Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical Applications

Article abstract of DOI:10.1002/cplu.201402031

A highly stable copper(I) complex was obtained starting from a copper(II) salt. This compound was characterized by a combination of several analytical techniques (UV/Vis spectroscopy, energy-dispersive X-ray spectroscopy, electrochemistry, and X-ray photo

Full text of DOI:10.1002/cplu.201402031

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DOI: 10.1002/cplu.201402031
Synthesis and Characterization of a Stable Copper(I)
Complex for Radiopharmaceutical Applications
Ewen Bodio,[a, b] Mohammed Boujtita,[a] Karine Julienne,[a] Patricia Le Saec,[c]
Sꢀbastien G. Gouin,[a] Jonathan Hamon,[d] Eric Renault,[a] and David Deniaud*[a]
A highly stable copper(I) complex was obtained starting from
a copper(II) salt. This compound was characterized by a combi-
nation of several analytical techniques (UV/Vis spectroscopy,
energy-dispersive X-ray spectroscopy, electrochemistry, and
X-ray photoelectron spectroscopy) and was shown to present
an N4Cu structure. These results were confirmed by a density
functional calculations study of the binding energy and the
electronic structure of model ligand and copper complexes.
Preliminary tests of complexation showed a high ability of the
corresponding ligand to chelate 64Cu in very diluted medium,
which is of interest for developing new positron emission to-
mography imaging agents. The stability and the kinetic inert-
ness of the complex are promising. In particular, it displayed
good redox stability, which is important because in vivo reduc-
tion or oxidation of the copper of Cu complexes can lead to
demetalation. The rapid microwave-assisted strategy used to
synthesize the ligand was applied to the synthesis of more
than ten ligands. One of these was functionalized by an amino
group to form a bifunctional chelate for a future bioconju-
gation for applications in nuclear medicine.
Introduction
Over recent years, medical imaging has become one of the
main interests in therapeutic chemistry. Progress in instrumen-
tation and the need to diagnose diseases at their early stages
are some of the reasons for such an interest. Moreover, identi-
fying the target(s) of a drug and understanding the mecha-
nism of action of a new compound are becoming essential re-
quirements for their acceptance in clinical-phase trials. This has
led to the development of the new field of theranostics. The
term theranostics has been coined to describe this emerging
area of research, which focuses on agents that could be used
in both imaging and therapy.[1] In our case, this consists of
taking advantage of the duality of an element such as copper,
which possesses both a b+ emitter (64Cu), used as a positron
emission tomography (PET) imaging agent, and a bꢀ emitter
(67Cu), used as a radiotherapeutic entity.
64
1
The long half-life of Cu (t = =12.7 h) allows a satisfactory
2
accumulation of radionuclides in the tumor.[2] Furthermore,
64Cu presents a good spatial resolution for PET imaging, equiv-
alent to 18F.[3] Some studies have shown that it gives the high-
est effective dose and, above all, that it can be used in prelimi-
nary dosimetry studies for radioimmunotherapy (use of radiola-
beled antibodies to target tumor cells and destroy them).[4] In
fact, the key problem in radioimmunotherapy is to be able to
measure the amount of radioactivity bound to the tumor cells
(as this depends on the kind of cancer, the vector, and even
on the patient). Thus, with 64Cu, a PET image can be obtained
and the radioactivity can be quantified. As the same vector
can be used to transport 67Cu to tumor cells, the pharmacoki-
netics will be the same and the quantity of 67Cu linked to the
tumor will be known.
[a] Dr. E. Bodio, Dr. M. Boujtita, Dr. K. Julienne, Dr. S. G. Gouin, Dr. E. Renault,
Dr. D. Deniaud
LUNAM Universitꢀ, CEISAM
Chimie et Interdisciplinaritꢀ, Synthꢁse, Analyse, Modꢀlisation
UMR CNRS 6230, UFR des Sciences et des Techniques
2 rue de la Houssiniꢁre, BP 92208, 44322 Nantes Cedex 3 (France)
E-mail: david.deniaud@univ-nantes.fr
To target copper selectively to cancerous tissues, a peptide,
peptidomimetic, or an antibody can be used. The key element
of this strategy is the bifunctional chelate (BFC), the entity that
binds the radionuclide to the vector. An ideal BFC binds the
targeted radiometal rapidly with a high specificity and yield.
Furthermore, the resulting complex should be both thermody-
namically stable and, more importantly, kinetically inert toward
in vivo transchelation or transmetalation processes. To form
a complex with copper, a large variety of acyclic, macrocyclic,
and macrobicyclic polyamine BFCs have been studied and re-
ported.[5] However, the choice of the chelator is critical given
that recent studies have shown that it can influence the radio-
labeling of the bioconjugate, its targeting, and its pharmacoki-
netics.[6] Clearly, it is still important to develop new copper che-
lators. Cyclen and cyclam macrocyclic derivatives have com-
[b] Dr. E. Bodio
Institut de Chimie Molꢀculaire de l’Universitꢀ de Bourgogne
UMR CNRS 6302, Universitꢀ de Bourgogne
9 avenue A. Savary, BP 47870, 21078 Dijon (France)
[c] P. Le Saec
Centre de Recherche en Cancꢀrologie de Nantes-Angers, UMR CNRS 6299
INSERM U892, Institut de Recherche Thꢀrapeutique, Universitꢀ de Nantes
9 quai Moncousu, 44093 Nantes Cedex 1 (France)
[d] J. Hamon
IMN, Institut des Matꢀriaux Jean Rouxel, UMR CNRS 6502
UFR des Sciences et des Techniques
2 rue de la Houssiniꢁre, BP 92208, 44322 Nantes Cedex 3 (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cplu.201402031.
