A Highly Efficient Copper-Mediated Radioiodination Approach Using Aryl Boronic Acids

Article abstract of DOI:10.1002/chem.201604105

A convenient and quantitative radioiodination method by copper-mediated cross-coupling of aryl boronic acids was developed. The mild labeling conditions, ready availability of the boronic acid substrate, simple operation, broad functional group tolerance and excellent radiochemical yield (RCY) make this a practical strategy for radioiodine labeling without further purification.

Full text of DOI:10.1002/chem.201604105

DOI: 10.1002/chem.201604105
Communication
&
Radiochemistry
A Highly Efficient Copper-Mediated Radioiodination Approach
Using Aryl Boronic Acids
Pu Zhang+,[a] Rongqiang Zhuang+,[a] Zhide Guo,[a] Xinhui Su,[c] Xiaoyuan Chen,*[b] and
Xianzhong Zhang*[a]
methods, there are some serious issues associated with them.
Abstract: A convenient and quantitative radioiodination
method by copper-mediated cross-coupling of aryl boron-
Chloramine T, one of the most commonly used oxidant, expos-
es the compounds to harsh oxidizing conditions and may
ic acids was developed. The mild labeling conditions,
cause a number of undesirable side reactions.[7] The molecular
ready availability of the boronic acid substrate, simple op-
iodine generated by the oxidant is volatile, thus limits the op-
eration, broad functional group tolerance and excellent ra-
eration to avoid airborne release. Furthermore, the low yields
diochemical yield (RCY) make this a practical strategy for
of the precursor synthesis[8] and low radiochemical yields
radioiodine labeling without further purification.
(RCY)[9] are also of concern. Radiodehalogenation, a straightfor-
ward radioiodination method of introducing radioiodine into
aromatic compounds without an oxidant, is induced by nucle-
Radiopharmaceuticals labeled with radioactive iodine isotopes
123I, 124I, 125I, and 131I) have always played a major role in nucle-
ophilic substitution. As this is an energy demanding process,
high temperature is required.[10] Another concern is the low
specific activity, which is due to the difficult separation of the
radiolabeled product from the precursor. Recently, Cant et al.[11]
reported a nickel-mediated direct radioiodination of aryl and
heteroaryl bromides with a single-step method, but this kind
of halogen-exchange reaction is restricted by the steric hin-
drance effect and the requirement of harsh temperature condi-
tions (1808C). Considering the drawbacks of these methods, it
is critical to develop a simple and practical new radioiodination
method through a mild and efficient reaction with high RCY
and specific activity for radiopharmaceutical applications.
The Chan–Evans–Lam reaction,[12] a copper-mediated oxida-
tive cross-coupling of aryl boronic acids and heteroatom nucle-
ophiles, is a major breakthrough in the C-heteroatom transfor-
mation for its mild reaction conditions and the ready availabili-
ty of the boronic acid substrates. Significant progress has been
made in expanding the scope and the application of this kind
of reaction in the past two decades.[13] Motivated by this pow-
erful synthetic methodology and the opportunity to develop
a better radioiodination method, we report herein a copper
mediated radioiodination using aryl boronic acids through
a Chan–Evans–Lam cross-coupling reaction.
