
timeframe proved suitable for comparison with a number of
supporting ligands. The Buchwald-type biaryl ligand, XPhos,
led to slightly improved CO-uptake, with a 63% conversion of
3 (entry 5), while the bidentate ligand dppf showed a 72%
conversion of 4 into 13CO-4 (entry 6). Conversely, when
XantPhos was employed, full conversion to acyl complex
13CO-5 was observed after only 8 min (entry 7). This remarka-
bly high CO-uptake ability of XantPhos ligated complexes
was further underlined when the analog complex originating
extrapolation of established conditions is generally not possi-
ble. Several strategies have been employed to promote trap-
ping of 11CO in the reaction container and ensure a fast reac-
tion, including the use of microautoclaves,14–16 microfluidics,17
and low-pressure chemical trapping. Thus, carbonylation
reactions can now be conducted to produce 11C-carbonyl la-
beled esters,18 carboxylic acids,19 amides,20–22 (hydrox-
yl)ureas,23,24 and malonates25 in respectable radiochemical
purity and yield. However, despite this apparent success, no
examples of routine uses of carbonylation for tracer produc-
tion exist. This lack of routine carbonylation for 11C-isotope
labeling is mainly due to the fact that the existing techniques
function only for less sophisticated molecules rather than for
more complex and pharmaceutically relevant substrates.
Hence, if carbonylation is to find a useful place in PET,
more efficient carbonylation techniques are required for the
synthesis of medicinally relevant but synthetically challenging
motifs.
One common feature of the transition metal-mediated car-
bonylation reactions listed above is the necessity of the aryl
halide starting material to undergo a number of reaction steps
approaching one full catalytic cycle of for example aminocar-
bonylation, disregarding catalyst regeneration, in order to
provide one radiolabeled molecule. When sterically or elec-
tronically demanding substrates are required, oxidative addi-
tion may be slow, thus resulting in the inefficient radiolabeling
of more challenging compounds within the PET-timescale
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from bromobenzene showed equally fast conversion to the
acyl complex, 13CO-6 (entry 8).33,34 On a similar timescale,
trialkylphosphine ligated palladium complexes 7 and 8 also
displayed full conversion to their corresponding acyl com-
plexes 13CO-7 and 13CO-8, respectively (entries 9 and 10).35,36
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Table 1. CO-Uptake by Phosphine Ligated Palladium
Oxidative Addition Complexesa
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Figure 1. Fixation of 11CO gas and delivery to reaction vial.
[11C]raclopride
Conversion
ligand
(complex)
time
[min]
[%]b
Initial attempts to employ aryl palladium complexes for
11C-labeling purposes were directed towards the 11C-carbonyl
radiolabeling of raclopride. This dopamine D2/D3 receptor
antagonist is commonly used as a PET tracer to assess the
degree of dopamine binding to the D2-dopamine receptor, and
is produced in PET-facilities as its 11C-methyl labeled analog.
Two ortho-substituents flank the central halide of a potential
coupling partner, 9, thereby hampering oxidative addition.33,38
entry
X
(13CO-complex)
100 (13CO-1)
59 (13CO-1)
100 (13CO-2)
50 (13CO-2)
63 (13CO-3)
72 (13CO-4)
100 (13CO-5)
100 (13CO-6)
100 (13CO-7)
PPh3 (1)
PPh3 (1)
PPh3 (2)
PPh3 (2)
1
2
3
4
5
6
7
8
9
-Br
-Br
-I
60
20
20
8
-I
-I
XPhos (3)
dppf (4)
8
-I
8
Scheme 2. Preparation of XantPhos Ligated Aryl Palladi-
um Complex 10 and its X-Ray Structurea
-I
XantPhos (5)
XantPhos (6)
P(t-Bu)3 (7)
8
-Br
-I
8
8
cataCXium A
100 (13CO-8)
10
-I
8
(8)
aReaction conditions: Ar–Pd complex (1–8) (0.03 mmol) and
CDCl3 (0.5 mL) in chamber 1. MePh213CO2H (0.62 mmol), KF
(0.65 mmol), and MeCN (0.5 mL) in chamber 2. Room tempera-
ture. bConversion to the acyl-complex was established by 1H-,
13C-, and 31P-NMR spectroscopy.
