Synthesis and characterisation of [Re(CO)3(SS)(P)] complexes: A [2+1] concept for 99mTc- and 188Re-radiopharmaceutical applications

Article abstract of DOI:10.1002/ejic.200500247

A new (SS)(P) coordination set based on the concurrent use of a dithiocarbamate and a functionalised phosphane is reported. The (SS)(P) fashion is achieved by applying the [2+1] mixed-ligand concept and makes it possible to obtain stable rhenium tricarbonyl complexes without employing tripodal bifunctional chelating agents (BFCAs). The coordination chemistry of the simple sodium N,N-dimethyldithiocarbamate and new functionalised phosphanes L1-L3 [L1 = Ph₂PCH₂CH₂C(O)OCH₃, L2 = Ph ₂PCH₂CH₂C(O)NHCH₂C(O)OCH ₃, L3 = Ph₂PCH₂CH₂C(O)NHCH ₂CH₂C(O)OCH₃] was studied by reaction with the rhenium complex [NEt₄]₂-[fac-Re(CO₃)Br ₃]. The rhenium tricarbonyl core was found to be stabilised by the SS chelation of dithiocarbamate and by the P coordination of the phosphane. Two synthetic pathways leading to the complexes [fac-Re(CO)₃(L)(MDTC)] (L = L1, L2, L3; MDTC = N,N-dimethyldithiocarbamate) are described. The structural characterisation of the isolated complexes by spectroscopic methods is reported, including X-ray crystallographic analysis for rhenium complexes with ligands L1 and L3. The homologous Tc-99m compounds with the same (SS)(P) coordination set were prepared at tracer level with the L2 and L3 ligands, and characterised by HPLC methods. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejic.200500247

FULL PAPER
Synthesis and Characterisation of [Re(CO)3(SS)(P)] Complexes: A [2+1]
Concept for 99mTc- and 188Re-Radiopharmaceutical Applications
Mattia Riondato,*[a] Davide Camporese,[a] David Martín,[b] Joan Suades,[b]
Angel Alvarez-Larena,[c] and Ulderico Mazzi[a]
Keywords: Carbonyl ligands / P ligands / Rhenium / S ligands / Technetium
A new (SS)(P) coordination set based on the concurrent use
the P coordination of the phosphane. Two synthetic pathways
of a dithiocarbamate and a functionalised phosphane is re- leading to the complexes [fac-Re(CO)3(L)(MDTC)] (L = L1,
ported. The (SS)(P) fashion is achieved by applying the [2+1]
mixed-ligand concept and makes it possible to obtain stable
rhenium tricarbonyl complexes without employing tripodal
bifunctional chelating agents (BFCAs). The coordination
chemistry of the simple sodium N,N-dimethyldithio-
carbamate and new functionalised phosphanes L1–L3 [L1 =
L2, L3; MDTC = N,N-dimethyldithiocarbamate) are de-
scribed. The structural characterisation of the isolated com-
plexes by spectroscopic methods is reported, including X-ray
crystallographic analysis for rhenium complexes with ligands
L1 and L3. The homologous Tc-99m compounds with the
same (SS)(P) coordination set were prepared at tracer level
with the L2 and L3 ligands, and characterised by HPLC
methods.