(
ar medicine and molecular imaging, for disease therapy with
bÀ emission (131I) and for in vivo non-invasive diagnosis and
therapy response monitoring with positron emission tomogra-
phy (PET) (124I) or single photon emission computed tomogra-
phy (SPECT) (123/125/131I).[1] The availability and well-defined
chemical properties of various radioactive iodine isotopes
make radioiodine a cornerstone in nuclear medicine.[2] Corre-
spondingly, the methods of labeling small molecules, peptides,
proteins, and antibodies with radioiodine will have a significant
impact on biomedical research and drug development.[3]
Although there have been a number of radioiodination
methods reported, they are generally restricted to using oxidiz-
ing agents to generate electrophilic iodine species such as mo-
lecular iodine or iodine monochloride, which then react with
an activated aromatic moiety or olefin group by electrophilic
substitution reactions[4] (for example, radioiododestannylation[5]
and radioiododeboronation[6]). Despite the wide use of these
[a] P. Zhang,+ R. Zhuang,+ Z. Guo, Prof. X. Zhang
Center for Molecular Imaging and Translational Medicine, State Key Labora-
tory of Molecular Vaccinology and Molecular Diagnostics, School of Public
Health, Xiamen University
Phenylboronic acid served as a model substrate to optimize
the labeling conditions. First, Cu2O was chosen as the cata-
lyst[14] and various ligands (Table 1) were examined to enhance
the efficiency of the copper-mediated reaction. When using
acetonitrile as the solvent, 1,10-phenanthroline was identified
as the most efficient ligand, which gave excellent RCY (>98%;
Table 1, Entry 1). Second, a series of Cu compounds were
chosen as catalysts; the RCY results shown in Table 1 demon-
strate that the catalytic efficiency of CuI compounds was much
higher than those of CuII compounds. Considering that the
iodine and chloride ions from the catalysts CuI and CuCl could
interfere with the radioiodine labeling progress, Cu2O was
chosen as the catalyst to perform other reactions. Then, we
Xiamen 361102 (P. R. China)
E-mail: zhangxzh@xmu.edu.cn
[b] Prof. X. Chen
Laboratory of Molecular Imaging and Nanomedicine (LOMIN)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
National Institutes of Health (USA)
Bethesda, Maryland 20892 (USA)
E-mail: shawn.chen@nih.gov
[c] Prof. X. Su
Zhongshan Hospital Affiliated of Xiamen University
Xiamen 361004 (P. R. China)
[+] These authors contributed equally to this work.
Supporting information for this article and ORCID(s) for the author(s) are
available on the WWW under:
http://dx.doi.org/10.1002/chem.201604105.
Chem. Eur. J. 2016, 22, 1 – 5
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
Table 1. Optimization of copper-mediated radioiodination of phenylbor-
onic acid.[a]
Entry
Ligand
Cu compound
RCY [%][b]
>98
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L1
L1
L1
L1
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
CuCl
CuCl2
CuBr2
37
26
5
4
>98
>98
12
5
[a] All reactions were performed using phenylboronic acid (2 mmol), aceto-
nitrile as solvent, Na131I (18.5—20 MBq, 5 mL in water) at 258C for one
hour. [b] Decay-corrected RCY determined by radio-HPLC.
turned our attention to the catalyst dosage (Supporting Infor-
mation, Table S1). The RCY remained high when the catalyst
concentration was as low as 5% (molar ratio) of the substrate
(98%; Supporting Information, Table S1, Entry 1). Results of re-
action time monitoring shown in the Supporting Information,
Table S1, confirmed that this radioiodination method was time-
dependent and the optimal reaction time was about 1 h,
which is acceptable for radioiodination labeling. The labeling
reactions under other commonly used solvents, such as metha-
nol, dichloromethane (CH2Cl2), tetrahydrofuran (THF), dimethyl-
formamide (DMF), and dimethyl sulfoxide (DMSO), were also
tested. Except for DMF and DMSO, all the other solvents could
be used and worked well for radioiodination (Supporting Infor-
mation, Table S1). Finally, the optimized labeling conditions
were as follows: substrate (2 mmol), Cu2O (0.4 mmol), and 1,10-
phenanthroline (0.8 mmol) dissolved in acetonitrile, Na131I
(18.5–20 MBq, 5 mL in water), reacted for 1 h at 258C to give
the final radio-product.
Scheme 1. Copper-mediated radioiodination. [a] 4 mmol triethylamine added,
[b] the precursor was dissolved in 10 mL pyridine, [c] reacted at 808C, [d] re-
acted under anhydrous conditions, [e] after deprotection of N-Boc with TFA.
hindrance effect may reduce the rate of this kind of cross-cou-
pling radioiodination reaction, when 2,4,6-trimethylphenylbor-
onic acid was chosen as the substrate, an increased reaction
temperature (808C) was required to have quantitative radiolab-
eling (Scheme 1, product 18).