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monly been used as copper chelators, owing to their commer-
cial availability, their good thermodynamic stability, and their
relatively rapid complexation kinetics. Nevertheless, almost all
of these BFCs have been shown to be susceptible to the re-
duction and release of copper, which is then transchelated to
proteins present in both blood and liver and results in high
liver uptake.[7] To overcome this poor kinetic inertness, cross-
bridged or macrobicyclic derivatives (e.g., CB-TE2A or SarAr)
have been studied as copper chelators but have shown either
very slow complexation kinetics[8] or poor electrochemical sta-
bility.[9] Copper complexes of bis(thiosemicarbazone) ligands
represent another important class of compounds and have
been investigated extensively, mainly for hypoxia imaging, in
the form of Cu-ATSM.[10] These kinds of ligands are of interest
because of their high complexation kinetics, the ease and effi-
ciency of their synthesis, and their ability to form neutral com-
plexes. Nevertheless, even though they show an excellent ther-
modynamic stability, copper complexes of bis(thiosemicarba-
zone) ligands have sometimes been reported as having a poor
kinetic inertness.[11]
Figure 1. Complexation of L1 with Cu(OAc)2.
Characterization of the complex CuL1
Although various crystallogenesis experiments (gel permeation,
“H-tube” crystallization, and slow solvent evaporation) were
performed, a monocrystal suitable for X-ray analysis could not
be obtained. Unfortunately, NMR and EPR studies of CuL1
were unsuccessful (relaxation was very fast and thus the NMR
signals were very broad and no significant EPR signal was ob-
served). Several analytical techniques were therefore combined
to determine the structure of the complex CuL1.
Our group reported the synthesis of new tetradentate li-
gands, with a bis(thiosemicarbazone) skeleton, which display
a high ability for chelating 64Cu in very diluted medium.[12] Al-
though these results were promising, some elements were
missing to consider these ligands good BFCs. First, the copper
complex obtained needed to be fully characterized: 1) ligand/
metal stoichiometry, 2) oxidation state of the copper,
3) number of different complexes formed, and 4) atoms chelat-
ing the metal. Then, the stability of the complex had to be
checked: 1) in acidic medium, 2) in the presence of other li-
gands or metals, and 3) upon redox processes (the reactions
CuII$CuI are the main explanation for the poor kinetic inert-
ness of most copper complexes). Finally, the ligand needed to
possess a group that could be functionalized, such as “NH2”,
for coupling with the vector.
Determination of the stoichiometry of the complex CuL1
The significant color change during the reaction (see Figure 1)
prompted us to study its evolution by UV/Vis spectrometry.
The UV/Vis spectrum of L1 displayed two main absorption
bands at 395 and 505 nm. On recording the spectrum of the
complex CuL1, only one main absorption band appeared at
440 nm (Figure 2). A deconvolution of this spectrum showed
that no signal of L1 remained. Moreover, monitoring by UV/Vis
spectroscopy over time clearly showed isosbestic points, and
the addition of a further one or two equivalents of copper did
not change the spectrum (Figures S1 and S2 in the Supporting
Information). It could thus be concluded that with one equiva-
Results and Discussion
A
preliminary study was performed with the ligand L1
(Scheme 1), which was chosen because the chlorine atoms on
this chelating agent could be used as probes for further
energy-dispersive X-ray spectrosco-
py (EDX) analysis. The ligand was
obtained in a three-step micro-
wave-assisted strategy described
previously.[12] The copper complex
CuL1 was synthesized by the reac-
tion of one equivalent of ligand L1
with one equivalent of copper(II)
diacetate in dimethylformamide
(DMF) for one hour at room tem-
perature or for five minutes at
Scheme 1. Structure of li-
110 8C under microwave (MW) irra-
gand L1.
diation (Figure 1).
Figure 2. UV/Vis absorption spectra of L1 and CuL1 (the spectra were re-
corded in DMF, [L1]=6ꢂ10ꢀ5 m, [CuL1]=3ꢂ10ꢀ5 m).
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lent of copper(II), all the ligand reacted with the copper (stoi-
chiometry L1/Cu: 1:1).
tential window in the range of ꢀ0.9 to 0.7 V, at which no elec-
trochemical response was observed for L1. Figure 5 displays
a quasi-reversible process for CuL1 with anodic and cathodic
peaks at potentials around 0.55 and 0.30 V versus SCE, respec-
tively. From the comparison between the voltammograms of
L1 and CuL1, a quasi-reversible redox process can be assigned
To confirm this conclusion, an EDX analysis linked to scan-
ning electron microscopy (SEM) was performed on L1 and
CuL1. The results pointed to the presence of two equivalents
of sulfur or of chlorine and one of copper. That meant that the
complex had a ligand/copper stoichiometry of 1:1. Moreover,
we took advantage of this analysis to take a picture of L1 and
CuL1, which displayed striking differences in appearance
(Figure 3). This stoichiometry was confirmed by mass spec-
trometry; the spectra (MALDI, 2,5-dihydroxybenzoic acid (DHB)
matrix) for CuL1 possess an isotopic pattern corresponding to
(CuL1+H+) at m/z=667.
Figure 3. Scanning electron microscopy (SEM) images of L1 and CuL1
(ꢂ220). Scale bars: 100 mm.
Determination of the oxidation state of the metal
Copper often undergoes oxidation and reduction reactions, so
it is worth checking its oxidation state. In the complexation re-
action, copper(II) was employed. To determine if it was Cu0,
CuI, or CuII in CuL1, a voltamperometric study was performed.
