A one-pot radioiodination of aryl amines: Via stable diazonium salts: Preparation of 125I-imaging agents

Article abstract of DOI:10.1039/c7cc06211g

An operationally simple, one-pot, two-step tandem procedure that allows the incorporation of radioactive iodine into aryl amines via stable diazonium salts is described. The mild conditions are tolerant of various functional groups and substitution patterns, allowing late-stage, rapid access to a wide range of ¹²⁵I-labelled aryl compounds and SPECT radiotracers.

Full text of DOI:10.1039/c7cc06211g

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DOI: 10.1039/C7CC06211G
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One-pot radioiodination of aryl amines via stable
diazonium salts: preparation of 125I-imaging agents†
Received 00th January 20xx,
Accepted 00th January 20xx
Nikki L. Sloan,a Sajinder K. Luthra,b Graeme McRobbie,b Sally L. Pimlottc and Andrew
Sutherland*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
An operationally simple, one-pot, two-step tandem an oxidative iodo-destannylation reaction (Fig. 1a).2,3a
procedure that allows the incorporation of radioactive While this method generates SPECT imaging agents with
iodine into aryl amines via stable diazonium salts is high specific activity and radiochemical purity,4 there are
described. The mild conditions are tolerant of various obvious toxicity risks associated with generation of clinical
functional groups and substitution patterns, allowing late- tracers from organotin compounds. In addition, the
stage, rapid access to a wide range of 125I-labelled aryl unstable nature of organotin compounds prevents long-
compounds and SPECT radiotracers.
term
storage
and
can
result
in
unreliable
radioiodinations.5 Although there are significant issues
associated with this approach, there have been relatively
few reports of new methods for the radioiodinaton of aryl
compounds.6 In 2013, we reported a nickel(0)-catalysed
radioiodination of aryl and heteroaryl bromides (Fig. 1b).7
While fast and efficient, this method requires elevated
temperatures (180 ºC) for complete conversion. More
recently, the groups of Gouverneur and Zhang described
the copper-mediated radioiodination of aryl boronic acids
and esters (Fig. 1c).8–11 As well as showing broad
substrate scope, these methods were used for the
preparation of various SPECT imaging agents.8,9
The combination of radionuclide labelled molecules and
nuclear imaging techniques has become important for the
study of dynamic biochemical processes at the molecular
and cellular level.1 The application of these technologies
has also extended into many aspects of medicine and
healthcare and include the diagnosis and prognosis of
disease, as well as utilisation in the drug discovery
process, such as understanding drug action and
establishing treatment strategies.2 A key technique within
this field is single photon emission computed tomography
(SPECT) which, in combination with radioactive tracers is
used for both preclinical in vitro measurements (123I/125I)
and in vivo diagnostic imaging (123I).3
Despite the importance of SPECT imaging, one of the
limitations preventing more widespread application of this
technique is the dearth of methods for incorporating
radioiodine into small molecules. In general, SPECT
tracers bearing an iodoarene unit are produced by a
substitution reaction using an electrophilic source of
radioactive iodine, prepared under oxidising conditions.3a
The most commonly used approach involves the
conversion of aryl halides into the corresponding
organostannane via palladium(0)-catalysis, followed by
We were interested in developing a new general
method for the radioiodination of aryl compounds with the
criteria of using widely available starting materials and
mild reaction conditions. The preparation of diazonium
salts from aryl amines followed by a Sandmeyer-type
reaction is a common approach for the preparation of aryl
iodides.12 However, previous attempts to use this two-
step transformation for radioiodination were largely
abandoned.13 The harsh acidic conditions required for the
formation of diazonium salts and their unstable,
potentially explosive nature led to unwanted by-products
and low radiochemical yields. Here we now report an
operationally simple, one-pot radioiodination of aryl
amines that overcomes these previous limitations.