Most importantly, Table 1 serves as a simple guideline for
which oxidative addition complexes will have the highest
probability of undergoing 11CO coordination and insertion to
form the 11CO-acyl complexes within a timeframe suitable for
PET chemistry. Not only does this study identify a number of
ligands suitable for coordinating CO, it also indicates that
iodide is a better choice as a counter ion than bromide for the
production of radiotracers, as CO uptake is faster in these
complexes.
Next the oxidative addition complex strategy was applied
for the introduction of the 11C-carbonyl radiolabel into struc-
turally different but pharmaceutically relevant molecules. To
this end, a simple 11CO trapping system derived from a setup
recently reported by Eriksson and coworkers was employed as
depicted in Figure 1.37 Upon reduction of 11CO2 over a pre-
heated molybdenum catalyst, concentration of the 11CO gas
was effected by condensation on a silica trap immersed in
liquid nitrogen. Subsequent release of the trapped 11CO into
the reaction vial was then achieved by simply heating the trap.
aFor full details, see Supporting Information. ORTEP representa-
tion of 10, 50% probability level.
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Table 2. Raclopride 11C-Carbonyl Labelinga
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9
entry
1
solvent
DMF
temp [°C]
trapping efficiency [%]
radiochemical purity [%]
radiochemical yield [%]
95
95
95
95
120
85
95
95
95
95
64
65
75
88
48
2
toluene
57
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3
4b
THF
64
88
56
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
62 ± 8
86
94 ± 1
80
57 ± 7 (n = 3)
5
69
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13
6
57
93
7c
8d
9e
10f
64
80
50
94
45
94
33
39
aReaction conditions: 10 (20 mg, 20 µmol), solvent (0.7 mL), 11 (7 mg, 60 µmol) in a 5 mL crimp-cap vial under argon. Upon delivery of
11CO, the reaction was heated for 10 min. See Supporting Information for full details. bAverage of three reactions. c10 (40 µmol), 11 (120
d
e
f
µmol). 10 (10 µmol). Reaction time 6 min. Aryl halide 9 (6.4 mg, 20 µmol), Pd(dba)2 (11.5 mg, 20 µmol), XantPhos (11.5 mg, 20
µmol), 11 (7 mg, 60 µmol), and Et3N (10 µL, 71 µmol) in dioxane (0.7 mL), 95 °C for 6 min with 11CO.
Furthermore, previous attempts by us to produce this radio-
tracer by aminocarbonylation employing non-labeled CO on a
sub-millimole scale, led to decomposition of the aryl iodide
under the basic conditions commonly required in aminocar-
bonylations. Similar attempts starting from the aryl bromide
gave only low conversion to raclopride in a slow reaction
unsuitable for PET-timescale.
observation was made when the reaction time was shortened
to 6 min. This is an interesting feature, considering the short
half-life of the 11C-isotope (entry 9). Lastly, repeating the
reaction conditions employed in entry 9, but using the free aryl
iodide 9 along with Pd(dba)2 and XantPhos in place of the pre-
generated complex 10, led to formation of 11C-carbonyl la-
beled raclopride in a significantly reduced radiochemical
purity of 39% and in a radiochemical yield of 13% (entry 10).