The electrochemical behavior of both free ligand L1 and
copper complex CuL1 was examined by cyclic voltammetry in
DMF containing 0.1 molLꢀ1 tetrabutylammonium hexafluoro-
phosphate. The free ligand L1 displayed an irreversible process
at a potential of about 0.85 V versus a saturated calomel elec-
trode (SCE; Figure 4) that could be attributed to the electro-
chemical oxidation of S or N centers. The electrochemical be-
havior of the complex CuL1 was thus examined within the po-
Figure 5. Electrochemical behavior of A) Cu complex CuL1 (2 mmolLꢀ1
)
within the potential range of ꢀ1.8 to 0.1 V at a glassy carbon working elec-
trode. B) Free Cu2+. Anhydrous and deoxygenated DMF containing tetrabu-
tylammonium hexafluorophosphate (0.1 molLꢀ1) was used as supporting
electrolyte. Scan rate: 50 mVsꢀ1. Potentials versus SCE.
to the copper complex indicating a stable binding between L1
and cationic copper metal. On performing cyclic voltammetry
at different scan rates (10, 20, 50, 100, and 150 mVsꢀ1), the
peak intensity increased with the square root of the scan rate,
thus indicating that the electrochemical response is controlled
by the diffusion process with anodic peak current intensity
1
=
2
Ipa =3.02v +0.01 in which 3.02 is the slope (mA) and v is the
scan rate (mVsꢀ1). Moreover, the ratio of the cathodic to
anodic peak was close to 1 at a low scan rate (10 mVsꢀ1) and
decreased to around 0.7 at a high scan rate (150 mVsꢀ1). The
peak-to-peak potential DE also increased from 121 to 203 mV,
respectively, when the scan rate increased from 10 to
150 mVsꢀ1. Based on these results, one can conclude a quasi-
reversible behavior of the complex CuL1 at the electrode/solu-
tion interface.
On scanning the potential in the cathodic direction, note
that no electrochemical response was observed until ꢀ1.2 V
versus SCE (Figure 5A). Below this value, an anodic peak was
observed at reverse scan at around ꢀ0.240 V with a sharp
shape. On the other hand, the electrochemical behavior of free
Cu2+ under the same experimental conditions showed catho-
Figure 4. Voltammograms of ligand L1 (2 mmolLꢀ1) and Cu complex CuL1
(2 mmolLꢀ1) at a glassy carbon working electrode. Anhydrous and deoxy-
genated DMF containing tetrabutylammonium hexafluorophosphate
(0.1 molLꢀ1) was used as supporting electrolyte. Scan rate: 50 mVsꢀ1. Poten-
tials versus SCE.
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dic and anodic waves at ꢀ0.05 and ꢀ0.367 V, respectively (Fig-
ure 5B). Based on this, we attributed the electrochemical be-
havior observed in Figure 5A to the anodic redissolving of Cu0,
previously deposited by the reduction of CuL1 at potential
values below ꢀ1.2 V versus SCE. These results indicate that the
quasi-reverse electrochemical behavior displayed in Figure 4
may easily be attributed to the redox process of the CuII com-
plex/CuI complex system.
Figure 6. Flexible coordination ability of the ligand.
The oxidation state of the copper was analyzed by X-ray
photoelectron spectroscopy (XPS). The part of the CuL1 XPS
spectrum corresponding to copper displayed two peaks at
953.5 and 933.6 eV (Figure S3). These values and the absence
of two satellite peaks (shake-up) confirmed the oxidation state
of the metal, and the formation of a CuI complex.[13]
This special feature increases the number of different com-
plexes that can be obtained. UV/Vis spectroscopy analyses and
an electrochemical study seemed to indicate the formation of
just one complex. This was confirmed by analyzing the part of
the CuL1 XPS spectrum corresponding to copper: there was
just one system of two signals for copper (corresponding to
The reduction of CuII salt to CuI was unexpected. It was par-
ticularly surprising to obtain a CuI complex that was totally air-
stable both in the solid state and in solution (for several
months). This phenomenon is not easy to explain. According
to the L1 voltammogram, L1 cannot be the reducing agent.
We also studied the redox behavior of L1 in basic medium to
see if the acetate ligands of Cu(OAc)2 could affect the redox
properties of L1. The work of Minaev and Bondarchuk perfectly
describes the numerous mechanisms that can explain the re-
duction of CuII to CuI.[14] One, in particular, attracted our atten-
tion: CuCl2 and Cu(OAc)2 can both be reduced in situ by the
solvent (e.g., acetone).[15] We think that such a reaction could
occur in our case and the high stability of the CuI complex
formed could act as the driving force. This result is noteworthy
because, although the chemistry of copper coordination is do-
minated by the complexes of CuII, many CuI derivatives are of
some interest.[5e,16] Moreover, it is important to have a CuI com-
plex for medical applications as the reduction of CuII com-
plexes in vivo often leads to demetalation.
1
3
2p = and 2p = copper electrons), which confirmed that just one
type of complex was formed.
2
2
Determination of the atoms chelating the metal
The environment around the copper was determined by XPS.
