Radioiodination of polymer-supported organotrifluoroborates

Article abstract of DOI:10.1002/jlcr.1837

To simplify the purification of radiolabeled compounds, a novel strategy that combines the advantages of polymer chemistry and organotrifluoroborate chemistry was examined. It was discovered that the no-carrier-added radioiodination of readily prepared Do

Full text of DOI:10.1002/jlcr.1837

Research Article
Received 11 May 2010,
Revised 20 July 2010,
Accepted 7 September 2010
Published online 30 November 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1837
Radioiodination of polymer-supported
organotrifluoroborates
Li Yong, Min-Liang Yao, Hall Kelly, James F. Green,
Ã
and George W. Kabalka
To simplify the purification of radiolabeled compounds, a novel strategy that combines the advantages of polymer
chemistry and organotrifluoroborate chemistry was examined. It was discovered that the no-carrier-added radioiodination
of readily prepared Dowex-supported organotrifluoroborates can be successfully achieved using a variety of oxidants,
including a polymer-supported oxidant.
Keywords: radioiodination; polymer; organotrifluoroborates; radiopharmaceuticals
Initially reactions using stable sodium iodide were examined
to verify that the Dowex-supported organotrifluoroborate
reagents were effective precursors for the iododeboronation
reaction and that the iodinated products could be readily
removed from the resin-supported precursors. Iodination of
Dowex-supported 2-naphthelenyltrifluoroborate was carried out
in the presence of oxidizing agents (chloramine-T and iodo-
beads were examined). The iodination of the Dowex-supported
organotrifluoroborate proceeded smoothly in refluxing THF-H2O
(v/v, 1:1) using either oxidant. After completion of the iodination
reaction, the product was extracted into hexane-ethyl acetate
(v/v, 20:1, 1 mL) and then purified using a small silica gel
column. Formation of 2-iodonaphthelene was verified by NMR
spectroscopy.
In light of the success of the preliminary iodination experi-
ments, the no-carrier-added radioiodination of a Dowex-sup-
ported trans-2-(4-trifluoromethylphenyl)-vinyltrifluoroborate was
examined using no-carrier-added Na123I in the presence of
various oxidants. Among the oxidants examined, chloramine-T
gave the highest radiochemical yield (65%) when compared to
peracidic acid (14%), hydrogen peroxide (0%), and iodo beads
(13%). In earlier radioiodination–deboronation studies, the use of
hydrogen peroxide consistently resulted in low yields of the
desired radioiodinated products.4,8 The no-carrier-added radio-
iodination of Dowex-supported organotrifluoroborate using iodo
beads is attractive because of the simple isolation of the
radiolabeled products after the reaction, only the desired
radiolabeled product is soluble in the reaction medium wheras
the polymeric precursor and oxidant are not. Therefore, additional
reaction parameters such as pH variations (using NaH2PO4-
Na2HPO4 buffers), reaction solvents, and reaction times were
The synthesis of molecules containing short-lived radioisotopes
has become increasingly important with the advent of tomo-
graphic imaging techniques that permit the evaluation of
dynamic processes and pathologies in vivo. Efficient methods
that facilitate either the preparation or purification of radio-
tracers have become increasingly important. To simplify
purification procedures, labeling strategies employing poly-
mer-supported1,2 and fluorous-tagged3 (a solution-phase analo-
gue of the solid-phase) precursors have been developed. The
principle of these strategies is that, after reaction with the
desired radionuclide, the radiolabeled product is released into
solution. The excess polymeric precursor is then easily removed
by simple filtration techniques.
Organoboron compounds are useful precursors for radio-
pharmaceutical preparations due to their ready availability and
low toxicity. Over the years, we have developed several methods
for incorporating short-lived and long-lived isotopes into useful
molecules based on organoborane, organoboronic acid, and
organotrifluoroborate intermediates.4,5 We also evaluated the
use of polymeric organoborane reagents a number of years
ago.1 As proof of principle, we synthesized polystyrene-
supported organoboranes and then successfully used them as
precursors in the preparation of nitrogen-13 labeled g-amino-
butyric acid and putrescine.6 However, this methodology found
few practical applications because the polymeric organoboron
precursors were unstable under atmospheric conditions. Recent
studies involving the organotrifluoroborate derivatives have
demonstrated that they are remarkably stable under atmo-
spheric conditions and can ‘carry’ a plethora of pharmaceutically
important functional groups late into reaction sequences.
To incorporate the advantages of polymer chemistry and
organotrifluoroborate chemistry into radiolabeling applications,
we have developed a straightforward method to synthesize
polymer-supported organotrifluoroborates using ion-exchange
in aqueous methanol at room temperature (Scheme 1).7 A series
of air- and water-stable Dowex-supported organotrifluorobo-
rates have been prepared. Herein we report their application in
radioiodination reactions.
Departments of Chemistry and Radiology, University of Tennessee, Knoxville, TN
37996-1600, USA
*Correspondence to: George W. Kabalka, Departments of Chemistry and
Radiology, University of Tennessee, Knoxville, TN 37996-1600, USA.
E-mail: kabalka@ion.chem.utk.edu
J. Label Compd. Radiopharm 2011, 54 173–174
Copyright r 2010 John Wiley & Sons, Ltd.