In order to test the reproducibility of the enclosed method,
the results displayed in entry 4 were reproduced by different
researchers at two separate PET-facilities at Aarhus, Denmark
and Uppsala, Sweden. In all cases, the high radiochemical
purity and yield were consistently obtained. Moreover, prepar-
ative HPLC purification of the product was successfully un-
dertaken to isolate 29–43 mCi (n=3) of [11C]raclopride as a
radiochemically pure sample with a decay corrected yield of
38–44% after 8 min of target irradiation. The specific activity
was determined to be 9–11 Ci/µmol-1, thus demonstrating one
of the advantages of radiolabeling with 11CO as very little
dilution by atmospheric 12CO is possible. These results consti-
tute the first 11C-labeling of an approved PET tracer by car-
bonylation with 11CO gas.40
The oxidative addition complex 10 bearing XantPhos was
prepared from the corresponding aryl iodide 9 and isolated by
trituration and filtration. X-ray data confirmed the proposed
structure (Scheme 2), and demonstrated XantPhos to form a
trans-complex as has been previously observed with other aryl
XantPhos-Pd complexes.39 This finding was also consistent
with the 31P-NMR spectrum displaying a singlet at 4.9 ppm.
After initials tests, it was found that combining complex
10 with (S)-(1-ethylpyrrolidin-2-yl)methanamine (11) in DMF
for 10 minutes at 95 °C after delivery of 11CO, radioanalytical
HPLC analysis of the crude mixture indicated a remarkably
clean transformation into 11C-labeled raclopride. Furthermore,
measuring the radioactivity in the reaction vial before and
after flushing of the vial headspace, proved that the complex
did indeed fixate the available 11CO efficiently (Table 2, entry
1). No additional base was necessary. Further investigation of
the reaction conditions demonstrated that alternative solvents
performed equally well (entries 2 and 3). Dioxane was main-
tained as the solvent for further examinations due to the excel-
lent radiochemical purity observed (entry 4). The trapping
efficiency could be increased by conducting the reaction at
[11C]olaparib
To further probe the applicability of the aryl palladium
complex strategy, we next investigated the 11C-labeling of the
PARP inhibitor, olaparib. This chemotherapeutic agent from
AstraZeneca has recently been approved in the EU for the
treatment of women with BRCA-mutated ovarian cancer. The
radiochemical 11C-labeling of this structural motif is inherently
challenging as the parent compound contains no functional
groups, which can be readily methylated to produce an 11C-
methyl analog.
o
120 C, which nevertheless resulted in a lower radiochemical
purity (entry 5). Conversely, reducing the reaction temperature
to 85 °C led to a drop in the trapping efficiency (entry 6).
Employing more of the reactants only decreased the radio-
chemical purity (entry 7), whereas lowering the amount of 10
slightly impeded the trapping efficiency, while the radiochem-
ical purity was essentially unchanged (entry 8). The same
Table 3. Olaparib 11C-Carbonyl Labelinga
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radiochemical purity [%]
trapping efficiency [%]
radiochemical yield [%]
ligand
(complex)
entry
[11C]olaparib
[11C]17
[11C]olaparib
[11C]17
9
L1, L2 = XantPhos
(14)
L1, L2 = XantPhos
(14)
1
36
<1
99
<1
36
10
11
12
13
14
15
16
17
2b
3
51
4
<1
<1
99
99
<1
<1
<1
51
4
L1 = L2= PPh3 (13)
<1
75 ± 10 (n = 3)
54
L1 = P(t-Bu)3 (15)
(L2 = open site)
4c
5d
<1
<1
76 ± 10
74
99 ± < 1
74
P(t-Bu)3 (12)
aReaction conditions: 13-15 (20 µmol), 16 (10 µL, 71 µmol), and dioxane (0.7 mL) in a 5 mL crimp-cap vial under argon. Upon delivery
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of 11CO, the reaction was heated to 105 °C for 10 min. See Supporting Information for full details. 120 °C, Average of three reactions.
dAryl iodide 12 (7.6 mg, 20 µmol), Pd(dba)2 (11.5 mg, 20 µmol), P(t-Bu)3 (11.5 mg, 20 µmol), and 16 (10 µL, 71 µmol) in dioxane (0.7
mL), 105 °C for 10 min with 11CO.