The signals displayed by the sulfur atom in the XPS spectra of
L1 and CuL1 were similar (Figure S5). Their environment is
thus very similar, which probably excludes a chelation of
copper by the sulfur atoms. These results are in agreement
with the recent work of Jin et al., who showed the formation
of copper(I) complexes by chelation of the nitrogen atom of
a thiazole.[17] On the contrary, the signals displayed by nitrogen
atoms in the spectra of L1 and CuL1 were very different
(Figure 7). A deconvolution of the “N-L1” signal led to three
peaks with the same area. Thus, each peak represents two ni-
Using Cu(p-CF3C6H4SO3), Cu(OAc), and Cu(CH3CN)4BF4 as the
source of copper(I), similar complexation experiments were
performed with L1, in DMF under microwave irradiation, to see
if the same type of UV/Vis spectra were obtained as with
Cu(OAc)2. Unfortunately, we came up against the problem of
the varying degree of solubility of copper(I) salts under the ex-
perimental conditions employed. The best results were ob-
tained with Cu(CH3CN)4BF4 for which the same absorption
band at 440 nm was observed, but at a lower intensity than
that of Cu(OAc)2 owing to the partial insolubility of CuI (Fig-
ure S4). This again supports the formation of a copper(I) com-
plex.
Determination of the number of different complexes formed
When designing our ligand, we wanted an ambidentate chelat-
ing agent able to bind an N4, N3S, or N2S2 ligand. To be ambi-
dentate, the ligand contains two thiazole rings. They are
bound to the ligand core by a single bond so that they can
rotate. Our hypothesis was that a hard metal would be chelat-
ed by the four nitrogen atoms (N4 complex), whereas a softer
metal would entail a rotation of the thiazole rings, thus ena-
bling sulfur atoms to replace one or two of the nitrogen atoms
(N3S or N2S2 complexes; Figure 6).
Figure 7. XPS spectra (N signal) of L1 and CuL1.
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trogen atoms of the ligand. This result was expected because
of the symmetry of the molecule. However, the symmetry was
lost after complexation and three different peaks were ob-
served after the deconvolution of the “N-CuL1” signal. These
results suggest that the complexation probably took place by
nitrogen atoms.
zone ligands. We report here the results obtained for the mon-
odeprotonated (CuLH) and dideprotonated (CuL)ꢀ complexes
(Table 1).
As for the diprotonated form, the structures of lowest
energy are the N4 conformers (Figure 8). For the monodeproto-
nated complex, the structure is not quite the same as for the
dideprotonated structure. The distances to the nitrogen shell
in the first coordination sphere of the copper are 1.98 and
1.94 ꢃ for the (CuLH)-N4 and 1.94 ꢃ for the (CuL)ꢀ-N4 com-
plexes. In both cases, the ligands chelate in a bidentate
manner, with only the thiazole groups coordinating through
nitrogen atoms. The copper stabilization energy is 788.75 and
1057.21 kJmolꢀ1 for the (CuLH)-N4 and (CuL)ꢀ-N4 complexes,
respectively. The complexation of cations with anionic hydra-
zones may lead to more stable complexes than with neutral
hydrazones (CuLH2)+-N4 because of the presence of electro-
static interactions (calculations are detailed in the Supporting
Information).
According to the work of Deng et al.,[18] the binding energy
of the peak at 402.1 eV (peak A, Figure 7) may correspond to
1s electrons involved in a nitrogen–copper covalent bond.
Thus, an explanation of the three different peaks for the CuL1
complex could be that one of the nitrogen atoms was cova-
lently bound to copper whereas the others formed longer-dis-
tance links. Following this hypothesis, the formation of the co-
valent bond could result from the deprotonation of NH of one
of the hydrazones by the acetate anion. Thus, by electronic de-
localization, a CuꢀN bond would form with the nitrogen of
a thiazole.[19] Infrared spectra of L1 and CuL1 were obtained to
give more clues. The decrease in the NꢀH band signals was
significant for the CuL1 spectrum but the signals did not dis-
appear. These observations are consistent with the deprotona-
tion of one of the two NꢀH bonds.
This theoretical study shows that, in vacuo, the copper
ligand complex is 1:1 regardless of the state of protonation. In
In view of these analyses, it could be assumed that the com-
plex CuL1 forms N4 chelate rings in which the copper(I) is
probably coordinated by N atoms with one covalent bond
(Figure 6). Although two-coordinated linear and three-coordi-
nated trigonal arrangements are known, CuI complexes are
mostly four-coordinated species adopting a tetrahedral geom-
etry.
Table 1. Copper stabilization energies [kJmolꢀ1], symmetry, and selected
distances [ꢃ] calculated at the B3LYP/6-311G/ECP(Cu(SDD)) level of theory
for (CuLH2)+-N4, (CuLH2)+-N3S1, and (CuLH2)+-N2S2 protonated complexes,
and monodeprotonated (CuLH)-N4 and dideprotonated (CuL)-N4 com-
plexes.
Complex
DEstab
Symmetry NthiazꢀCu SthiazꢀCu NhydrꢀCu
(CuLH2)+-N4
493.20 C2
444.22 C1
369.72 C2
788.75 C1
1057.21 C2v
1.954
1.924
–
–
3.188
To rationalize the experimental results, a model of ligand
and copper complexes was optimized in vacuo by using densi-
ty functional theory (DFT). The selected geometric parameters
of computed complexes are presented in Table 1. In all these
conformers, namely (CuLH2)+-N4, (CuLH2)+-N3S1, and (CuLH2)+
-N2S2, the metal cation interacts mainly with two centers of the
ligand. The distances between ligating atoms and the Cu+ ion
lie between 1.92 and 1.95 ꢃ for the binding modes with the ni-
trogen of the thiazole and between 2.27 and 2.30 ꢃ for the
binding modes with the sulfur of the thiazole, respectively
(Table 1). These values are partially in agreement with experi-
mental structural data from the Cambridge Structural Database
(CSD) for small molecules and
2.769[a]
3.816[a]
(CuLH2)+-N3S1
(CuLH2)+-N2S2
(CuLH)-N4
2.301
2.274
–
3.561
1.979[a]
1.915[a]
3.241[a]
3.093[a]
(CuL)ꢀ-N4
1.943
–
3.192
[a] The symmetry is C1 for this structure, thus implying that the copper
atom is not in the axis of symmetry as in the case of the structure
(CuLH2)+-N4.
the Protein Data Bank (PDB): the
copper(I)-binding complexes in
the CSD have coordinating dis-
tances of 1.90(6) ꢃ for CuꢀN and
2.17(2) ꢃ for CuꢀS in bidentate
ligands.[20] The binding mode
with the sulfur of the thiazole is
disadvantaged in such com-
plexes. In fact, the stabilization
energy is lower when the sulfur
is involved in the complexation
of copper.
