Copper-mediated nucleophilic radiobromination of aryl boron precursors: Convenient preparation of a radiobrominated PARP-1 inhibitor

Article abstract of DOI:10.1016/j.tetlet.2018.04.024

The copper-mediated nucleophilic radiobromination of aryl boron precursors with a radiobromide ion is a novel radiolabeling method that is efficient and robust. High radiochemical conversion (RCC) was observed using a variety of solvents, temperatures and catalysts. The reaction is also clean and is feasible for purification to obtain high chemical and radiochemical purity. This method provides a very useful route for the preparation of radiobrominated pharmaceuticals, including a radiobromine labeled PARP-1 inhibitor, and it is a valuable addition to the family of copper-mediated radiolabeling processes.

Full text of DOI:10.1016/j.tetlet.2018.04.024

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-mediated nucleophilic radiobromination of aryl boron
precursors: Convenient preparation of a radiobrominated PARP-1
inhibitor
a
a
b
Dong Zhou a, , Wenhua Chu , Thomas Voller , John A. Katzenellenbogen
⇑
a Department of Radiology, School of Medicine, Washington University in Saint Louis, Saint Louis, MO 63110, United States
b Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The copper-mediated nucleophilic radiobromination of aryl boron precursors with a radiobromide ion is
a novel radiolabeling method that is efficient and robust. High radiochemical conversion (RCC) was
observed using a variety of solvents, temperatures and catalysts. The reaction is also clean and is feasible
for purification to obtain high chemical and radiochemical purity. This method provides a very useful
route for the preparation of radiobrominated pharmaceuticals, including a radiobromine labeled PARP-
1 inhibitor, and it is a valuable addition to the family of copper-mediated radiolabeling processes.
Ó 2018 Published by Elsevier Ltd.
Received 20 February 2018
Revised 2 April 2018
Accepted 10 April 2018
Available online xxxx
Keywords:
Labeling method
Nucleophilic radiobromination
Boron reagents
Bromine-76
Bromine-77
Auger electron radiation
PET imaging
Introduction
when in close proximity to DNA strands but causes little damage
outside the nucleus; this renders Auger electron radiation therapy
Radiobromine-labeled compounds can be used for positron
emission tomography (PET) imaging (i.e. 76Br) and for radiation
therapy (i.e. 77Br), making the radiobrominated pharmaceutical a
theranostic pair for radiotherapy and PET imaging. Radiobromine
has some advantages over radiofluorine (18F) and radioiodine:1
unlike bromine, fluorine only has one radioisotope (18F) that is use-
ful for PET imaging; bromine is smaller in size than iodine, and the
CABr bond is stronger than the C-I bond, leading to greater in vivo
stability and potentially better pharmacokinetic and pharmacody-
namics properties for the brominated compounds; the accumula-
tion of radioiodide in the thyroid is also not a problem for
radiobromide.2 Among the bromine radioisotopes, [76Br] bromide
and [77Br] bromide can be produced practically by a medical cyclo-
tron in high specific activity by the 76/77Se(p,n) 76/77Br nuclear reac-
tion on a 76Se- or 77Se-enriched Cu2Se target.3 76Br (55% b+, 45% EC,
a promising approach for the treatment of cancer.4
Oxidative electrophilic radiobromination (Fig. 1a) is a com-
monly used method.1 However, due to the high reactivity of the
brominating intermediate under no-carrier-added (NCA) condi-
tions, this oxidative method for radiolabeling may not always
afford the desired product.5 The copper-catalyzed halogen-
exchange reaction is a nucleophilic substitution approach, but gen-
erally requires high temperatures and is seldom used (Fig. 1b).6
Recently, we reported that radiobromination of iodonium precur-
sors by nucleophilic substitution gave high radiochemical conver-
sion (RCC), but it produced two major radioactive products
(Fig. 1c).7 Significant progress has also been reported for copper-
mediated nucleophilic substitution of aryl boron precursors with
[
18F]fluoride, radioiodides and [11C]HCN, reactions that proceeded
with high RCC.8–12 Herein, we report the radiobromination of aryl
boron precursors using copper-mediated nucleophilic substitution
(Fig. 1d).
t
1/2 = 16 h) is used mainly for PET imaging; 77Br (99% EC, t1/2 = 57
h) is an Auger electron emitter and can be used for radiotherapy.
