Nickel-mediated radioiodination of aryl and heteroaryl bromides: Rapid synthesis of tracers for SPECT imaging

Article abstract of DOI:10.1002/anie.201302800

Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [¹²³I]- and [ ¹²⁵I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[¹²³I]-A85380 (see scheme, Boc=tert- butyloxycarbonyl, cod=1,5-cyclooctadiene, TFA=trifluoroacetic acid). Copyright

Full text of DOI:10.1002/anie.201302800

Angewandte
Chemie
DOI: 10.1002/anie.201302800
Radiochemistry
Nickel-Mediated Radioiodination of Aryl and Heteroaryl Bromides:
Rapid Synthesis of Tracers for SPECT Imaging**
Alastair A. Cant, Sue Champion, Rajiv Bhalla, Sally L. Pimlott, and Andrew Sutherland*
Molecular imaging technologies in combination with radio-
nuclide-labeled molecules allow the noninvasive study of
biological processes in vivo at the molecular, cellular, and
whole-organ level.[1–3] The development of these techniques
has had a significant impact on healthcare with their use in
clinical diagnosis, drug development in the preclinical and
clinical phase, and biomedical research. In particular, the use
of single photon emission computed tomography (SPECT)
with radioiodinated probes has found widespread application
in biological research (125I) and diagnostic imaging (123I),
specifically with diseases associated with the central nervous
system.[2,3]
Labeling of small molecules for SPECT imaging using
radioiodine is generally restricted to electrophilic aromatic
substitution of activated arenes or iodo-demetalation of
arenes and alkenes.[1–5] The most commonly used approach
is a two-step procedure that involves a palladium(0)-catalyzed
stannylation of a halogenated arene or alkene followed by an
oxidative iodo-destannylation (Scheme 1a). This method
tends to generate iodinated compounds with excellent radio-
chemical purity and high specific activity.[6] However, there
are issues with this approach, such as toxicity concerns
associated with the potential of organotin residues in clinical
preparations of radioiodinated molecular imaging agents.
Furthermore, organotin compounds can be unstable, resulting
in unreliable radioiodination reactions. This also restricts the
viability of widespread distribution and long-term storage of
these precursors in healthcare facilities.
We now report a nickel-mediated, single-step halogen-
exchange reaction for the rapid and direct radioiodination of
aryl and heteroaryl bromides that overcomes these limitations
(Scheme 1b). As well as exploring the scope of this trans-
formation for the preparation of a range of [125I]-labeled
compounds, we also demonstrate its application for the
synthesis of 5-[123I]-A85380, a SPECT tracer used for imaging
neuronal nicotinic acetylcholine receptors (nAChR) in
humans.[7–10]
Optimal reaction conditions for a nickel(0)-mediated
halogen-exchange reaction were explored using 2-bromo-
naphthalene 1a as a substrate (Table 1). Nickel(0)-mediated
Table 1: Optimization of the nickel(0)-mediated radioiodination of 2-
bromonaphthalene.[a]
Entry
T [8C]
Ni compound/ligand
RCY [%][b]
1
2
3
4
5
6
7
160
160
160
160
180
180
180
–
0
7
NiBr2/nBu3P
NiBr2/dppb
NiBr2
NiBr2
Ni
19
19
29
26
93
Scheme 1. Radioiodination of aryl bromides.
[Ni(cod)2]
[a] All reactions were performed using 2-bromonaphthalene (2 mmol)
and 2.5–3.5 MBq [125I]-NaI. [b] Determined by HPLC. NMP=N-methyl-2-
pyrrolidinone.
[*] Dr. A. A. Cant, Dr. A. Sutherland
WestCHEM, School of Chemistry, University of Glasgow
G12 8QQ, Glasgow (UK)
E-mail: Andrew.Sutherland@glasgow.ac.uk
Homepage: http://www.chem.gla.ac.uk/staff/andrews/
Dr. S. Champion, Dr. S. L. Pimlott
halogen-exchange reactions have been reported previously
using either zinc[11a] or an electrochemical cell[11b] to reduce
a NiII catalyst to the active Ni0 species.[12] However, under
these reducing conditions, Ullmann-type homocoupled prod-
ucts are also formed. Therefore, based on our previous study
of aromatic Finkelstein reactions of aryl bromides,[13] the use
of tri-n-butylphosphine to mediate the reduction of nickel(II)
bromide giving a nickel(0) species for oxidative addition into
West of Scotland Radionuclide Dispensary
University of Glasgow & NHS Greater Glasgow and Clyde
G11 6NT, Glasgow (UK)
Dr. R. Bhalla
GE Healthcare, The Grove Centre
White Lion Road, HP9 7LL, Amersham (UK)
[**] Financial support from the Scottish Funding Council, SINAPSE, and
GE Healthcare is gratefully acknowledged. We would also like to
thank M. Beglan and Dr. T. H. Flowers for performing AAS
measurements.