Formation of the diazonium salts under mild conditions,
using
a
polymer-supported nitrite reagent and p-
toluenesulfonic acid (p-TsOH) as the proton source,
followed by direct radioiodination, has produced labelled
products in high radiochemical yield (Fig. 1d). Application
of this new strategy for the preparation of various SPECT
imaging agents is also described.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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2a. In particular, a concentration of 0.018 molV/LiewoAfrt1iclae O(n0li.n5e
mg of 1a in 200 µL of solvent) gave DaOnI:e10x.c10e3ll9e/Cn7tCRC0C6Y211oGf
93% (entry 3). The corresponding radio-HPLC
chromatogram for this reaction showed a particularly
clean transformation with no other radiolabelled side-
products (Fig. 2). Other variables of the one-pot tandem
process were also investigated such as reaction
temperature and the number of equivalents of reagents
(entries 4–8). Higher temperatures led to a drop in RCY
due to the formation of 4-nitrophenol as a side-product,
while higher quantities of reagents again led to inefficient
mixing of the small scale reaction and lower RCY.
Although high RCY was achieved using one equivalent of
both reagents (entry 7), the conditions used in entry 3
were deemed optimal for radioiodination.
a) Two-step radioiodo-destannylation approach
(Me3Sn)2
Pd(0)
125I
Br
SnMe3
[
125I]NaI
oxidant
R
R
R
b) Nickel(0)-mediated radioiodination of aryl bromides
[Ni(cod)2]
Br
125I
[
125I]NaI
NMP
R
R
c) Copper-mediated radioiodination of aryl boronic acids and esters
[Cu]
B(OR’)2
*I
1,10-phenanthroline
R
R
Na*I, MeOH/H2O
or MeCN
* = 123 or 131
d) One-pot radioiodination of anilines- This work
p-TsOH.H2O
MeCN
+
125I
NH2
N2
[
125I]NaI
Table 1 Optimisation of the one-pot diazotisation-radioiodination of 4-
nitroaniline (1a).a
TsO-
R
R
R
NMe3 NO2
125I
NH2
NMe3 NO2
Fig. 1 Methods for radioiodination of arenes.
p-TsOH.H2O
[
O2N
O2N
125I]NaI
1a
2a
A number of groups have shown that the key
limitations associated with the standard conditions of
diazonium salt formation, such as the use of strong acids
and sodium nitrite, which can lead to the release of
nitrogen oxides, can be avoided using a polymer-
supported nitrite reagent.14 These are simply prepared by
the ion exchange of tetraalkylammonium functionalised
resins, such as Amberlyst A-26, using an aqueous
solution of sodium nitrite. Filimonov and co-workers have
combined the use of a polymer-supported nitrite with mild
acidic conditions (p-TsOH) and showed that the resulting
tosylate diazonium salts were thermally stable and could
be used for the stepwise preparation of aryl iodides under
aqueous conditions.14c,d These advances served as a
starting point for the development of our rapid, one-pot
tandem radioiodination of aryl amines.
MeCN, 2 h
Entry
Conc. of 1a
(mol/L)
0.18
Eq. of
reagentsb
Temp (ºC)
RCY (%)
20
20
20
20
40
60
20
20
4
1
2
3
4
5
6
7
8
3
3
3
3
3
3
1
6
44
93
80
65
54
82
43
0.07
0.018
0.009
0.018
0.018
0.018
0.018
All reactions were performed using a 4–6 MBq solution of [125I]NaI in water
(0.01 mL). b Polymer-supported nitrite and p-TsOH.
a
Our initial studies focused on the development of a
mild, one-pot diazotisation-iodination of aryl amines that
would also be amenable for radioiodination. Preliminary
optimisation studies with 4-nitroaniline (1a) showed that
when using acetonitrile as the solvent, all the reagents
(polymer-supported nitrite, p-TsOH and sodium iodide)
could be added together, resulting in fast and efficient
tandem conversion to the corresponding iodide, 2a (86%
yield). These conditions were then investigated for the
radioiodination of 4-nitroaniline (1a), where radiochemical
yields (RCY) were determined by radio-HPLC analysis of
the crude product.15 Using [125I]NaI (4–6 MBq solution in
water) as the limiting reagent and three equivalents of
both the polymer-supported nitrite reagent and p-TsOH
gave a low RCY (Table 1, entry 1). The concentration of
1a in the reaction mixture was then varied and using
more dilute conditions, which allowed better mixing of
reagents, resulted in a dramatic increase in the RCY of
125I
O2N
2a
Fig. 2 Chromatogram obtained by analytical radio-HPLC of the reaction
mixture from the radioiodination of 4-nitroaniline (1a), showing a 93% yield
of radioiodide incorporation.