Auger electron radiation is very short range and thus is highly toxic
Results and discussion
⇑
Corresponding author at: 510 S. Kingshighway Blvd, Saint Louis, MO 63110,
United States.
76Br and 77Br were produced and isolated as bromide ions in
water (1–1.5 mL). Normally, the bromide is thoroughly dried at
E-mail address: zhoud@wustl.edu (D. Zhou).
https://doi.org/10.1016/j.tetlet.2018.04.024
0040-4039/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Zhou D., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.04.024

2
D. Zhou et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Radiobromination of aromatic compounds.
elevated temperature under a flow of argon or nitrogen,7 however,
in this study the bromide ion in water was used directly without
drying. To determine the best reaction conditions, we followed a
typical protocol reported for the radiofluorination of aryl boron
precursors, using Cu(OTf)2(Py)4 as the catalyst and 4-
formylphenylboronic acid (1) as the model compound.8,9 First,
we explored solvents commonly used in radiochemistry (acetoni-
trile, DMSO, DMF, and DMA). All of the solvents afforded almost
quantitative RCC (Table 1), however, multiple side-products were
observed in acetonitrile. The precursor proved to be stable in the
other solvents, and only one side-product was observed in small
amounts. DMSO gave the best performance and was used in all
subsequent evaluations.
Table 2
Effect of temperature on radiobromination.a
Entry
Temperature (°C)
RCC (%)b
1
2
3
4
110
80
65
98
98
97
97
RT
a
See Table 1 for the reaction conditions (Solvent: DMSO).
Reaction time: 20 min, except for RT (40 min).
b
Table 3
Effect of reaction concentration on radiobromination.a
The temperature dependence of the radiobromination RCC was
studied. Labeling was complete at room temperature, which
resulted from using large amounts of reagents (Table 2). Tempera-
tures of 80 °C or 110 °C were used for subsequent experiments to
ensure that the reaction would be complete within 20 min. When
the amount of boron precursor was reduced to less than 1 mg, a
practical amount for the preparation of radiopharmaceuticals,
RCC still remained high (Table 3), and subsequent experiments
were performed on the same scale (6 mmol boron reagent). The
high RCC clearly benefits from the high efficiency of the nucle-
ophilic substitution with the bromide ion and the stability of the
Entry
1/Cu(OTf)2(Py)4 (mg/mg)
RCC (%)
1
2
3
4
5
9/18
4.5/9
1.8/3.6
0.9/1.8
0.36/0.72
98
98
98
98
96
a
DMSO (1 mL), 110 °C/20 min.
Table 4
Effect of water content on radiobromination.a
Entry
Water (mL)
DMSO (mL)
RCC (%)
1
2
3
4
5
10
25
50
100
500
500
500
500
500
500
98
98
97
94
92b
Table 1
Effect of solvent on RCC.a
a
1 (0.9 mg, 6 mmol), Cu(OTf)2(Py)4 (1.8 mg, 2.65 mmol), [77Br]bromide (0.1 mCi in
5 mL water), DMSO (0.5 mL), 80 °C/20 min.
b
76% as the desired product and 16% as 4-bromobenzoic acid, determined by
HPLC.
Entry
Solvent
RCC (%)b
Table 5
Effect of carrier addition on radiobromination.a
1
2
3
4
Acetonitrile
DMSO
DMF
98
98
98
98
Entry
1 (mmol)
Bromide (mmol)b
RCC (%)
DMA
1
2
3
6
6
6
0.01
0.1
1
98
98
41c
1 (9 mg, 60 mmol), Cu(OTf)2(Py)4 (18 mg, 26.5 mmol), [77Br]bromide (0.1 mCi in
5 mL water), solvent (1 mL), 110 °C/20 min.
a
b
a
b
c
Water (1 mL) was added to the reaction mixture in order to solubilize any free
See Table 4 for the reaction conditions.