the C Br bond, followed by halogen exchange with [125I]-NaI
À
and subsequent reductive elimination was initially investi-
gated.[14] At 1608C, this approach gave low radiochemical
yields (RCYs) of [125I]-2-iodonaphthalene 2a (entry 2).[15]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302800.
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Attempted iodination using other phosphine ligands, such as
bis(diphenylphosphinobutane) (dppb), gave similar results
(entry 3). Several attempts using nickel bromide without an
exogenous ligand and increasing the reaction temperature to
1808C did not result in any substantial improvement in
radiochemical yield (entries 4 and 5).
Although we were aware that the presence of the bromide
ion from the nickel complex could interfere with the
equilibrium of the halogen exchange, our previous success
with nickel(II) bromide during our non-radioactive study
demonstrated that iodination could be achieved using an
excess of NaI.[13] However, these initial results from the
development of a radioiodination reaction showed that when
the iodide ion, in this case [125I]-NaI, is the limiting reagent,
the equilibrium of halogen exchange is inhibited by the
presence of an excess of bromide ions. Therefore, we next
investigated non-halogen-containing sources of nickel(0).
While nickel powder gave low conversion because of poor
solubility, the reaction with bis(1,5-cyclooctadiene)nickel(0)
was successful. At 1808C, with a reaction time of one hour,
Figure 1. Chromatogram obtained by analytical radio-HPLC of the
reaction mixture from the radioiodination of 4-bromonitrobenzene
(1b), showing a yield of radioiodide incorporation of 96%.
reactions with no side products from processes such as SNAr
reactions (see Figure 1). [123I]- and [125I]-SPECT imaging
agents are generally prepared in low micromole quantities
and so the scalability of this transformation was investi-
gated.[2,3] The nickel(0)-mediated radioiodination of sub-
strates 2a–2h was also performed at a 4 mmol scale of
substrate. These reactions gave the [125I] products in similar
radiochemical yields (85–91%) as observed with the reaction
on a 20 mmol scale. Further studies using 2-bromonaphthalene
2a at 0.4 and 0.2 mmol were also implemented and consis-
tently afforded [125I]-2-iodonaphthalene in high radiochem-
ical yields.[17] Another important issue in developing new
radiolabeling methods for molecular imaging is that the
targets can be quickly and easily purified and are not
contaminated with by-products or reagents. For all the
reactions described in this manuscript, purification was
easily achieved using standard HPLC methods. Several of
the purified products were then analyzed by atomic absorp-
tion spectroscopy for the presence of nickel. Within the
detection level of this method (2.5 mgkgÀ1), nickel species
could not be detected in any of these samples.
[
125I]-2-iodonaphthalene 2a was produced in a radiochemical
yield of 93% (entry 7).[16]
The reaction conditions identified for the radioiodination
of 2-bromonaphthalene were evaluated for the preparation of
a range of [125I]-iodinated aryl and heteroaryl compounds
(Scheme 2). Electron-rich and electron-deficient o-, m-, and
p-substituted aryl compounds (2a–2h) were all compatible
and converted in excellent radiochemical yield under the
standard reaction conditions. While the temperature required
for this transformation is higher than that for other radio-
iodination methods,[6,7] analysis by radio-HPLC showed clean
As well as exploring the scope of radioiodination for the
synthesis of standard [125I]-aryl iodides, application of this
transformation to the preparation of more functionalized
compounds and imaging agents that are currently used
clinically was also investigated. Iniparib, the first poly(ADP-
ribose) polymerase (PARP) inhibitor to proceed to phase III
clinical trials for the treatment of triple-negative breast cancer
was rapidly produced in radioiodinated form using the nickel-
mediated halogen-exchange reaction.[18] Reaction of 4-
bromo-3-nitrobenzamide using [Ni(cod)2] (cod = 1,5-cyclo-
octadiene) and [125I]-NaI gave [125I]-iniparib 2i in 93%
radiochemical yield. This result now allows access to a new
SPECT imaging agent for the development of novel PARP
inhibitors. The nickel-mediated radioiodination reaction was
also employed for the preparation of 5-[125I]-A85380 2j,
a SPECT tracer used for imaging neuronal nicotinic acetyl-
choline receptors (nAChR) in humans.[7–10] Radioiodination
of
(2S)-3-bromo-5-{[1-(tert-butoxycarbonyl)-2-azetidinyl]-
methoxy}pyridine followed by removal of the tert-butyloxy-
carbonyl (Boc) protecting group mediated by trifluoroacetic
acid (TFA) gave 5-[125I]-A85380 2j in 95% radiochemical
yield. Some limitations using the nickel-mediated radioiodi-
nation reaction were also discovered. For example, attempted
Scheme 2. Scope of the [Ni(cod)2]-mediated radioiodination. Reactions
were performed using substrate (20 mmol) and [125I]-NaI (2.5–
3.5 MBq). Radiochemical yields were determined by HPLC. [a] After
deprotection of N-Boc group with TFA.