2 | J. Name., 2012, 00, 1-3
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The optimised radioiodination conditions were
evaluated for the preparation of a range of 125I-labelled
aryl compounds (Scheme 1). Under these standard
View Article Online
DOI: 10.1039/C7CC06211G
125I
NMe3 NO2
NH2
R
R
p-TsOH.H2O
125I]NaI, MeCN
20 ºC, 2 h
conditions,
electron-deficient
and
electron-rich
[
1a-m
125I
2a-m
compounds (1a–1h) with various substitution patterns
were found to be compatible and converted to the 125I-
iodinated compounds in excellent RCYs. Only two
substrates required further optimisation. The highest RCY
of 97% for 4-[125I]iodoanisole (2c) was achieved when the
one-pot tandem process was conducted at 40 ºC, while a
four-hour reaction gave the best RCY (94%) for 2-
MeO
125I
125I
125I
MeO
O2N
Br
MeO
OMe
2d, 94%
NO2
2c, 97%a
125I
2a, 93%
2b, 73%
OMe
125I]iodobenzophenone (2e).
COPh
125I
[
125I
MeO
MeO
125I
Having demonstrated the general scope of the one-pot
tandem diazotisation-radioiodination process on simple
arenes, the next stage of this work was to show that it
could also be applied to the synthesis of more complex
biologically active aryl iodides and SPECT radiotracers
(2i–2m, Scheme 1).16 Again, using [125I]NaI as the limiting
reagent in dilute conditions, it was found that an increase
in the amount of both the polymer-supported nitrite and p-
TsOH (to six equivalents) was required to achieve good
yields for a two hour reaction. Further optimisation
showed that a higher reaction temperature (60 ºC) gave
improved RCYs for some of the substrates. Overall, the
one-pot transformation was effective for all the targets,
leading to a new radiosynthesis of the well-established
imaging agents iomazenil (2i),17 a SPECT tracer of
central-type benzodiazepine receptors in brain tissue,
CN
Cl
2h, 64%
2e, 94%b
2f, 83%
2g, 61%
N
125I
CO2Et
N
NH
N
N
H
N
125I
O
Iomazenil (2i), 92%c
CNS1261 (2j), 64%c
O
N
NEt2
N
O
NMe2
125I
125I
IBOX (2k), 47%
CNS1261 (2j)18 a radioligand of the N-methyl-
D-aspartate
O
2l, 50%c
(NMDA) receptor and IBOX (2k), a SPECT imaging agent
of amyloid plagues.19 The best result was achieved for
NH
N
[
125I]iomazenil (2i), with a particularly clean reaction and a
O
125I
RCY of 92%. This is higher than the reported oxidative
iodo-destannylation of a tri-n-butylstannane precursor
(70%), which was complicated by the formation of non-
radioactive reduced and halogenated by-products.20 The
synthesis of [125I]iomazenil (2i) was also found to be
highly reproducible, with a RCY of 89 ± 8% (n = 9). This
study has also allowed the first preparation of a
radioiodinated version of quinoline-2-carboxamide 2l, a
high affinity agent (Ki 5 nM) for the translocator protein
(TSPO), a membrane protein that is overexpressed
during chronic neurodegeneration or acute brain injury.21
As a radiosynthesis of this compound is now developed,
the full potential of this tracer can be explored as a
potential SPECT imaging agent of neuroinflammation
processes associated with TSPO. The one-pot
diazotisation-radioiodination was also effective for the
preparation of phthalazinone 2m, which is a nanomolar
inhibitor (IC50 7 nM) and SPECT imaging agent of
poly(ADP-ribose) polymerase-1 (PARP-1), a therapeutic
target for the treatment of cancer.22 The previous 125I-
labelled synthesis of 2m was achieved by solid-state
halogen exchange using a bromide precursor. Although
this did give a 90% RCY, a reaction temperature of 210
ºC was required.