The characteristics of hydra-
zone complexes are often relat-
Figure 8. Structures of the (CuLH2)+-N4, (CuLH)-N4, and (CuL)ꢀ-N4 conformers calculated at the B3LYP/6-311G/
ed to the deprotonation/proto-
nation behavior of the hydra- ECP(Cu(SDD)) level of theory.
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addition, the complex formed is of the type N4 (Figure 6) in
which copper is complexed mainly by the two nitrogen atoms
of the thiazoles, thus confirming the results obtained by XPS.
Stability of complexes
Stability and kinetic inertness are the essential properties
needed for complexes used in nuclear medicine. They prevent
compounds from releasing radionuclides in the human body
because of molecules able to chelate copper (e.g., albumin,
metallothionein) or free metallic ions. First, the stability of the
complex in acidic conditions was checked. To do this, HCl
(100 mL, concentration 0.1m) was added directly to a solution
of CuL1. Immediately, a broad absorption band appeared from
380 to 400 nm whereas the 440 nm band almost vanished.
This new band must correspond to a protonated species of
the complex. Moreover, the neutralization of the solution by
the same amount of NaOH (100 mL, concentration 0.1m) led to
a spectrum very similar to the initial spectrum of CuL1 (the ac-
quisition was done immediately after the addition; Figure S6).
Even after several hours in the presence of acid, the initial
spectrum was always recovered. It is worth remembering that
the complexation was complete after one hour at room tem-
perature, so acid could not have destroyed the complex, and
that after addition of base, the complex was formed again in
less than three minutes (time needed to acquire a spectrum).
We thus concluded that CuL1 is stable at pH 4.
The stability of the CuL1 complex compared to other chelat-
ing agents of copper(II) (1,4,7,10-tetraazacyclododecane-
1,4,7,10-tetraacetic acid (DOTA) and ethylenediaminetetraacetic
acid (EDTA)) and copper(I) (bicinchonic acid and bathocuproine
disulfonate) was investigated. Complex CuL1 was reacted with
an excess of ligands in a DMF/acetate buffer (1:1 v/v) or in
DMF. In every case, no bands characteristic of ligand L1 ap-
peared, even after 24 hours, which indicated that copper was
not released. These experiments suggest a good stability for
CuL1 under the conditions employed. To determine the risk of
release of copper in the body because of another metal,
a transmetalation reaction was tried using Zn(OAc)2. The
choice of zinc was justified by the similarity of the hard–soft
acid–base (HSAB) character of copper and zinc and the similari-
ty of their biological targets (it is known that a trace-element
cure containing a large amount of zinc causes copper deple-
tion). The complex ZnL1 was synthesized by reacting one
equivalent of L1 with one equivalent of Zn(OAc)2. The lmax dis-
played by the spectrum of ZnL1 was clearly different from that
of CuL1. If CuL1 was reacted with 15 equivalents of Zn(OAc)2,
no ZnL1 signal appeared even after one day (Figure 9). This
implies an excellent stability of CuL1 in the presence of zinc.
The same experiment was performed with Ca(OAc)2·H2O,
Pb(OAc)4, Fe(OAc)2, Mg(NO3)2·6H2O, Mn(OAc)3·2H2O, and KNO3,
and in every case, no transmetalation was observed (Figur-
es S7–S12). Thus, we can conclude that the risk of release of
metal in the organism is very low. These encouraging results
prompted us to perform a preliminary complexation test using
radioactive copper.
Figure 9. UV/Vis absorption spectra of CuL1, CuL1+Zn, and ZnL1 (the spec-
tra were recorded in DMF, [CuL1]=3ꢂ10ꢀ5, [ZnL1]=3ꢂ10ꢀ5, 15 equivalents
of Zn(OAc)2 were used).
Radiolabeling
Chelating a radionuclide is very demanding for a ligand. It in-
volves a complexation in acidic buffer medium (to prevent the
formation of metallic hydroxides), at room temperature (to be
compatible with biological vectors), in a short time (short radi-
onuclide half-life), and in a very diluted medium (high dilution
of radionuclide source: 10ꢀ6 to 10ꢀ8 m).[21] We have described
the excellent abilities of L1 to chelate radioactive copper (64Cu)
in acid medium at room temperature, in 30 minutes at
10ꢀ9 m.[12] Thin-layer chromatography (TLC) associated with an
appropriate eluent enabled the free form of the radionuclide
to be separated from the complexed one, as the former does
not migrate in the established conditions. Radioactivity on the
TLC plates was quantified by using a phosphorimager. As the
staining intensity is a function of the locally emitted radioactiv-
ity, the rate of complexation can be measured. The experimen-
tal results revealed a high chelation rate of 70% when one
equivalent of L1 was used, and more than 80% when ten
equivalents were used. As radioactive sources and buffered sol-
utions contain unknown and varying amounts of nonradioac-
tive isotopes that compete with the radionuclide, an excess of
ligand was used to ensure the total complexation of the cat-
ionic species. In comparison with currently used chelating
agents, this appears to be a very competitive ligand.[22] These
experiments also suggest that the complexation kinetics is
very fast even in hostile conditions. These results encouraged
us to synthesize the bifunctional analogues of ligand L1.