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radioiodination of Br-PK11195 to give [125I]-PK11195 2k, 1.0 CimmolÀ1. Identification of the product was confirmed
a
SPECT imaging agent of the translocator protein using HPLC by co-injection with a cold sample of 5-I-A85380.
(TSPO),[19] returned none of the expected [125I] product. In The more traditional two-step synthesis of 7 involving
this case, the halogen-exchange reaction with [Ni(cod)2] is formation of an organotin intermediate from 6 followed by
likely restricted by the steric congestion associated with the o- an oxidative [123I] iodo-destannylation reaction produces
substituted bromobenzene moiety.[20]
isolated 7 in comparable radiochemical yields (40–61%)
Having demonstrated the scope of [125I] radioiodination and radiochemical purity (> 95%) but generally with higher
typically used in preclinical imaging development, we wanted specific activities (1.7–149 CimmolÀ1).[7,8,9a] However, the syn-
to show that this approach could also be utilized for the thesis of the organotin precursor from 6 gives yields of only
effective preparation of [123I]-labeled compounds for clinical 42–44%,[8,22] and subsequent iodo-destannylation using chlor-
applications. This was achieved with a short five-step syn- amine-T as the oxidant produces a non-radioactive chloro-
thesis of 5-[123I]-A85380, the SPECT tracer used for imaging pyridine by-product, which decomposes further during the
nAChRs (Scheme 3). Because of the issues associated with radiochemical synthesis to give a nonseparable, highly potent
nAChR ligand.[7] Therefore, the use of our single-step, nickel-
mediated radioiodination gives 7 in significantly higher
overall yield without any purification issues.
A proposed reaction mechanism that is consistent with the
known chemistry of nickel(0)[11,23] and our data is shown in
Scheme 4. In this pathway, the electron-rich nickel(0) per-
Scheme 4. Proposed mechanism for the radioiodination of aryl bro-
mides with nickel(0).
Scheme 3. Radiosynthesis of 5-[123I]-A85380 (7). n=number of inde-
pendent experiments.
forms an oxidative addition with the aryl bromide, giving
a nickel(II) species. In the presence of radiolabeled sodium
iodide, a halogen exchange takes place. The resulting Ar–
NiII–*I species then undergoes reductive elimination to form
previous syntheses of the bromo-substituted precursor of 5- the radioiodinated aryl iodide product and regenerate Ni0. In
[
123I]-A85380,[8] a new approach was developed during these transition-metal-catalyzed halogen-exchange reactions, an
studies. Under standard conditions, the amino group of excess of the halide nucleophile is normally added to drive
commercially available (2S)-2-azetidinecarboxylic acid (3) the equilibrium of the process. In our case, where sodium
was protected with an N-Boc group, followed by chemo- iodide is the limiting reagent, the equilibrium is likely assisted
selective reduction of the carboxylic acid with borane. by the formation of the sodium bromide by-product.