For the purpose of labeling peptides, proteins, or antibodies
with radioiodine, the active ester of 4-carboxyphenylboronic
acid (PB-NHS) was synthesized and then labeled with 131I (131I-
SIB) (Scheme 1, product 19). The in vivo stability, versatility,
and feasibility of radioiodination of monoclonal antibodies
through succinimidyl para-iodobenzoate (SIB) has been dem-
onstrated by Wilbur et al.[15] The new method was used for the
radioiodination of the NHS ester (Scheme 2), which resulted in
a higher RCY (Figure 1, 99%) than those previously reported
(ca. 60–90%).[15] Furthermore, the peptide c(RGDyk) and the
The above conditions were used to test a variety of sub-
strates (Scheme 1) to explore the scope and limitation of this
labeling method. Under the optimized standard labeling condi-
tions, aryl boronic acids bearing different substituents includ-
ing formyl, nitro, cyano, hydroxyl, and ester groups and hetero-
arenes, such a as 3-furanboronic acid and pyridine-4-boronic
acid, were used as substrates and labeled with 131I in high
RCYs (Scheme 1). As illustrated in Scheme 1, in the presence of
electron-withdrawing or electron-donating substituents, the
substrates were all converted into the desired products with
excellent RCYs. Unprotected carboxyl is a special substituent
for this reaction because it can affect the coordination be-
tween the catalyst and aryl boronic acids; therefore, when la-
beling 4-carboxyphenylboronic acid (2 mmol), triethylamine
(4 mmol) was added to the mixture and a high RCY (98%) was
obtained (Scheme 1, product 14). Considering that the steric
Scheme 2. Synthesis of 131I-SIB.
&
&
Chem. Eur. J. 2016, 22, 1 – 5
www.chemeurj.org
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Figure 1. HPLC analysis of 131I-SIB and non-radioactive reference with UV and
radiometric detection.
Scheme 3. Synthesis of 131I-MIBG.
protein bovine serum albumin (BSA) were successfully labeled
with 125I using 125I-SIB, and the SPECT imaging results con-
firmed the good targeting ability and in vivo stability of the ra-
diopharmaceuticals synthesized using this labeling method
(Figure 2 and the Supporting Information, Figure S1).
Figure 2. SPECT imaging of c(RGDyk) labeled with 125I using 125I-SIB.
Figure 3. HPLC analysis of 131I-MIBG and non-radioactive references with UV
and radiometric detection.
Having demonstrated the generality of this radioiodination
method, the preparation of a clinically used imaging agent
was also investigated. Iodine-123- and iodine-131-labeled met-
aiodobenzyl-guanidine (123I-MIBG and 131I-MIBG) have been
used clinically for diagnosis and therapy of neuroectodermally
derived tumors like pheochromocytoma, carcinoid tumors, and
neuroblastoma for decades.[16] 123/131I-MIBG are generally syn-
thesized from the precursor of non-radioactive iodinated MIBG
coupling radioiodination is efficient, low-cost, technically
simple, and unlike other electrophilic labeling methods, re-
quires no oxidizing agents to produce molecular iodine and
iodine monochloride. Most importantly, the reaction conditions
are quite mild and most of the substrates were converted into
the desired products with excellent RCYs at room temperature.
The radioiodinated NHS ester (131I-SIB) was also obtained in
high RCY as an intermediate for a versatile radiolabeling pro-
cess with good in vivo stability and feasibility, which has been
demonstrated in the literature. All of these advantages make
this new radioiodination method attractive for clinical applica-
tions.
(
127I-MIBG) using a halogen exchange reaction. Consequently,
the radiolabeled product can’t be separated from the precur-
sor, which resulted in rather low specific activity. For 123/131I-
MIBG, about one molecule in 2000 was radiolabeled.[17] The
non-radiolabeled precursors competing against 123/131I-MIBG for
the norepinephrine transporter have a negative effect on diag-
nosis and therapy and may cause side-effects when the patient
is given escalation doses. Therefore, there is an unmet pressing
need for no-carrier-added radioiodinated MIBG for clinical ap-
plications. To address this challenge, we synthesized 131I-MIBG
(Scheme 1, product 20) using this newly developed radioiodi-
nation method (Scheme 3), with very high RCY (Figure 3, 98%).