N
N
F
O
2m, 59%
a
Scheme 1 Scope of one-pot diazotisation-radioiodination.
Reaction
b
c
was performed at 40 ºC.
performed at 60 ºC
Reaction required 4 h.
Reaction was
As well as using widely available starting materials,
avoiding highly toxic reagents and harsh conditions, it
should be emphasised that other advantages of this one-
pot diazotisation-radioiodination process are a very
simple work-up procedure and isolation protocol.
Following completion of the reaction, the radioactive
mixture is filtered to remove the polymer-supported nitrite,
diluted and purified directly by HPLC to yield the 125I-
labelled compounds. These advantages were exemplified
with validation of the one-pot method for the synthesis
and purification of
[
125I]iomazenil (2i). The amine
precursor 1i was treated with [125I]NaI (4–6 MBq),
polymer-supported nitrite and p-TsOH at 60 ºC for 2
hours (Scheme 2). After HPLC purification, [125I]iomazenil
(2i) was isolated in 75 ± 10% radioactivity yield. The
radiochemical purity of 2i was measured as >99%, with a
This journal is © The Royal Society of Chemistry 20xx
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molar activity of 16.2 ± 1.22 GBq µmol–1. As with all
reactions, identification of the product was confirmed
using HPLC, demonstrating co-elution with a sample of
unlabelled iomazenil.
7
8
A. A. Cant, S. Champion, R. Bhalla, S. L. Pimlott and A.
View Article Online
Sutherland, Angew. Chem. Int. Ed.,D2O0I:1130.,105329,/C778C2C90.6211G
T. C. Wilson, G. McSweeney, S. Preshlock, S. Verhoog,
M. Tredwell, T. Cailly and V. Gouverneur, Chem.
Commun., 2016, 52, 13277.
9
P. Zhang, R. Zhuang, Z. Guo, X. Su, X. Chen and X.
Zhang, Chem. Eur. J., 2016, 22, 16783.
N
N
NMe3 NO2
10 Radioiodination of boron derived arenes using
chloramine-T has also been reported: (a) P. C.
Srivastava, A. P. Callahan, E. B. Cunningham and F. F.
Knapp, J. Med. Chem., 1983, 26, 742. (b) L. Yong, M.-
L. Yao, J. F. Green, H. Kelly and G. W. Kabalka, Chem.
Commun., 2010, 46, 2623.
11 A copper mediated non-radioactive iodination of aryl
boronate esters using iodide as the limiting reagent has
been reported: B. M. Partridge and J. F. Hartwig, Org.
Lett., 2013, 15, 140.
CO2Et
CO2Et
p-TsOH.H2O
N
N
[
125I]NaI, MeCN
60 ºC, 2 h
N
N
125I
NH2
O
O
1i
2i
radioactivity yield: 75 ± 10% (n = 2)
radiochemical purity: >99% (n = 2)
molar activity: 16.2 ± 1.22 GBq µmol–1 (n = 2)
Scheme 2 Radiosynthesis of [125I]iomazenil (2i).
12 (a) T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17,
1633. (b) H. H. Hodgson, Chem. Rev., 1947, 40, 251.
(c) C. Gali, Chem. Rev., 1988, 88, 765.
13 (a) G.-J. Meyer, K. Rössler and G. Stöcklin, J. Am.
Chem. Soc., 1979, 101, 3121. (b) S. M. Moerlein, C. A.
Mathis and Y. Yano, J. Labelled Compd. Radiopharm.,
1986, 33, 1237. (c) D. S. Wilbur, Bioconjugate Chem.,
1992, 3, 433.
In summary, an operationally simple, one-pot two-step
tandem process for the preparation of radioiodine
containing arenes from readily available anilines has
been developed. The use of mild conditions for diazonium
salt formation resulted in a process with broad scope that
is tolerant of a wide range of functional groups and
substitution patterns. In particular, this process allowed
the preparation of a range of important SPECT imaging
14 (a) M. Caldarelli, I. R. Baxendale and S. V. Ley, Green
Chem., 2000, 2, 43. (b) J. Merrington, M. James and M.