Incorporation of the 5-bromo-3-pyridinol moiety is normally
In summary, a single-step method for generating [123I]-
achieved using a Mitsunobu reaction, however, problems and [125I]-SPECT imaging agents has been developed using
associated with purification led to the isolation of the coupled a rapid nickel(0)-mediated halogen-exchange reaction of aryl
product in only modest yields.[8] In this study, this obstacle was and heteroaryl bromides. The transformation was compatible
overcome using a low-molecular-weight MPEG-supported with a wide range of electron-rich and electron-deficient o-,
version of diethyl azodicarboxylate (MDEAD; reported by m-, and p-substituted aryl compounds and was utilized for the
Hartley and co-workers), which can be removed at the end of preparation of biologically active compounds, such as ini-
the reaction by solid-phase extraction with silica gel.[21] In the parib, a PARP inhibitor, and 5-I-A85380, a SPECT tracer for
first example of the use of this technology for the preparation imaging nAChRs in humans. The novel features of this
of an ether, the Mitsunobu reaction of alcohol 4 with 5- approach include the generation of these compounds directly
bromo-3-pyridinol 5 in the presence of MDEAD gave the from readily accessible, nontoxic, stable precursors as well as
coupled product 6 in 82% yield. The key radioiodination a short reaction time that allows facile preparation and
reaction was then performed under our optimized conditions purification of these SPECT imaging agents within the
using [123I]-NaI (74 MBq, 237.4 CimmolÀ1). Purification of the relatively long half-lifes of the isotopes involved (123I:
iodinated product by HPLC followed by TFA-mediated 13.2 h, 125I: 59.4 days). We expect this method to be widely
removal of the Boc protecting group gave 5-[123I]-A85380 7 utilized for the synthesis and development of SPECT radio-
in 46% isolated radiochemical yield, with a radiochemical ligands, and, although outside the scope of this study, the
purity of higher than 99% and with a specific activity of transformation also has the potential for [131I] labeling of
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[15] Radiochemical yield refers to the yield of a radiochemical
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present.
compounds for application in radiotherapy. Further studies to
extend the scope of this transformation for the preparation of
other imaging agents are currently underway.
Experimental Section
A solution of [123I]-NaI in 0.05m NaOH (74 MBq, 237.4 CimmolÀ1) in
a 2 mL reaction vial was blown to dryness under a stream of argon.
[Ni(cod)2] (0.5 mg, 1.8 mmol) was added, followed by a solution of
(2S)-3-bromo-5-{[1-(tert-butoxycarbonyl)-2-azetidinyl]methoxy}pyri-
dine (6) (1.5 mg, 4.4 mmol) in NMP (40 mL). The mixture was
vortexed and heated at 1808C for 0.75 h. After cooling to room
temperature, the reaction mixture was diluted with a solution of
acetonitrile (30 mL) in water (470 mL). A small sample was removed
for analytical HPLC to assess the incorporation of radioiodide. The
crude product was purified by semipreparative HPLC to separate the
5-[123I]-Boc-A85380 from precursor 6. The fraction containing 5-[123I]-
Boc-A85380 7 was evaporated to dryness, reconstituted in acetonitrile
(3 ꢀ 200 mL) and transferred to a conical-bottom vial. The intermedi-
ate product was blown to dryness under a stream of argon. Trifluoro-
acetic acid (300 mL) was then added, the mixture was vortexed and
heated at 558C for 0.25 h to effect deprotection. The final product was
blown to dryness under a stream of argon, then reconstituted in 0.9%
saline to afford 5-[123I]-A85380 7 in (46 Æ 8)% isolated radiochemical
yield, with specific activity of (1.00 Æ 0.19) CimmolÀ1 (n = 3). Quality
control was performed by analytical HPLC and radiochemical purity
was higher than 99% (n = 3). The identity of the product was
confirmed by co-injection with a cold sample of 5-I-A85380.
[16] The use of [Ni(cod)2] is critical for the success of the radio-
iodination. For example, repeating the reaction of entry 5 in
Table 1 (NiBr2 at 1808C) with two equivalents of the cod ligand
results in a similar yield (33%). This result shows that Ni0 is
important for an efficient process and that in the optimized
reaction (Table 1, entry 7), the role of the cod ligand is to
facilitate solubilization of the nickel species.
Received: April 4, 2013
Revised: April 30, 2013
Published online: June 18, 2013
[17] At 0.4 and 0.2 mmol scale, [125I]-2-iodonaphthalene 2a was
produced in 87% and 76% radiochemical yields, respectively.
[18] a) E. C. Y. Woon, M. D. Threadgill, Curr. Med. Chem. 2005, 12,
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Keywords: aryl bromides · halogen exchange · imaging agents ·
nickel · radioiodination
.
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