L. Yong et al.
Table I. No-carrier-added radioiodination of Dowex-sup-
ported organotrifluoroborates
Ar BF3K
+
+
OH-
NR3
Ar BF
3 NR3
+
-
Na123
I
polymer-supported
quaternary amine
123I
Ar BF3
Ar
THF-H2O (1:1)
reflux
NR3
-
+
Scheme 1. Synthesis of Dowex-supported organotrifluoroborate reagents.
Ar
Reaction
time (min)
Radiochemical
yield (%)
examined for radioiodinations using iodo beads. However, no
enhancements in radiochemical yields were observed.
Phenyl
2-Naphthelenyl
4-Ph-phenyl
20
20
25 (20)
20
20 (25)
20
20
20
25 (30)
29
34
67 (45)
46
95 (90)
37
0
33
65 (48)
No-carrier-added radioiodinations of a series of Dowex-
supported organotrifluoroborates were then examined using
chloramine-T as the oxidant. The radioiodinations proceeded
rapidly for organotrifluoroborates bearing electron-donating
groups (Table I). The presence of a nitro group completely
inhibited the reaction (an observation that had been made
earlier).8 After filtering the reaction mixture through a silica
Sep-Pak Plus cartridge (Waters), the radiochemical purity of the
products typically exceeded 98% (Figure 1).
4-tBu-phenyl
3,5-Dimethyphenyl
3,4,5-Trimethoxyphenyl
4-NO2-phenyl
(E)-2-(Phenyl)vinyl
(E)-2-(40-CF3-phenyl)vinyl
Typical procedure for no-carrier-added radioiodination
1800
1600
1400
1200
1000
800
The Dowex-supported organotrifluoroborate (10 mg), aqueous
THF (500 mL), and the oxidant were added to a 2 mL Wheaton vial
and the vial capped with a rubber-seal. No-carrier-added Na123
I
(37 MBq, 0.1% aqueous NaOH) in water (100mL) was then added
to the vial and the mixture stirred at 601C. The reaction progress
was monitored by radio-TLC. After completion, the product was
extracted into hexane-ethyl acetate (v/v, 20:1, 1 mL) and then the
organic layer was passed through a silica gel cartridge using
hexanes as eluant. The total synthesis time was about 40–50 min.
In conclusion, the no-carrier-added radioiodination of Dowex-
supported organotrifluoroborates was achieved. The radiolabeling
of the Dowex-supported organotrifluoroborates occurred success-
fully using a varitey of oxidants but chloramine-T generated the
highest yields of the desired product. Overall, the yields obtained
parallel those achieved in previous small molecule studies (non-
polymeric organotrifluoroborates) but tended to be slightly lower,
presumabley due to the heterogenious reaction conditions.
600
400
200
0
0
20
40
60
80
100
position (mm)
Acknowledgement
Figure 1. Radio-TLC of I-123 labeled trans-2-(4-trifluoromethylphenyl)vinyl iodide
after filtration through a Sep-Pak Plus silica cartridge.
