Rapid Cu-Catalyzed [211At]Astatination and [125I]Iodination of Boronic Esters at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.8b00232

Access to ²¹¹At- and ¹²⁵I-radiolabeled compounds in excellent RCCs and RCYs was achieved in just 10 min at room temperature using a Cu catalyst. The reaction conditions are applicable to a broad class of aryl and heteroaryl boronic reagents with varying steric and electronic properties as well as late-stage astatination and iodination of anticancer PARP inhibitors. This protocol eliminates the traditional need for toxic organotin reagents, elevated temperatures, and extended reaction times, providing a more practical and environmentally friendly approach to developing α-emitting radiotherapeutics.

Full text of DOI:10.1021/acs.orglett.8b00232

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid Cu-Catalyzed [211At]Astatination and [125I]Iodination of Boronic
Esters at Room Temperature
Sean W. Reilly, Mehran Makvandi,* Kuiying Xu, and Robert H. Mach*
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: Access to 211At- and 125I-radiolabeled compounds in excellent RCCs and RCYs was achieved in just 10 min at
room temperature using a Cu catalyst. The reaction conditions are applicable to a broad class of aryl and heteroaryl boronic
reagents with varying steric and electronic properties as well as late-stage astatination and iodination of anticancer PARP
inhibitors. This protocol eliminates the traditional need for toxic organotin reagents, elevated temperatures, and extended
reaction times, providing a more practical and environmentally friendly approach to developing α-emitting radiotherapeutics.
adiohalides are powerful imaging, diagnostic, and
therapeutic tools with vast applications in nuclear
isotopes, the scarcity of radioisotope production sites capable of
making 211At, and lack of understanding of the chemical
behavior of the element.6 An efficient late-stage astatination
strategy would provide a much-needed platform for developing
211At-based α-emitting therapeutics.
R
medicine.1 Of such, the α-emitting radionuclide 211At provides
an attractive approach to developing cancer therapeutics by
delivering high linear energy transfer (LET) radiation that, on
the atomic level, is more efficient at causing DNA damage than
β− emitters.2 While this radiation dose is highly cytotoxic to the
targeted cancer cell, the surrounding healthy tissue is spared
because of the 50−70 μm path length of the α particle.3
Compared to other α-emitting nuclides such as 212Bi (t1/2 = 1
Traditional routes to astatinated compounds proceed
through electrophilic destannylation of an organotin functional
group, allowing rapid incorporation of 211At (Scheme 1a).1,7,8
However, handling of toxic alkyltin reagents is required to
develop the aryl stannane precursors, and only modest yields of
the 211At-radiolabeled products are achieved. This is attributed
to the multiple oxidation states astatine can adopt, which makes
it difficult to obtain the desired, and nonstable, At+ species for
electrophilic substitution.9,10 In 2016, Brechbiel and co-workers
illustrated the use of aryl iodonium salts to access astatinated
aryl compounds through an SNAr mechanistic pathway
(Scheme 1b).11 This detailed report also demonstrated how
the regioselectivity was driven by electronic effects, as 211At
product formation proceeded with high selectivity for the aryl
ring containing the most electron-withdrawing substituent at
the para position. Despite the high yields obtained using this
method, astantination of the conjugate aryl group results in
unwanted side-product formation.
h), 213Bi (t1/2 = 46 min), and 226Th (t1/2 = 30 min), 211At (t1/2
=
7.2 h) displays a half-life that is economically viable for
radiochemistry, quality control, and transportation, which
allows the radionuclide to target less accessible tumor cells in
living systems.4 The 7.2 h half-life of 211At is better suited to
fast targeting vectors that are retained in tumors such as small
molecules. Although many groups have explored astatinated
peptides and antibodies, a recent study demonstrated that
oxidative lysosomal degradation of these targeting agents results
in dehalogenation in vivo.5 While 225Ac (t1/2 = 10 days), 223Ra
(t1/2 = 11.4 days), and 227Th (t1/2 = 18.7 days) have more
favorable half-lives for antibodies, these α-emitters require
ligand chelation in order to form stable chemical complexes
that often escape the respective radiobioconjugates. These
radionuclides also emit unwanted decay products and are
ineffective after a single α decay, resulting in toxic daughter
isotopes, which can be distributed throughout the body.4
Despite the clear advantages 211At offers, synthetic method-
ologies that can provide access to astatinated compounds are
exceedingly rare, mainly because of the absence of stable At
On the basis of previous reports illustrating the versatility of
the Chan−Evans−Lam reaction12−14 to access radioiodinated
and -fluorinated compounds via boronic reagents,15−22 we
Received: January 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00232
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Routes to 211At-Labeled Compounds
nylboronic N-methyliminodiacetic acid (MIDA) ester (entry
12), a pyramidalized class of boryl reagents, but low RCCs were
obtained (entry 12).