Ph2PCH2CH2C(O)OCH3, L2
= Ph2PCH2CH2C(O)NHCH2-
C(O)OCH3, L3 = Ph2PCH2CH2C(O)NHCH2CH2C(O)OCH3]
was studied by reaction with the rhenium complex [NEt4]2-
[fac-Re(CO3)Br3]. The rhenium tricarbonyl core was found to
be stabilised by the SS chelation of dithiocarbamate and by
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
system (bifunctional chelating agent, BFCA) that is able to
stabilise and keep the metal far from the target molecule.[4]
In recent years, Tc and Re radiopharmaceutical chemis-
try with the cation fac-[M(H2O)3(CO)3]+ has been intensely
stimulated by the fundamental contributions of Alberto,
Schibli and Schubiger with the development of novel and
simple methods for preparing the aqua ions fac-
Introduction
The most important goal of radiopharmacy is the appli-
cation of radiolabelled compounds in medicine for non-
invasive diagnostic and therapeutic purposes. Technetium-
99m is a γ-emitter with optimal characteristics that is widely
employed in nuclear medicine for imaging and is readily
available as pertechnetate from the 99Mo/99mTc generator.[1]
Rhenium-188 appears to be promising as a candidate for
the treatment of neoplasia for its β– emission and is avail-
able as perrhenate from a commercially available 188W/
188Re generator, proposed by Oak Ridge National Labora-
tory (USA).[2]
For the development of site-directed diagnostic and
therapeutic radiopharmaceuticals, a biomolecule (hor-
mones, peptides) with high affinity for a receptor target
should be labelled to deliver the radionuclide in a specific
body region.[3] However, labelling a biomolecule might give
an important alteration of its biological properties due to
the link with transition metals such as Tc or Re. Hence,
the most successfully employed procedure at present is the
“bifunctional approach”. This consists of a chelating
[
99mTc(H2O)3(CO)3]+ and fac-[188Re(H2O)3(CO)3]+.[5] The
interest in the design of radiopharmaceuticals with car-
bonyl ligands results from their high thermodynamic sta-
bility, small size, kinetic inertia and in vivo stability.[6]
Furthermore, the [M(CO)3]+ moiety allows the use of a
wide range of ligand systems, therefore many different che-
lating sets have been tested.[7]
In this context, several research groups are currently
looking for an “ideal building block” with an optimised
in vitro and in vivo behaviour. In the last few years, these
complexation studies have been principally focused on the
development of tridentate BFCAs to obtain a tripodal
mode of coordination (Scheme 1). Nevertheless, tricoordina-
tion can also be achieved by using a mixture of two li-
gands, one bidentate L2 and one monodentate L1 to pro-
duce an [M(L2)(L1-Biomol)(CO)3] complex by means of a
[2+1] mixed-ligand approach (Scheme 1).[8] A recent paper
has reported the use of this “[2+1]” approach to prepare
new fac-M(CO)3 compounds for radiopharmaceutical use
from a dithiocarbamate and a monodentate isocyanide li-
gand.[9]
[a] Department of Pharmaceutical Sciences, University of Padova,
Via Marzolo 5, 35131 Padova, Italy
[b] Department of Chemistry, Universitat Autònoma de Barcelona,
08193 Bellaterra, Spain
[c] X-ray Diffraction Service, Universitat Autònoma de Barcelona,
08193 Bellaterra, Spain
4048
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejic.200500247
Eur. J. Inorg. Chem. 2005, 4048–4055

[Re(CO)3(SS)(P)] Complexes for 99mTc and 188Re Radiopharmaceuticals
FULL PAPER
This study presents the syntheses and structural charac-
terisation of three phosphane ligands and the [2+1] rhenium
complexes obtained by combining the prepared phosphanes
and sodium MDTC with the [Re(CO)3]+ moiety.
Scheme 1. Two different approaches for the stabilisation of a tricar-
bonylrhenium or -technetium core (M = Re/Tc).
Results and Discussion
Synthesis of the Ligands
Here, we report an investigation where we propose a suit-
able chelating system for the stabilisation of the fac-[M-
The synthesis and characterisation of the phosphane es-
(CO)3]+ moiety by the [2+1] mixed-ligand approach, based ter ligand L1 has been reported previously.[14,15] We ob-
on the simple N,N-dimethyldithiocarbamate (MDTC) as bi- tained the same compound using an alternative preparation
dentate ligand and a functionalised phosphane as mono- starting from succinimidyl 3-diphenylphosphanylpropion-
dentate ligand. The phosphane acts as a bifunctional agent ate. The new functionalised phosphanes L2 and L3 were
because it contains an anchor group that is useful for the prepared by reaction of the same activated ester with the
conjugation with the biological vector, while MDTC acts as amino acid derivatives glycine methyl ester (L2) and β-ala-
a co-ligand as it is able to neutralise and stabilise the metal nine methyl ester (L3; Scheme 2) using modifications of the
system.