Bradley, Chem. Commun., 2002, 140. (c) V. D.
Filimonov, M. Trusova, P. Postnikov, E. A.
Krasnokutskaya, Y. M. Lee, H. Y. Hwang, H. Kim and
K.-W. Chi, Org. Lett., 2008, 10, 3961. (d) M. E. Trusova,
E. A. Krasnokutskaya, P. S. Postnikov, Y. Choi, K.-W.
Chi and V. D. Filimonov, Synthesis, 2011, 2154
15 The radiochemistry nomenclature used in this paper is
in accordance with the new guidelines recommended by
the Society of Radiopharmaceutical Sciences. See:
http://www.srsweb.org/nomenclature-guidelines and: P.
H. Elsinga, EJNMMI Radiopharmacy and Chemistry,
2017, 2:2.
agents, including
[
[
125I]iomazenil,
[
125I]CNS1261 and
125I]IBOX, as well as the first radiosynthesis of a high
affinity agent of TSPO, that can now be used to study
neuroinflammation. Current studies are investigating the
application of this method for the development of novel
SPECT imaging agents and the use of solid-phase
extraction for more simple and rapid purification.
Financial support from Medical Research Scotland
(studentship to N.L.S.), G.E. Healthcare Ltd and the
University of Glasgow is gratefully acknowledged.
16 See supplementary information for full details on the
synthesis of each amine precursor.
17 For example: (a) S. S. Zoghbi, R. M. Baldwin, J. P.
Seibyl, M. S. Al-Tikriti, Y. Zea-Ponce, M. Laruelle, E. H.
Sybirska, S. W. Woods, A. W. Goddard, R. T. Malison,
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and S. Kagami, Brain and Development, 2012, 34, 478.
18 (a) J. Owens, A. A. Tebbutt, A. L. McGregor, K.
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J. Durant and J. McCulloch, Nucl. Med. Biol., 2000, 27,
557. (b) R. J. J. Knol, K. De Bruin, B. L. F. Van Eck-
Smit, S. Pimlott, D. J. Wyper and J. Booij, Synapse,
2009, 67, 557.
19 Z.-P. Zhuang, M.-P. Kung, C. Hou, K. Plössl, D.
Skovronsky, T. L. Gur, J. Q. Trojanowski, V. M.-Y. Lee
and H. F. Kung, Nucl. Med. Biol., 2001, 28, 887.
20 B. J. McBride, R. M. Baldwin, J. M. Kerr and J.-L. Wu,
Appl. Radiat. Isot., 1991, 42, 173.
21 A. Blair, L. Stevenson, D. Dewar, S. L. Pimlott and A.
Sutherland, MedChemCommun., 2013, 4, 1461.
22 F. Zmuda, G. Malviya, A. Blair, M. Boyd, A. J.
Chalmers, A. Sutherland and S. L. Pimlott, J. Med.
Chem., 2015, 58, 8683.
Notes and references
1
2
3
(a) S. M. Ametamey, M. Honer and P. A. Schubiger,
Chem. Rev., 2008, 108, 1501. (b) P. W. Miller, N. J.
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4
5
For example: S. L. Pimlott, L. Stevenson, D. J. Wyper
and A. Sutherland, Nucl. Med. Biol., 2008, 35, 537.
For example: A. G. Horti, A. O. Koren, K. S. Lee, A. G.
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(a) N. L. Sloan and A. Sutherland, Synthesis, 2016, 48,
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7CC06211G
Graphical Abstract Graphic:
p-TsOH.H2O
125I]NaI, MeCN
N2+ TsO-
125I
NH2
Via:
[
R
R
R
NMe3 NO2
N
125I
CO2Et
N
O
N
NH
NMe2
125I
N
N
N
H
125I
O
IBOX
Iomazenil
CNS1261
Graphical Abstract Text:
A mild, general and efficient one-pot tandem process that produces radioiodinated
SPECT imaging agents from readily available aryl amines via stable diazonium salts
has been developed.