Furthermore, the radiolabeled product 131I-Boc-MIBG could be
separated well from the labeling precursor by high per-
formance liquid chromatography (HPLC) as illustrated in
Experimental Section
General radioiodination procedure: Precursor (2 mmol) was added
into one 1.5 mL reaction vial; 50 mL of a solution of Cu2O/1,10-phe-
nanthroline in acetonitrile, which contained Cu2O (0.4 mmol) and
1,10-phenanthroline (0.8 mmol), was then added to the vial. Na131
I
(18.5–20 MBq) in 5 mL of water was added to the preceding mix-
ture and reacted for 1 h at 258C.
Figure 3 and the Supporting Information, Figure S2, which Acknowledgements
could improve the specific activity significantly.
In conclusion, a highly efficient new copper-mediated radio-
iodination method using Cu2O/1,10-phenanthroline as a cata-
lyst was developed for the facile radioiodination of aromatic
and heteroaromatic boronic acid systems. This kind of cross-
This study was financially supported by the National Key Basic
Research Program of China (2014CB744503) and the National
Natural Science Foundation of China (21271030, 81471707)
Chem. Eur. J. 2016, 22, 1 – 5
www.chemeurj.org
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
[8] R. M. Baldwin, Y. Zea-Ponce, M. Laurelle, M. S. Al-Tikriti, E. H. Sybirska,
R. T. Malison, J. L. Neumeyer, R. A. Milius, S. Wang, M. Stabin, Nucl. Med.
Biol. 1993, 20, 597–606.
and partially by the Fundamental Research Funds for the Cen-
tral Universities (20720150063, 2013SH009).
[9] G. W. Kabalka, M.-L. Yao, J. Org. Chem. 2009, 694, 1638–1641.
[10] a) J. Liefhold, M. Eisenhut, J. Labelled Compd. Radiopharm. 1986, 23,
1239–1241; b) A. R. Wafelman, M. C. Konings, C. A. Hoefnagel, R. A.
Maes, J. H. Beijnen, Appl. Radiat. Isot. 1994, 45, 997–1007.
[11] A. A. Cant, S. Champion, R. Bhalla, S. L. Pimlott, A. Sutherland, Angew.
Chem. Int. Ed. 2013, 52, 7829–7832; Angew. Chem. 2013, 125, 7983–
7986.
[12] a) D. M. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters, Tetrahedron Lett.
1998, 39, 2933–2936; b) P. Y. Lam, C. G. Clark, S. Saubern, J. Adams,
M. P. Winters, D. M. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941–
2944; c) D. A. Evans, J. L. Katz, T. R. West, Tetrahedron Lett. 1998, 39,
2937–2940.
[13] a) J. X. Qiao, P. Lam, Boronic Acids: Preparation and Applications in Or-
ganic Synthesis Medicine and Materials (Volumes 1 and 2), Second Edi-
tion 2011, 315–361; b) P. J. Moon, H. M. Halperin, R. J. Lundgren,
Angew. Chem. Int. Ed. 2016, 55, 1894–1898; Angew. Chem. 2016, 128,
1926–1930; c) N. Nebra, V. V. Grushin, J. Am. Chem. Soc. 2014, 136,
16998–17001.
[14] R. Zhuang, J. Xu, Z. Cai, G. Tang, M. Fang, Y. Zhao, Org. Lett. 2011, 13,
2110–2113.
[15] D. S. Wilbur, S. W. Hadley, M. D. Hylarides, P. G. Abrams, P. A. Beaumier,
A. C. Morgan, J. M. Reno, A. R. Fritzberg, J. Nucl. Med. 1989, 30, 216–
226.
[16] B. Shapiro, L. Fig, M. Gross, B. Shulkin, J. Sisson, in Nuclear Oncology,
Springer, 1999, pp. 3–31.