published procedures.[10,16] All these results are consistent
Phosphane ligands are well known for their capability with the ability of succinimidyl 3-diphenylphosphanylpro-
to form very stable and inert bonds with organometallic pionate to act as a synthon for preparing phosphane-
fragments. Succinimidyl 3-diphenylphosphanylpropionate derivatised compounds. All ligands were obtained in good
was selected as the BFCA because it can be simultaneously yields (70–75%) after purification by flash column
linked to
a
metal centre and to
a
biomolecule chromatography as pale-yellow pure oils (air-sensitive com-
(Scheme 2).[10,11]
pounds) and were characterised by NMR (1H, 13C, 31P) and
To evaluate the viability of this new [2+1] mixed-ligand FT-IR spectroscopy and ESI mass spectrometry.
approach we synthesised phosphane derivatives with ami- The collected data are consistent with the proposed
noacid methyl esters following the above reaction. These structures and can be compared with the characterisation
ligands can simulate the presence of a conjugated targeting reported for similar ligands.[11,16] The 31P NMR spectra of
biomolecule and test the potential application of the new L1–L3 show a sole singlet in the range δ = –13.9/–14.4 ppm
[2+1] mixed-ligand system in the presence of a biomolecule characteristic of a ligand containing a diphenylphosphane
anchored to the monodentate ligand.
group. The formation of the amide bond in L2 and L3 is
The coordination chemistry of the phosphane derivatives evidenced by the IR spectra, which show a strong band near
and sodium MDTC was studied by reaction with “cold” 1650 cm–1, and by the proton signals of the amide group
[NEt4]2[Re(CO3)Br3].[12] Rhenium complexes are structural observed at δ = 6.12 (L2) and 6.03 ppm (L3) in the 1H
models of technetium complexes due to the lanthanide con- NMR spectra. The presence of a methyl ester group in L1–
traction that ensures that the analogous complexes display L3 was evidenced in the IR spectra by a strong absorption
1
very similar coordination parameters and physical proper- between 1738–1752 cm–1 and by a singlet in the H NMR
1
ties.[13]
spectra at around δ = 3.65 ppm. The H and 13C NMR
Scheme 2. General syntheses for biomolecule-functionalised phosphanes and synthesis of the phosphane ligands L1–L3.
www.eurjic.org
Eur. J. Inorg. Chem. 2005, 4048–4055
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4049

M. Riondato, D. Camporese, D. Martín, J. Suades, A. Alvarez-Larena, U. Mazzi
FULL PAPER
spectra display the signals of all organic groups involved in even in solution (organic solvents). No decomposition was
ligands L1–L3. Finally, the identities of L1–L3 were con- observed after many weeks.
firmed by the positive ion ESI mass spectra, which display
The presence of the fac-[Re(CO)3] fragment in complexes
C1–C3 was revealed by the three characteristic CO stretch-
ing bands (C1: 2016, 1921 and 1890 cm–1) observed in the
IR spectra.[18–21] This technique also supplies useful infor-
mation about the coordination of the dithiocarbamate li-
an intense signal assigned to the [M + H]+ cation.
Complexation Studies
The great capability of phosphorus() to form stable gand, since a single, strong band at 1522–1526 cm–1 was
complexes with transition metals in low oxidation states is observed, which was assigned to the C–N stretching of a
well known, and coordination studies employing phospha- symmetrical bidentate dithiocarbamate.[22] The C=O
nes with the ReI tricarbonyl core have been carried out and stretching vibrations of the ester and amide groups are sim-
reported in the literature.[17–20] Benak et al. have demon- ilar to those of the free ligand, and were accorded to the
strated that the reaction between [Re(CO)5Cl] and a di- exclusion of these groups from the participation in the me-
phenylphosphane ester affords the mononuclear tricarbonyl tal sphere.