Acknowledgment is made to the Donors of U.S. Department of
Energy and the Robert H. Cole Foundation for support of this
research. We also thank Frontier Scientific, Inc. for supplying a
number of organoboron reagents and Dr. Thomas Lee Collier for
his insightful comments.
Med. Biol. 2000, 27, 803; (g) D. H. Hunter, M. Janabi, PCT Int. Appl.
2002070020, 2002; (h) S. Mundwiler, L. Candreia, P. Hafliger,
K. Ortner, R. Alberto, Bioconjugate Chem. 2004, 15, 195;
(i) A. G. Hernan, P. N. Horton, M. B. Hursthouse, J. D. Kilburn, J.
Organometallic Chem. 2006, 691, 1466; (j) R. W. Riddoch,
P. Schaffer, J. F. Valliant, Bioconjugate Chem. 2006, 17, 226; (k)
M. Gacek, H. Priebe, N. J. Osborn, PCT Int. Appl., 2007066089, 2007.
[3] (a) A. Donovan, J. Forbes, P. Dorff, P. Schaffer, J. Babich,
J. F. Valliant, J. Am. Chem. Soc. 2006, 128, 3536; (b) J. W. McIntee,
C. Sundararajan, A. C. Donovan, M. S. Kovacs, A. Capretta,
J. F. Valliant, J. Org. Chem. 2008, 73, 8236.
[4] (a) G. W. Kabalka, J. Label. Compd. Radiopharm. 2007, 50, 888;
(b) G. W. Kabalka, Acc. Chem. Res. 1984, 17, 215.
[5] (a) G. W. Kabalka, M.-L. Yao, J. Organometallic Chem. 2009, 694,
1638; (b) H. M. Schuller, G. W. Kabalka, U.S. Patent Appl Pub. US
2006067879, 2006.
References
[1] (a) G. W. Kabalka, M. M. Goodman, J. F. Green, R. Marks, D. Longord,
J. Label. Compd. Radiopharm. 1993, 32, 165; (b) G. W. Kabalka,
J. F. Green, M. M. Goodman, J. T. Maddox, S. J. Lambert,
Radioparmaceutical synthesis via boronated polymers, in Current
Topics in the Chemistry of Boron (Eds.: G. W. Kabalka), The Royal
Society of Chemistry, Cambridge, UK, 1994, pp. 199–203.
[2] (a) P. A. Culbert, D. H. Hunter, React. Polym. 1993, 19, 247;
b) K. Kowai, H. Ohta, M. A. Channing, A. Kubodera, W. C. Eckelman,
Appl. Radiat. Isotopes, 1996, 47, 37; (c) L. P. Szajek, M. A. Channing,
W. C. Eckelman, Appl. Radiat. Isotopes, 1998, 49, 795;
(d) D. H. Hunter, X. Zhu, J. Label. Compd. Radiopharm. 1999, 42,
653; (e) A. Pollak, D. G. Roe, C. M. Pollock, L. F. L. Lu,
J. R. Thornback, J. Am. Chem. Soc. 1999, 121, 11593; (f) R. Dunn-
Dufault, A. Pollak, J. Fitzgerald, J. R. Thornback, J. R. Ballinger, Nucl.
[6] (a) G. W. Kabalka, Z. Wang, J. F. Green, M. M. Goodman, Appl. Rad.
Isotopes, 1992, 43, 389; (b) G. W. Kabalka, V. Namboodiri,
M. Akula, Radiolabel. Compds. Radiopharm. 2001, 42, P5793.
[7] L. Yong, M.-L. Yao, J. F. Green, H. Kelly, G. W. Kabalka, Chem.
Commun. 2010, 46, 2623.
[8] (a) G. W. Kabalka, A. R. Mereddy, Tetrahedron Lett. 2004, 45, 343;
(b) G. W. Kabalka, A. R. Mereddy, Nucl. Med. Biol. 2004, 31, 935.
www.jlcr.org
Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 173–174