The optimized conditions were then applied to radio-
iodination and -astatination of aryl boronic esters with varying
functional groups (Scheme 2). The HPLC chromatograms of
Scheme 2. Scope of 125I and 211At Radiolabeling of Boronic
a
Esters
adapted a similar strategy to access 211At-labeled hetero(aryl)
synthons. This study complements those previous studies as
well as the Cu-assisted halogenation reports by Sanford and
Scott,23−25 demonstrating facile access to versatile α-emitting
synthetic building blocks.
In 2016, Zhang and co-workers outlined a Cu/ligand-
catalyzed radioiodination methodology using boronic acid
precursors, achieving good radiochemical conversions (RCCs)
in 1 h at room temperature.22 Therefore, we began our initial
investigation by screening several Cu sources in order to
identify an efficient catalyst for 125I radiolabeling of aryl boronic
esters that could be translated to astatination. Using the
Cu(pyridine)4OTf complex, we were able to obtain excellent
RCCs of 2 (Table 1, entry 5) in just 10 min at room
temperature with no ligand additives. Analogous boryl reagents
of 1 (entries 9−11) were also compatible with the outlined 125
I
radiolabeling protocol. We then investigated 4-methoxyphe-
Table 1. Optimization of 125I Radiolabeling of 4-
a
Methoxyphenyl Boryl Reagents
a
Standard conditions: 1 (15 μmol), Cu(pyridine)4(OTf)2 (0.75
b
entry
R
Cu source
mol %
RCC (%)
μmol), Na[125I] or Na[211At] solution (3−6 MBq) in 150 μL of
c
MeOH/ACN (4:1). RCCs for 125I- and 211At-labeled compounds were
1
2
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
none
none
0
5
5
5
5
5
1
5
5
5
5
5
NC
c
b
determined by radio-TLC (n = 3). RCCs for the 125I- and 211At-
Cu2O
NC
labeled compounds were determined by radio-HPLC (n = 3).
3
Cu(CO2CH3)2
7
1
4
Cu(OCOCF3)2·H2O
Cu(CH3CN)4OTf
50
91
95
80
NC
99
89
99
1
2
1
8
5
the respective nonradioactive 127I standards were used to
identify both the 125I- and 211At-labeled products because of the
nearly identical retention times of the radiolabeled congeners
resulting from the chemical similarities of iodine and astatine
(see the Supporting Information).
6
Cu(pyridine)4(OTf)2
Cu(pyridine)4(OTf)2
Cu(pyridine)4(OTf)2
Cu(pyridine)4(OTf)2
Cu(pyridine)4(OTf)2
Cu(pyridine)4(OTf)2
Cu(pyridine)4(OTf)2
7
d
c
8
9
B(OH)2
BF3K
1
4
1
10
11
12
We found the reaction conditions to be well-tolerant of both
electron-rich and -poor substrates (3a−c), including sterically
crowded substrates (3b and 3c), which have been reported to
slow down the transmetalation step in Cu-catalyzed radio-
labeling protocols.17,21,22 Excellent 125I and 211At RCCs were
also obtained with morpholine and piperazine substrates (3i
and 3j), which are prevalent nitrogen heterocycles found in
many bioactive compounds and FDA-approved drugs.26
Quantitative 125I and 211At RCCs were observed with 3k,
e
Bnep
f
MIDA
47 14
a
Standard conditions: 1 (15 μmol), Cu source (0.75 μmol), Na[125I]
b
solution (3−6 MBq) in 150 μL of MeOH/ACN (4:1). Determined
by radio-HPLC (average of n ≥ 2 runs). Product identities were
determined by HPLC using 4-iodoanisole as the reference standard.
c
d
e
NC = no conversion. No substrate was used. Bnep = boronic acid
f
neopentylglycol ester. MIDA = N-methyliminodiacetic acid.