complexes fac-[Re(CO)3ClL2] (L = phosphane) with the me-
The 31P NMR spectra of complexes C1–C3 show the
tal centre stabilised by the two phosphorus ligands.[18] San- complete absence of the corresponding free ligand, and dis-
tos et al. have explored the coordination ability of tridentate play a sole signal in the range δ = 5–8 ppm, thus confirming
hetero-functionalised diphenylphosphanes and obtained the absence of isomers. A significant downfield shift with
mainly PO or PN bicoordinated complexes.[19,20] In both respect to the resonance of the free ligands (δ = –14 to
cases tricoordination is generally not achieved, and the last –16 ppm) was observed, in agreement with the formation of
position of the metal coordination sphere is occupied by a a phosphorus–metal bond. The coordination of the phos-
halogen. Furthermore, the formation of different isomers is phane ligand is also evidenced by the 13C NMR spectra,
1
2
often observed when bidentate ligands are employed.[21]
which show an important increase of the JP,C and JP,C
The use of sodium MDTC and diphenylphosphane in couplings of the methylene groups with respect to the values
the [2+1] strategy has the potential advantage of producing observed in the free ligands. These data are in accordance
monomeric and neutral tricoordinate complexes. Only one with literature reports.[11,17,18] Furthermore, the simulta-
phosphane coordinates to rhenium in a monodentate fash- neous presence of MDTC and phosphane ligands with the
ion to produce minimal steric impact between the aliphatic rhenium tricarbonyl core is also consistent with the 1H
chain and the metal sphere.
The rhenium() tricarbonyl complexes C1–C3 were pre- coordination to the fragment fac-[Re(CO)3]+.
pared in two different ways, as shown in Scheme 3. In the Single crystals of complexes C1 and C3 were obtained
NMR, 13C NMR and ESI-MS data, supporting the (SS)(P)
two-step pathway, or “indirect synthesis”, complexes C1– by recrystallisation and their structures were determined by
C3 were formed from an intermediate dithiocarbamate X-ray methods. Perspective views of both molecules are dis-
complex. This complex was synthesised in the first step by played in Figures 1 and 2, respectively. Selected bond
simple addition of sodium MDTC to a solution of the rhe- lengths and angles are collected in Table 1. The simulta-
nium tricarbonyl precursor [Re(CO)3Br3]2– in methanol. neous coordination of the chelated dithiocarbamate and the
The resulting product was not characterised; however, we phosphane to the fac-[Re(CO)3]+ fragment confirms the
suppose that a neutral soluble monomeric SS-bicoordinated proposed structure and therefore the formation of the target
species is formed, as reported by Gorshkov et al. for similar [2+1] mixed-ligand rhenium tricarbonyl complexes. The co-
dithiocarbamates with the [Re(CO)3]+ moiety.[9] The simple ordination geometry around the metal atom can be de-
substitution of a coordinated methanol by a monodentate scribed as a slightly distorted octahedron. The principal dis-
phosphane ligand (L1–L3) blocks the coordination vacancy tortion comes from the bite angle of the chelated dithiocar-
and leads to the target complexes (C1–C3) in good yields bamate ligand, which forces the S–Re–S angles to be near
after purification by flash chromatography. The solid com- 70°, a common value in other metal complexes with che-
pounds are remarkably inert and stable to air and moisture, lated dithiocarbamates.[23] The almost identical Re–S dis-
Scheme 3. Syntheses of the complexes C1–C3 by the one-step and two-step approaches.
4050
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
Eur. J. Inorg. Chem. 2005, 4048–4055

[Re(CO)3(SS)(P)] Complexes for 99mTc and 188Re Radiopharmaceuticals
FULL PAPER
tances indicate that the dithiocarbamate ligand links to rhe-
nium in a symmetrical bidentate mode in both complexes.