b
c
Preparation of the XantPhos ligated oxidative addition com-
Scheme 3. Preparation of the PPh3 and XantPhos Ligated
Aryl Palladium Complexes 13 and 14a
plex from aryl iodide 12, by reaction with Pd(dba)2 and
XantPhos in dioxane at room temperature, yielded complex 14
in a respectable yield (Scheme 3). When this complex was
subjected to the conditions identified in Table 2, analytical
HPLC of the crude reaction mixture indicated formation of
one major radioactive species. However, upon co-injection
with olaparib, it was clear that the product was not the desired
amide (Table 3, entry 1). The same unwanted product was
observed when substituting XantPhos for PPh3 with complex
13, albeit with a low trapping efficiency. To confirm the iden-
tity of this side product, a range of possible structural candi-
dates were prepared and co-injected with an analytical amount
of freshly prepared reaction mixture. In this way, formation of
the corresponding 11C-labeled carboxylic acid was confirmed,
however only in minor quantities. The identity of the major
product was determined when the cold amide 12C-17 was
synthesized and co-injected as a reference.
The origin of this product is suggested to arise from aryl
scrambling of the phenyl groups from the supporting
XantPhos ligand onto the aryl palladium complex. Such find-
ings have precedence in the literature although the quantitative
nature of this scrambling was surprising.41 To demonstrate
whether this aryl scrambling had occurred during the car-
bonylation reaction, or if the complex isolated and used as the
starting material was actually the phenyl palladium complex, a
crystal structure of 14 was required. Unfortunately, crystals of
the XantPhos ligated palladium complex 14 suitable for X-ray
diffraction studies could not be isolated in our hands. Howev-
er, inspection of the crystal structure of 13 showed that no
phenyl group migration had occurred prior to the carbonyla-
tion reaction (Figure 2). We suggest that this result can be
extrapolated to the XantPhos ligated complex 14, as 13 also
produce exclusively the scrambled product 11C-17.
aFor full details, see Supporting Information section.
Figure 2. ORTEP representation of 13, 50% probability level.
Increasing the reaction temperature only served to provide
better trapping of 11CO, but did not improve the selectivity
(entry 2). Consequently, non-aryl based phosphine ligands
were considered. P(t-Bu)3 ligated oxidative addition complex
15
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Table 4. JNJ-31020028 11C-carbonyl labelinga
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trapping efficiency
(%)
radiochemical purity
(%)
radiochemical yield
entry
1
ligand (complex)
base (equiv)
TEA (1)
(%)
L1 = L2= PPh3 (19)
-
-
-
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
L1, L2 = XantPhos
(20)
2b
DBU (4)
16
23
4
4
3c
4d
5
DBU (4)
-
36
-
10
-
-
DBN (4)
15
6
3
0.5
-
6
Proton-sponge (4)
TMGN (4)
Me-TBD (4)
Me-TBD (4)
-
7
22
38
42
-
-
8
55
25
21
11
9e
L1, L2 = XantPhos
(20)
10 f
11g
Me-TBD (6)
Me-TBD (6)
48 ± 7
55 ± 7
25 ± 4 (n = 3)
XantPhos (18)
21
<5
<1
aReaction conditions: 19–20 (22 mg, 20 µmol), 21 (7 mg, 18 µmol), and dioxane (0.7 mL) in a 5 mL crimp-cap vial under argon. Upon
delivery of 11CO, the reaction was heated to 95 °C for 10 min. See Supporting Information for full details. 90 °C. 100 °C. The lithium
amide of 21 (14 mg, 36 µmol) was used. See Supporting Information for full details. e115 C. fAverage of three reactions. gAryl iodide 18
(5.6 mg, 20 µmol), Pd(dba)2 (11.5 mg, 20 µmol), XantPhos (11.5 mg, 20 µmol), 21 (7.0 mg, 18 µmol), and Me-TBD (18 µL, 125 µmol) in
dioxane (0.7 mL), 95 °C for 10 min with 11CO.
b
c
d
could be prepared by reacting the appropriate aryl halide with
Pd(cod)(CH2TMS)2 (Scheme 4).42,43
tions but starting from the corresponding aryl iodide 12 led to
product formation in reduced radiochemical yield, mainly
caused by inferior radiochemical purity (entry 11).