NaBr in water (1 mL).
110 °C/20 min.
[
77Br]bromide in the reaction vessel; RCC was measured by radio-TLC (silica gel/
ethyl acetate), and the reaction mixture was analyzed by radio-HPLC.
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D. Zhou et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 6
reagents under the base-free conditions. It has been shown previ-
ously that water is well tolerated in the nucleophilic substitution
reaction with bromide using aryl iodonium salts as precursors.7
Using 1:1 DMSO/water, RCC remained high (>90%) (Table 4). How-
ever, a radioactive by-product was observed in this model reaction
that appeared to be 4-bromobenzoic acid, the oxidation product of
4-bromobenzaldehyde, according to HPLC. The water tolerance for
this radiobromination is in sharp contrast to that of radiofluorina-
tion, which afforded no RCC in the presence of water (data not
shown). As water is tolerated, radiobromination using aryl boron
precursors can be carried out in aqueous solution, which is advan-
tageous because it reduces the overall time and manipulations
involved in the radiolabeling process. It also lowers the radiation
exposure to a radiochemist and increases the reliability of the
radiochemistry.
Effect of the amount of catalyst-Cu(OTf)2(Py)4.a
Entry
Cu(OTf)2(Py)4 (mg)
RCC (%)
1
2
3
4
0.9
95
93
56
59
0.45
0.18
0.09
a
1 (0.9 mg, 6 mmol), [77Br]bromide (0.1 mCi in 5 mL water), DMSO (0.5 mL), 80 °C/
20 min.
Table 7
Effect of the type of copper (II) catalyst.a
Entry
[Cu]
RCC (%)
Carrier-added radiobromination was also carried out in order to
simulate large-scale radiolabeling. RCC remained high even with
the addition of 0.1 mmol of carrier (Table 5). This result also indi-
cates the high efficiency of the nucleophilic substitution of the
boron precursor with the bromide ion.
Cu(OTf)2(Py)4 is an efficient catalyst for the nucleophilic radio-
bromination of aryl boron precursors (Table 6). Pleasingly, reduc-
ing the catalyst loading to 0.1 mg (0.13 mmol) still gave over 50%
RCC within 20 min. Other copper catalysts, Cu(OTf)2 and CuSO4-
1
2
3
4
None
Cu(OTf)2(Py)4
Cu(OTf)2
CuSO4Á5H2O
0
98
99
92
1 (0.9 mg, 6 mmol), catalyst (2.65 mmol), [77Br]bromide (0.1 mCi in 10 mL water),
DMSO (0.5 mL), 110 °C/20 min.
a
Table 8
Efficacy of catalysts in radiobromination.a
Entry
1
[Cu]
Temp/Time
RCC (%)
Cu(OTf)2(Py)4
80 °C/20 min
105 °C/10 min
80 °C/20 min
105 °C/10 min
14
92b
0
2
Cu(OTf)2
30b
a
2 (6 mmol), catalyst (2.65 mmol), [77Br]bromide (0.1 mCi in 10 mL water), DMSO
(0.5 mL).
Fig. 3. Influence of reactive groups on radiobromination. (X = 1 equivalent in
molarity).
b
After 80 °C/20 min, the reaction was further heated at 105 °C for 10 min.
Fig. 2. Copper-mediated radiobromination of model compounds. Reaction condition: precursor (6 mmol), Cu(OTf)2(Py)4 (2.65 mmol), [77Br]bromide (0.1 mCi in 5–10 mL
water), DMSO (500 mL), 80 °C/20 min (except as noted). Note: (a) RCC was 16% at 80 °C/20 min; (b) In addition, 4-bromobenzoic acid was observed in 5% and 3% (pin),
respectively.
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D. Zhou et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 4. Synthesis of the boronic ester precursor and radiosynthesis of the olaparib derivative.