The SCS plane of the dithiocarbamate is nearly coincident
with the SReS plane, with S42–Re–S41 and S41–C43–S42
angles of 2.2(4)° and 4.7(5)° for C1 and C3, respectively
Consequently, the metal atom, the dithiocarbamate and the
two carbonyl ligands trans to sulfurs lie in a slightly dis-
torted plane. The third carbonyl and the Re–P bond are
arranged almost perpendicular to this plane, and the Re–P
distances for both C1 and C3 are in the range observed for
other diphenylphosphanyl–metal complexes. It should be
pointed out that the ester and amido groups of the func-
tionalised phosphanes are located away from the metal
atom. This result is relevant with regard to radiopharma-
ceutical applications since the amino acid fragment linked
to the phosphane is not affected by the coordination to the
metal. Another interesting point concerns the similar Re–C
distances observed in the fac-Re(CO)3 fragments despite the
different electronic characteristics of the ligands located in
the trans position (dithiocarbamate or phosphane). The
Re–C distances of carbonyl ligands trans to phosphane are
comparable with the carbonyls trans to dithiocarbamate
both for C3 and C1. This fact could be related to the capa-
bility of phosphane and dithiocarbamate ligands to form
similar strong bonds with rhenium and to the observed ex-
perimental stability and kinetic inertia of the studied com-
plexes.[22]
Figure 2. ORTEP diagram of C3 showing 50% probability ellip-
soids (hydrogen atoms omitted for clarity).
Table 1. Selected bond lengths [Å] and angles [°] for C1 and C3.
C1
C3
Re–P
Re–C11
Re–C21
Re–C31
Re–S41
Re–S42
S41–C43
S42–C43
C43–N44
S41–Re–S42
P–Re–S41
P–Re–S42
C11–Re–C21
C21–Re–C31
C11–Re–C31
C11–Re–P
S41–Re–C31
S42–Re–C21
S41–C43–S42
2.495(2)
1.911(8)
1.929(6)
1.898(6)
2.508(2)
2.511(2)
1.715(6)
1.718(6)
1.327(7)
70.18(5)
88.63(5)
88.16(5)
89.1(3)
2.492(2)
1.943(10)
1.905(10)
1.913(9)
2.516(2)
2.507(2)
1.733(8)
1.710(8)
1.313(10)
70.00(7)
88.86(7)
84.08(7)
87.6(4)
89.0(4)
88.5(4)
178.1(3)
99.9(3)
101.3(3)
113.6(5)
89.8(3)
89.0(3)
177.5(2)
100.3(2)
99.8(2)
114.3(4)
the complexes synthesised by the two-step method. On
comparing the two methods, the yields seem to be indepen-
dent of the reaction path, but in the second case the product
is obtained in a simple one-step reaction. In the reaction
with a ligand mixture, the main product was still the
tricoordinate monomeric neutral complex. The absence of
significant quantities of phosphane complexes or dithiocar-
bamate complexes (or bidentate complexes in general) as
by-products is a relevant result since it could be related to
the peculiar thermodynamic stability of the tripodal (SS)(P)
donor set for the metal tricarbonyl core.
Figure 1. ORTEP diagram of C1 showing 50% probability ellip-
soids (hydrogen atoms omitted for clarity).
The one-step synthesis of complexes C1–C3 by direct re-
action between the rhenium precursor [Re(CO)3Br3]2– and
an equimolecular mixture of dithiocarbamate and phos-
phane was studied in order to evaluate whether the charac-
terised complexes are the main products by this pathway
Labelling Studies with 99mTc
The preparations of the homologous radioactive com-
(Scheme 3). This reaction can be regarded as a test at plexes were studied under no-carrier-added conditions by
macroscopic concentrations of the viability for future ligand substitution with the precursor fac-[99mTc(H2O)3-
development of a [2+1] mixed-ligand kit for radiopharma- (CO)3]+ and checked by HPLC analysis. The labile water
ceutical applications.[24] Complexes C1–C3 were obtained ligands can easily be replaced by more stable and inert li-
in good yields (68–75%) by this direct pathway and they gands. This reaction has been explored with DMTC[9] and
display identical spectroscopic and analytical parameters to phosphane ligands.[20,25,26]
Eur. J. Inorg. Chem. 2005, 4048–4055
www.eurjic.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4051

M. Riondato, D. Camporese, D. Martín, J. Suades, A. Alvarez-Larena, U. Mazzi
FULL PAPER
Scheme 4. Syntheses of the radio complexes C4 and C5 by the one-step approach.