B
DOI: 10.1021/acs.orglett.8b00232
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
providing access to 125I- and 211At-labeled benzoate N-
hydroxysuccinimide esters, compounds commonly employed
in radiolabeling of proteins.1,27,28 Good RCCs continued with
nitrogen and sulfur heterocyles, including five-membered-ring
systems as well (4l−p).
We next examined the efficiency of the method for 125I and
211At radiolabeling of molecules with potential clinical
applications (Scheme 3). Thus, we applied this radiolabeling
Scheme 3. Access to 125I- and 211At-Labeled PARP-1
Inhibitor Compounds via Boronic Ester Precursors 5a and
a
5b
Figure 1. Current synthetic radiolabeling routes of 6b.
Scheme 4. Access to 125I- and 211At-Labeled PARP-1
Inhibitor Compounds via Boronic Ester Precursor 5c
a
a
Standard conditions: 1 (15 μmol), Cu(pyridine)4(OTf)2 (0.75
μmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.75 μmol), Na[125I]
or Na[211At] solution (3−6 MBq) in 150 μL of MeOH/ACN (4:1).
RCCs and RCYs for 125I- and 211At-labeled compounds were
determined by radio-HPLC (n = 3).
approach to poly(ADP−ribose) polymerase inhibitors
(PARPi), effective cancer therapeutics for patients with
BRCA mutations,29 a current research focus in our laboratory.
However, using the optimized conditions with PARPi
precursors 5a and 5b, we achieved RCYs of only 61% and
69%, respectively. When utilizing a 1:1 ratio of Cu-
(pyridine)4(OTf)2 and the electron-rich ligand 3,4,7,8-
tetramethyl-1,10-phenanthroline, we obtained excellent RCCs
and RCYs of 6a and 6b.
The RCYs of 6b obtained using our catalytic approach rival
those in previous reports, outlined in Figure 1, which require
reaction temperatures of 100 °C or greater30,31 or reaction
times of 2 to 4 h.32,33 Although the astatinated analogue of 6b
was disclosed by Reiner and co-workers34 (no RCY reported),
they reported a 3 h synthetic procedure with 211At, an unusual
approach considering the 7.2 h half-life of the radionuclide.
Finally, we prepared 5c to access our previously reported
[
125I]KX135 and [211At]MM4 using our Cu/ligand protocol
a
Standard conditions: 1 (15 μmol), Cu(pyridine)4(OTf)2 (0.75
(Scheme 4). Compared with tin precursor 5c′, we were able to
obtain greater RCCs and RCYs using 5c with 125I and 211At
under much milder reaction conditions.
We have demonstrated the first approach to astatinated
compounds using boronic ester precursors, providing an
efficient and nontoxic protocol that eliminates the traditional
need for toxic organotin reagents. This divergent synthesis
delivers exceptional radionuclide incorporation for 125I and
211At at room temperature and is applicable to simple and
μmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.75 μmol), Na[125I]
or Na[211At] solution (3−6 MBq) in 150 μL of MeOH/ACN (4:1).
RCCs and RCYs for 125I- and 211At-labeled compounds were
determined by radio-HPLC (n = 3).
complex boronic ester precursors, allowing late-stage radio-
labeling with heavy halides. This platform can be applied to
C
DOI: 10.1021/acs.orglett.8b00232
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(17) Wilson, T. C.; McSweeney, G.; Preshlock, S.; Verhoog, S.;
Tredwell, M.; Cailly, T.; Gouverneur, V. Chem. Commun. 2016, 52,
13277.
other diverse and biologically relevant precursors, providing a
more practical approach for developing α-emitting therapeutics.