[17] R. J. Mairs, S. H. Cunningham, J. Russell, A. Armour, J. Owens, K. McKel-
lar, M. N. Gaze, J. Nucl. Med. 1995, 36, 1088–1095.
Keywords: copper catalysts
radiochemistry · radioiodination · radiopharmaceuticals
·
molecular imaging
·
[1] a) S. L. Pimlott, A. Sutherland, Chem. Soc. Rev. 2011, 40, 149–162;
b) M. J. Adam, D. S. Wilbur, Chem. Soc. Rev. 2005, 34, 153–163.
[2] a) C. Kratochwil, F. Giesel, W. Mier, U. Haberkorn, J. Nucl. Med. 2015,
56(S3), 216; b) J. Taki, H. Wakabayashi, A. Inaki, K. Ogawa, I. Matsunari,
M. Hiroe, K. Imanaka-Yoshida, K. Shiba, S. Kinuya, J. Nucl. Med. 2015,
56(S3), 1473; c) M. Williams, J. Christoforidis, K. Kumar, K. Briley, M.
Knopp, J. Nucl. Med. 2015, 56(S3), 1066; d) M. Ksepka, M. Becker, A.
Naidu, L. Sokol, S. Basak, J. Kempf, J. Nucl. Med. 2014, 55(S1), 1266.
[3] a) J. P. Dzandzi, D. R. Beckford Vera, A. R. Genady, S. A. Albu, L. J. Eltring-
ham-Smith, A. Capretta, W. P. Sheffield, J. F. Valliant, J. Org. Chem. 2015,
80, 7117–7125; b) R. Yan, K. Sander, E. Galante, V. Rajkumar, A. Badar, M.
Robson, E. El-Emir, M. F. Lythgoe, R. B. Pedley, E. ꢁrstad, J. Am. Chem.
Soc. 2013, 135, 703–709; c) M. Eisenhut, W. Mier, in Handbook of Nucle-
ar Chemistry, Springer, 2011, pp. 2121–2141.
[4] R. H. Seevers, R. E. Counsell, Chem. Rev. 1982, 82, 575–590.
[5] R. Hanson, G. Tonnesen, W. McLaughlin, W. Bloomer, D. Seitz, J. Labelled
Compd. Radiopharm. 1981, 18, 128–129.
[6] a) G. W. Kabalka, E. E. Gooch, K. A. Sastry, J. Nucl. Med. 1981, 22, 908–
912; b) G. W. Kabalka, R. S. Varma, Tetrahedron 1989, 45, 6601–6621;
c) L. Yong, M.-L. Yao, J. F. Green, H. Kelly, G. W. Kabalka, Chem. Commun.
2010, 46, 2623–2625; d) G. W. Kabalka, M.-L. Yao, M. Akula, L. Yong,
Pure Appl. Chem. 2012, 84, 2309–2315.
[7] a) R. Baldwin, T. Lin, J. Radioanal. Chem. 1981, 65, 163–165; b) C. N.
Bakker, F. M. Kaspersen, Int. J. Appl. Radiat. Isot. 1981, 32, 176–178; c) B.
Stagg, J. M. Temperley, H. Rochman, Nature 1970, 228, 58–59; d) N. M.
Alexander, J. Biol. Chem. 1974, 249, 1946–1952.
Received: August 30, 2016
Published online on && &&, 0000
&
&
Chem. Eur. J. 2016, 22, 1 – 5
www.chemeurj.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Radiochemistry
P. Zhang, R. Zhuang, Z. Guo, X. Su,
X. Chen,* X. Zhang*
&& – &&
A Highly Efficient Copper-Mediated
Radioiodination Approach Using Aryl
Boronic Acids
A convenient and quantitative radioio-
dination method was developed by
using a copper-mediated cross-coupling
of aryl boronic acids with high radio-
chemical yields (RCY) under mild label-
ing conditions. The variety of precur-
sors, simple operation, and broad func-
tional-group tolerance make it practical
for radioiodine labeling without further
purification.
Chem. Eur. J. 2016, 22, 1 – 5
www.chemeurj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