Á5H2O, also afforded high RCC. No RCC was obtained in the control
reaction without copper (Table 7). The catalytic efficacy of the
nucleophilic radiobromination reaction was studied using a less
reactive boron precursor, 4-(dimethylamino)phenylboronic acid
(2). Cu(OTf)2(Py)4 is more efficient in catalyzing the radiobromina-
tion with the less reactive precursor, though required a higher
temperature to complete the reaction (Table 8). The optimal per-
formance of Cu(OTf)2(Py)4 is consistent with that reported for cop-
per-mediated radiofluorination of aryl boron precursors.8,9
The radiobromination of other aryl boron precursors is shown
in Fig. 2. All the reactions afforded very high RCC using 6 mmol of
the precursor at 80 °C or 110 °C. Only the dimethylamine-substi-
tuted precursor required 110 °C to complete the reaction, most
likely due to the strong electron-donating property of dimethy-
lamino group. Boron precursors appear to be stable under these
base-free conditions. Even the base-liable NHS ester can be labeled
directly in high yield under these conditions. Only tiny amounts of
by-product, presumably the protonated compound,13 was
observed at 80 °C. At 110 °C, more by-product was detected but
still remained minimal. In the copper-mediated radiofluorination
of aryl boron precursors, one of the major by-products is the pro-
tonated material, which may coelute with the fluorinated product
upon HPLC, making effective purification a major challenge.13 By
contrast, the brominated product is well separated from the proto-
nated by-product, enabling the final radiobrominated product to
be more readily obtained in high chemical and radiochemical
purity.
ing boronic acid precursor (1 mg), we were able to produce the
radiobromine-labeled derivative in aqueous DMSO in 99% RCC (n
= 2) (Fig. 4). Most significantly, the precursor is stable, and the
desired product is well separated from other minimal amount of
by-products, ensuring that the final product can be purified in high
chemical and radiochemical purity and in high specific activity
(See Fig. S2).
Conclusion
We have developed a novel radiobromination method using
copper-mediated nucleophilic substitution of aryl boron precur-
sors and the radiobromide ion. This method is highly efficient
and robust, affording the radiobrominated product in high RCC
under a variety of conditions. The method is also ideal for purifica-
tion, providing radiobromine-labeled pharmaceuticals with high
chemical and radiochemical purity and high specific activity. Using
this method, a bromo-derivative of olaparib was synthesized in
high RCC with feasible purification as a potential radiopharmaceu-
tical for PARP-1. This method provides a very useful route for
radiobromination and is a valuable addition to the family of cop-
per-mediated radiolabeling processes.
Acknowledgements
This work was supported by the National Institutes of Health
R01CA025836 (JAK) and WUSTL MIR Pilot fund.
The robustness of the nucleophilic radiobromination of boron
reagents was studied by spiking in other reagents with functional
groups that are typically detrimental to nucleophilic substitution
or may cause other side reactions. As shown in Fig. 3, a phenol
group had little or no effect on the radiobromination RCC or the
formation of by-products. The carboxylic acid group reduced the
RCC significantly, even with the addition of only one equivalent.
This is different from the result for 4-bromobenzoic acid (Fig. 2),
which was used as a pinacol ester instead of a boronic acid. A sto-
ichiometric amount of a secondary amine (piperazine) has little
effect on RCC, also a fivefold excess led to a significant decrease
in RCC. However, the boron precursor is not very stable under
these conditions with the NAH group, according to HPLC analysis.
In the radiofluorination reports, the presence of nitrogen in the aryl
precursor, especially amines containing the NAH group, reduce
RCCs to very low levels.14 Because many pharmaceuticals contain
nitrogen, this observation suggests the broad applicability of this
method for the preparation of radiobrominated pharmaceuticals.
Olaparib is a clinical drug, targeting poly (ADP-ribose) poly-
merase-1 (PARP-1) for the treatment of cancer. Fluorine-18 and
radioiodine-labeled derivatives of olaparib have been synthesized
using multiple-steps or unconventional methods as potential
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.04.024.
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Please cite this article in press as: Zhou D., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.04.024