(18) Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.;
ASSOCIATED CONTENT
* Supporting Information
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Huiban, M.; Passchier, J.; Mercier, J.; Genicot, C.; Gouverneur, V.
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Angew. Chem., Int. Ed. 2014, 53, 7751.
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Chem. - Eur. J. 2016, 22, 16783.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00232.
General methods and radiolabeling protocol; synthesis,
characterization, and 1H and 13C spectra of boronic ester
precursors and 127I standards; and UV-HPLC and radio-
HPLC chromatograms; and radio-TLC traces (PDF)
(23) Ichiishi, N.; Canty, A. J.; Yates, B. F.; Sanford, M. S. Org. Lett.
2013, 15, 5134.
AUTHOR INFORMATION
Corresponding Authors
■
(24) Makaravage, K. J.; Brooks, A. F.; Mossine, A. V.; Sanford, M. S.;
Scott, P. J. H. Org. Lett. 2016, 18, 5440.
(25) Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.;
Sanford, M. S.; Scott, P. J. H. Org. Lett. 2014, 16, 3224.
(26) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257.
(27) Wilbur, D. S.; Hadley, S. W.; Hylarides, M. D.; Abrams, P. G.;
Beaumier, P. A.; Morgan, A. C.; Reno, J. M.; Fritzberg, A. R. J. Nucl.
Med. 1989, 30, 216.
*M.M.: Phone (215) 746-8755. E-mail: makvandi@
pennmedicine.upenn.edu.
*R.H.M.: Phone: (215) 746-8233. E-mail: rmach@
pennmedicine.upenn.edu.
ORCID
Sean W. Reilly: 0000-0002-1656-1895
Robert H. Mach: 0000-0002-7645-2869
Notes
(28) Guer
́
ard, F.; Navarro, L.; Lee, Y.-S.; Roumesy, A.; Alliot, C.;
Cherel, M.; Brechbiel, M. W.; Gestin, J.-F. Bioorg. Med. Chem. 2017,
́
25, 5975.
The authors declare no competing financial interest.
(29) Wang, Y.-Q.; Wang, P.-Y.; Wang, Y.-T.; Yang, G.-F.; Zhang, A.;
Miao, Z.-H. J. Med. Chem. 2016, 59, 9575.
ACKNOWLEDGMENTS
■
(30) Zmuda, F.; Malviya, G.; Blair, A.; Boyd, M.; Chalmers, A. J.;
Sutherland, A.; Pimlott, S. L. J. Med. Chem. 2015, 58, 8683.
(31) Webster, S.; O’Rourke, K. M.; Fletcher, C.; Pimlott, S. L.;
Sutherland, A.; Lee, A.-L. Chem. - Eur. J. 2018, 24, 937.
(32) Salinas, B.; Irwin, C. P.; Kossatz, S.; Bolaender, A.; Chiosis, G.;
Pillarsetty, N.; Weber, W. A.; Reiner, T. EJNMMI Res. 2015, 5, 1.
(33) Sloan, N. L.; Luthra, S. K.; McRobbie, G.; Pimlott, S. L.;
Sutherland, A. Chem. Commun. 2017, 53, 11008.
(34) Reiner, T.; Lewis, J. S.; Weber, W.; Rodriguez, B. S.; Carney, B.;
Carlucci, G. WO2016033293A1, 2016.
(35) Makvandi, M.; Xu, K.; Lieberman, B. P.; Anderson, R. C.;
Effron, S. S.; Winters, H. D.; Zeng, C.; McDonald, E. S.; Pryma, D. A.;
Greenberg, R. A.; Mach, R. H. Cancer Res. 2016, 76, 4516.
The Department of Energy is gratefully acknowledged for
financial support (Grant DE-SC0017250646 to R.H.M.).
S.W.R. conducted this research through the support of training
grant 5T32DA028874-07.
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DOI: 10.1021/acs.orglett.8b00232
Org. Lett. XXXX, XXX, XXX−XXX