Scheme 4. Preparation of the P(t-Bu)3 Ligated Aryl Palla-
dium Complex 15a
[11C]JNJ-31020028
Finally, 11C-carbonyl labeling of the brain-penetrant hu-
man neuropeptide Y Y2 receptor antagonist JNJ-31020028,
was undertaken.44 Labeling of this tracer is currently achieved
through 11C-methylation of the amide nitrogen to form the N-
methylated analog.45 Pd-catalyzed carbonylative assembly of
this molecule from a nitrogen nucleophile 21 and a biaryl
halide is complicated both by the ortho-pyridyl substituent on
aryl halide 18 resulting in increased sterical hindrance, as well
as the poor nucleophilicity of the aniline. To this end, com-
plexes 19 and 20 were synthesized. Attempts to prepare the
P(t-Bu)3 or cataCXium A ligated complexes unfortunately
only led to decomposition of the starting material (Scheme 5).
Initial attempts on the aminocarbonylation with 19 and
12CO demonstrated that the addition of base was essential for
useful turnover. Therefore Et3N was applied, when complex
19 was reacted with amine 21 in the PET-setup. However, no
11CO trapping was observed (Table 4, entry 1). On the other
aFor full details, see supporting information.
Attempts to prepare this complex starting from
Pd(dba)2/P(t-Bu)3 or Pd(P(t-Bu)3)2 only led to complex prod-
uct mixtures, which proved difficult to purify. The reaction of
complex 15 with 11CO and amine 16 at 105 C for 10 min in
dioxane, led to remarkably clean conversion into 11C-carbonyl
labeled olaparib in a 99% radiochemical purity. Furthermore,
in accordance with the findings in Table 1, the complex exhib-
ited an excellent trapping efficiency. Employing these condi-
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hand, the XantPhos ligated palladium complex 20 afforded for successfully producing the radiolabeled target structure in
1
2
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4
5
6
7
8
product as determined by analytical HPLC, when DBU was
used as the base, albeit not in a synthetically useful yield (en-
try 2). Increasing the reaction temperature only led to a trade-
off with the trapping efficiency and the radiochemical purity
(entry 3). Speculating whether the low turnover could be relat-
ed to the poor reactivity of the aniline coupling partner, an
attempt was made to prepare the more reactive lithium amide
by treatment of 21 with t-BuLi.46 However, this approach
again led to no improvement (entry 4). On the other hand, a
profound effect of reactivity was observed when a series of
other organobases were tested. With the bases DBN, proton-
sponge, and TMGN only a low trapping of the 11CO gas was
observed. But with the guanidine base Me-TBD, both the
trapping efficiency and the radiochemical purity of the product
increased dramatically (entry 8).
a synthetically useful yield. It is our belief, that this strategy
will pave the way for the use transition metal mediated car-
bonylations employing 11CO as a future labeling strategy for
PET-tracers with clear benefits for diagnostic and drug devel-
opment use.
ASSOCIATED CONTENT
Supporting Information
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Experimental details and characterization data. This information
is available free of charge via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Scheme 5. Preparation of the PPh3 and XantPhos Ligated
Aryl Palladium Complexes 19 and 20a
ts@chem.au.dk
gunnar.antoni@akademiska.se
Funding Sources
We are deeply appreciative of generous financial support from the
Danish National Research Foundation (grant no. DNRF59), the
Villum Foundation, the Danish Council for Independent Re-
search: Technology and Production Sciences, the Lundbeck
Foundation, the Carlsberg Foundation, and Aarhus University for
generous financial support of this work.
ACKNOWLEDGMENT
The authors are grateful to Dr. Jacob Overgaard for the X-ray
crystallographic analysis, Niels Nielsen and Steffan Jensen for the
construction of the CO set-up, and Dr. Philippe Hermange for the
initial experiments with raclopride.
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31020028 with a good purity profile and in a synthetically
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