Synthesis of the bifunctional chelate
We were able to synthesize a fine-tunable ligand through
a two- or three-step microwave-assisted strategy (Scheme 2,
and Schemes S1 and S2). The R1 group provides a binding site
and the variation of R2, R3, and R4 enables the chelation prop-
erties of the ligand (changing electronic and steric effects) to
be modified.
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We broadened the scope of our
Table 2. Yields of ligands L1–L11.
strategy[12] by using 2,6-diacetyl-
pyridine instead of isophthalalde-
hyde (L7) and by functionalizing
the central aromatic ring (L8–L10;
Table 2). However, our objective
was the synthesis of an efficient
BFC. This ligand needs a functional
group to be bound to a vector.
Ligand R1
R2
R3
R4
X
Steps Yield [%][b]
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
H
H
H
H
H
H
H
tBu
pClC6H4
F3C
H
H
H
H
H
H
H
H
H
CH3
H
H
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
3
3
3
2
2
2
3
5
7
7
8
69
74
71
99
71
93
48
43
61
26
24
EtO2C
[a]
pClC6H4
[a]
[a]
F3C
EtO2C
H
H
H
pClC6H4
pClC6H4
pClC6H4
Scheme 2. General structure
of the tetradentate ligand L1– The one most often used is “NH2”
L11 (for R1, R2, R3, R4, and X,
see Table 2).
OC12H25
OC2H4-NHBoc pClC6H4
OC2H4-NH2 pClC6H4
because it can be involved in the
H
H
H
H
formation of a peptide bond, or be
transformed into isothiocyanate to
form a thiourea bond.[23] We chose to introduce the functional
group on the arene bearing the
two arms of the complex, to
have the smallest influence on
the chelation. Starting from 1a–
c, obtained in a three- or four-
step process (syntheses are pre-
sented in Scheme S3), the li-
gands L8–L10 were isolated in
good yields by the microwave-
assisted sequence described pre-
viously (Scheme 3).
[a] R2CO, where R2 =H. [b] Overall yield of isolated product.
The different functionaliza-
tions on position 5 of the aro-
matic ring, especially when 1a
Scheme 3. Synthesis of ligands L8–L11. Boc=tert-butoxycarbonyl, TFA=trifluoroactic acid.
was used, proved that steric hin-
drance did not disturb the con-
struction of the arms of the ligand. The second strategy, which
provided 1b and 1c, enabled the easy introduction of different
groups or linkers on the chelating agent. The Boc group of
L10 could easily be removed in TFA at room temperature in
less than one hour to afford the free amino ligand L11 in 91%
yield. It is important to highlight the fact that the hydrazones
are not at all acid-sensitive. This means that they will be stable
in a biological medium, especially in the slightly acidic sur-
roundings of tumors.
the copper seems to be complexed mainly by the two nitro-
gen atoms of the thiazoles. The electrochemical study of the
complex CuL1 displayed a quasi-reversible process with anodic
and cathodic peaks at potentials of about 0.55 and 0.30 V
versus SCE, respectively, thus indicating a stable CuII/CuI com-
plex system. This latter point is important because in vivo re-
duction of stable CuII complexes to form CuI products can lead
to demetalation. Furthermore, this investigation has demon-
strated a good kinetic inertness for CuL1 against competing
metals and ligands (Zn, Fe, Ca, Mg, Pb, K, bathocuproine disul-
fonate, DOTA, and EDTA). One of these ligands was functional-
ized by an amino group to form a bifunctional chelate that
could be bound to a biological vector to be used in nuclear
medicine. Moreover, a preliminary study with radioactive
copper has shown the great potential of these ligands, given
their very rapid complexation kinetics. These new derivatives
thus offer a viable and original route for copper binding for
targeted imaging.
Preliminary complexation tests were performed on L11. This
BFC displayed a similar behavior to L1: quantitative complexa-
tion in diluted media, similar UV/Vis spectra for the ligand and
the complex CuL11 (Figure S13), and a similar mass spectrum.
Thus, we have developed a versatile and efficient method of
designing new chelating agents, which enables a linker to be
easily constructed on the aromatic ring. The overall yields were
good to excellent, even for compounds that required a multi-
step synthesis (Table 2). Moreover, we succeeded in synthesiz-
ing our target L11, a BFC, which could be bound to a vector
through its amino group.
Experimental Section
Materials and methods
Conclusion
NMR spectra were recorded at room temperature with a Bruker
Avance 300 Ultra Shield or eBruker Avance III 400 spectrometer.
Chemical shifts are reported in parts per million (ppm); coupling
constants are reported in Hertz (Hz). Infrared (IR) spectra were re-
corded with a Bruker Vector 22 FTIR spectrometer using KBr films
By combining different analytical techniques, we have demon-
strated the formation of N4 copper(I) complexes from a copper(-
II) salt. This work was completed by a theoretical molecular
modeling study, which confirmed the N4 complexes in which
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or KBr pellets. Low-resolution mass spectra were recorded with
a Thermo Electron DSQ spectrometer. High-resolution mass spec-
trometry (HRMS) was performed with a Bruker Autoflex III Smart-
Beam spectrometer (MALDI). Microanalyses were performed on
a Thermo Scientific FLASH 2000 Series CHNS/O Analyzer. Melting
points were determined in open capillary tubes and are uncorrect-
ed. EDX elemental analyses were measured on a JEOL 5800 LV in-
strument with an EDX probe; analyses are semiquantitative be-
cause of the use of element standards. XPS spectra were recorded
on a Leybold LHS11 MCP apparatus. SEM experiments were per-
formed on a JEOL 6400F microscope. All reagents were purchased
from Acros Organics or Aldrich and were used without further pu-
rification. Column chromatography was conducted on silica gel
Kieselgel SI60 (40–63 mm) from Merck. Reactions requiring anhy-
drous conditions were performed under argon. Dichloromethane
was distilled from calcium hydride under nitrogen prior to use. Tet-
rahydrofuran was distilled from sodium/benzophenone under
argon prior to use. Microwave experiments were conducted in
sealed vials in commercial microwave reactors especially designed
for synthetic chemistry (MultiSYNTH, Milestone). The instrument
featured a special shaking system that ensured high homogeneity
of the reaction mixtures. It was equipped with an indirect pressure
control through precalibrated springs at the bottom of the vessel
shields and with a fiber-optic contact thermometer (FO) for accu-
rate temperature measurement. Cyclic voltammetry was performed
using a three-electrode system. Potential was applied between
a glassy carbon electrode and a Pt counter electrode, and a saturat-
ed calomel electrode (SCE) was used as the reference. A solution of
tetrabutylammonium hexafluorophosphate in anhydrous and de-
oxygenated DMF was used as the supporting electrolyte.
(15 molꢀ1 m3 cmꢀ1); MS (MALDI, DHB/CH3CN): m/z (%): 627
[M+Na]+, 605.1 [M+H]+; HRMS (MALDI DHB/CH3CN): m/z calcd for
C28H18Cl2N6O2S2 +Na+: 627.0207 [M+Na+]; found: 627.0234.
2,2’-[5-(2-Aminoethoxy)-1,3-phenylene]bis(methan-1-yl-1-ylidene)-
bis(hydrazin-1-yl-2-ylidene)bis(thiazole-5,2-diyl)bis[(4-chlorophenyl)-
methanone] (L11): Ligand L10 (0.2 mmol, 1 equiv) was dissolved in
TFA (3 mL). The reaction mixture was stirred for 1 h at room tem-
perature. Solvent was removed under reduced pressure. The resi-
due was dissolved in dichloromethane (1 mL) then water (2 mL)
was added. The solution was treated with 1m sodium bicarbonate
solution until effervescence stopped and the mixture was slightly
basic. Dichloromethane (50 mL) was added and then the mixture
was extracted with three 15 mL portions of dichloromethane. The
organic layers were evaporated at reduced pressure to give com-
1
pound L11 as an orange powder (91%). M.p. 247–2498C; H NMR
(300 MHz, [D6]DMSO): d=3.29 (m, 2H; CH2), 4.27 (m, 2H; CH2), 7.39
(s, 2H; Har), 7.43 (s, 1H; Har), 7.55 (d, J=8.4 Hz, 4H; Har), 7.73 (d,
J=8.4 Hz, 4H; Har), 7.80 (s, 2H; Hthiaz), 8.16 ppm (s, 2H; CHN);
13C NMR (100 MHz, [D6]DMSO): d=38.5, 65.2, 111.6, 120.2, 124.5,
128.5, 130.0, 135.7, 137.0, 137.7, 144.6, 152.3, 158.5, 177.7,
184.3 ppm; IR (KBr): n˜ =3182, 3069, 2931, 2759, 1679, 1615, 1568,
1504, 1432, 1326, 1279, 1256, 1201, 1173, 1109, 1090, 1012, 878,
840, 800, 749, 680, 471 cmꢀ1; UV/Vis (DMF): lmax (10ꢀ3 e)=394 (22),
509 nm (15 molꢀ1 m3 cmꢀ1); MS (MALDI, DHB): m/z (%): 686.1
[M+Na]+, 666.1. [M+H]+; HRMS (MALDI DHB/CH3CN): m/z calcd for
C33H23Cl2N7O3S2 +Na+: 686.0579 [M+Na]+; found: 686.0563.
Synthesis
General procedure for complexes
For the synthesis of 1b, 1c, and L2–L10, see the Supporting Infor-
mation.
Ligand Lx (0.05 mmol, 1 equiv) and monohydrate Cu(OAc)2
(0.05 mmol, 1 equiv) were dissolved in DMF (4 mL) in a 10 mL mi-
crowave reactor, which was placed in the microwave oven. The re-
actor was heated from room temperature to 1208C (FO) for 2 min
by monomode microwave irradiation (power: 150 W, stirring: 50%,
ventilation: 1/3), maintained at 1208C for 15 min (power: 50 W, stir-
ring: 50%, ventilation: 1/3), and allowed to cool to room tempera-
ture (power: 0 W, stirring: 50%, ventilation: 3/3). The solution was
concentrated under reduced pressure. The residue was suspended
in dichloromethane (10 mL) and washed five times with 15 mL of
water. The organic layer was evaporated under reduced pressure.
The residue was suspended in dichloromethane, isolated by filtra-
tion, and washed with dichloromethane.
2,2’-[1,3-Phenylenebis(methan-1-yl-1-ylidene)]bis(hydrazin-1-yl-2-yli-
dene)bis(thiazole-5,2-diyl)bis[(4-chlorophenyl)methanone] (L1): 2,2’-
[1,3-Phenylenebis(methan-1-yl-1-ylidene)]bis{N-[(dimethylamino)-
methylene]hydrazinecarbothioamide} (see the Supporting Informa-
tion, compound 3) was dissolved in DMF (4 mL) in a 10 mL micro-
wave reactor and the appropriate a-bromoketone (1.42 mmol,
2 equiv) was added. The solution turned orange. After 2 min of stir-
ring, distilled triethylamine (2.13 mmol, 3 equiv) was added. The
solution turned dark red. The reactor was heated from room tem-
perature to 508C (FO) for 1 min by monomode microwave irradia-
tion (power: 70 W, stirring: 30%, ventilation: 1/3), maintained at
508C for 9 min (power: 30 W, stirring: 50%, ventilation: 1/3), and
allowed to cool to room temperature (power: 0 W, stirring: 50%,
ventilation: 3/3). The solution was concentrated under reduced
pressure. The residue was suspended in dichloromethane (20 mL)
and washed five times with water (30 mL). The organic layer was
evaporated under reduced pressure. The residue was suspended in
dichloromethane, isolated by filtration, and washed with dichloro-
methane, which gave compound L1 as a pale yellow powder
[5-(4-Chlorobenzoyl)-2-{[3-({2-[5-(4-chlorobenzoyl)thiazol-2-yl]hydra-
zono}methyl)benzylidene]hydrazono}thiazol-3(2H)-yl]copper (CuL1):
Brown powder; yield: 95%; IR (KBr): n˜ =3446, 3062, 1588, 1526,
1496, 1477, 1398, 1348, 1288, 1255, 1199, 1174, 1088, 1013, 958,
918, 888, 840, 748, 686, 628, 600 cmꢀ1; UV/Vis (DMF): lmax (10ꢀ3 e)=
440 nm (33 molꢀ1 m3 cmꢀ1); EDX: Cu/Cl and Cu/S ratios were 1:1;
MS (MALDI, DHB/CH3CN) m/z (%): 667 [M+H]+, 605 [MꢀCu+H] for
C28H17Cl2N6O2S2Cu.
1
(70%). M.p. 205–2068C; H NMR (300 MHz, [D6]DMSO): d=7.56 (t,
J=7.7 Hz, 1H; Har), 7.60 (d, J=8.5 Hz, 4H; Har), 7.81 (m, 2H; Har),
7.83 (d, J=8.5 Hz, 4H; Har), 7.94 (s, 2H; Hthiaz), 7.97 (s, 1H; Har),
8.24 (s, 2H; CH=N), 12.90 ppm (bs, 2H; NH); 13C NMR (100 MHz,
[D6]DMSO): d=125.6, 127.2, 127.6, 127.9, 128.6, 130.3, 134.4, 136.4,
136.8, 145.2, 150.1, 173.2, 184.4 ppm; IR (KBr): n˜ =3451, 3187, 3059,
2761, 1614, 1588, 1568, 1507, 1485, 1438, 1397, 1323, 1278, 1257,
1200, 1174, 1100, 1090, 1013, 933, 906, 879, 842, 792, 750, 687,
628, 596 cmꢀ1; UV/Vis (DMF): lmax (10ꢀ3 e)=395 (46), 505 nm
2,2’-[5-(2-Aminoethoxy)-1,3-phenylene]bis(methan-1-yl-1-ylidene)-
bis(hydrazin-1-yl-2-ylidene)bis(thiazole-5,2-diyl)bis[(4-chlorophenyl)-
methanone]copper (CuL11): Brown powder; yield: 99%; IR (KBr):
n˜ =3407, 3123, 1659, 11606, 1495, 1472, 1398, 1348, 1283, 1255,
1173, 1133, 1088, 1013, 958, 918, 874, 840, 745, 685 cmꢀ1; UV/Vis
(DMF): lmax (10ꢀ3 e)=440 nm (36 molꢀ1 m3 cmꢀ1); MS (MALDI, DHB/
CH3CN) m/z (%): 727 [M+H]+.
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Radiolabeling
Acknowledgements
Copper-64 dichloride in 0.1m hydrochloric acid was obtained from
ARRONAX cyclotron (Saint-Herblain, France). Radionuclide purity
was determined by gamma spectroscopy using a DSPEC-JR-2.0
type 98-24B HPGE detector (AMETEK) and chemical purity was con-
trolled by inductively coupled plasma–optical emission spectrosco-
py with an iCAP 6500 DUO instrument (Thermo Fisher Scientific).
TLC analyses were performed using silica gel on TLC-PET foils
(Fluka Analytical). TLC plates were revealed on a storage phosphor
screen by using a Cyclone Plus phosphor imager (PerkinElmer). The
ligand was radiolabeled with 64Cu by addition of 64CuCl2 solution
(40 to 60 MBq; metal composition: 10 ppm of copper for 60 ppm
total metals) in 2.5m ammonium acetate (pH 5.5) to chelating
agent L1 (1 or 10 equiv) in DMF. The solution was stirred at room
temperature for 30 min and the radiolabeled 64CuL1 was obtained
in 70% (for 1 equiv) or 80% (for 10 equiv) radiochemical yield. The
radiochemical purity was >95% as measured by TLC (the eluent
used was a mixture of acetic acid and ethyl acetate (1:1)). The spe-
We are grateful to the French Ministry of Education and to the
Centre National de la Recherche Scientifique (CNRS) for financial
support. This research used the CPU resources of the CCIPL
(Centre de Calcul Intensif des Pays de Loire). This study was also
supported by a grant from the French National Agency for Re-
search called “Investissements d’Avenir”, Equipex ArronaxPlus no.
ANR-11-EQPX-0004 and from the “Region Pays de la Loire”
(NUCSAN project).
Keywords: chelates · copper · density functional calculations ·
ligand design · radiopharmaceuticals
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ꢀ
ꢁ
ꢀ Ecomplex ꢀ monomers Ei þ BSSE
P
i
ð1Þ
DEstab
¼
n
P
Cuþ
i
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P
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the complex.i
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Published online on June 24, 2014
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