We used the representative ligands L2 and L3 to simulate
the presence of a biomolecule conjugated to the phosphorus
Conclusions
The coordinating chelating system (SS)(P) appears to be
atom of the phosphane (Scheme 4). The one-step synthesis
was used to evaluate the (SS)(P) approach because it is the
more attractive method for preparing radiopharmaceuti-
cals. So, we added the dithiocarbamate and the phosphane
ligand at the same time. The lipophilic character of di-
phenylphosphanes justified the use of ethanol to prepare
the mixed-ligand solution. HPLC analysis showed that the
addiction of the ligand mixture to the precursor fac-
promising for a future medical application since complexes
with the [Re(CO)3]+ moiety can easily be prepared in a one-
step synthesis (useful in the design of a commercial kit),
with good yields, and the synthesised products are very
stable. The achieved tricoordination presented in this paper
is very versatile and offers the possibility to link a wide
range of target molecules to the monodentate phosphane.
Furthermore, the chemistry of dithiocarbamates is well
understood, and it is relatively easy to synthesise derivatives
with different residues to modulate the hydro- or lipophilic
characteristics of the desired complexes. Indeed, this [2+1]
integrated approach with a symmetric bidentate chelating
agent also avoids the formation of stereoisomers, which are
often detected when using non-symmetric bidentate ligands
or tridentate BFCA. The isomer formation influences the
specific receptor binding because of the different metal–li-
gand orientation and may produce labelled species with dif-
ferent affinity for the same target, principally for small bi-
omolecules.[27] From the perspective of developing a new
drug, single and chemically stable products are essential for
FDA approval.[8a]
[
99mTc(H2O)3(CO)3]+ led to the formation of a major com-
pound in both cases. The retention times between the two
99mTc compounds (13.27 min for C4 and 13.44 min for C5)
and the analogous Re complexes (13.39 and 13.54 min for
C2 and C3, respectively) are almost identical (Figure 3).
These results are consistent with the structure of the
Re(CO)3(SS)(P) coordination system for the radio com-
plexes C4 and C5.
Tc-99m labelling studies using the one-step method have
confirmed the capability to produce (SS)(P) radio com-
plexes. The next step will be to test the stability and kinetic
inertia of the prepared compounds in order to evaluate
their application for the formulation of new radiopharma-
ceuticals.
We conclude that the present [2+1] complex fashion
could be a useful building block in the design and develop-
ment of new target-specific 99mTc and 186/188Re radiophar-
maceuticals based on the tricarbonyl concept.
Figure 3. HPLC UV trace of the rhenium complex C3 and γ-trace
of the radioactive 99mTc complex C5.
The labelling reactions were also studied under different
reaction conditions (pH temperature, reaction time, rea-
gents’ concentration and ratio) in order to obtain the op-
timised protocols. Reaction of a 4:1 mixture of MDTC and
phosphane ligands at 80 °C for 60 min was found to give
the best results in terms of yields.
To confirm the [2+1] coordination set, the precursor was
reacted under the same conditions, but with only dithiocar-
bamate or with only phosphane ligands in the reaction mix-
ture. The labelling mixtures were analysed by HPLC to de-
termine the retention times of the products. DMTC reacts
with the tricarbonyl radioactive moiety to give a unique
peak at 14.21 min, while the reaction with the phosphane
ligands gave two peaks at 10.98/11.57 min (L2) and 11.38/
12.12 min (L3). These results support the formation of
Experimental Section
Materials and Analytical Methods: All reactions were performed
under nitrogen using standard Schlenk tube techniques. Solvents
were degassed and tested for peroxides prior to use. All chemicals
and solvents were reagent grade and were used without further pu-
rification. Infrared spectra were recorded with a Perkin–Elmer 1710
FT spectrometer as KBr pellets. The NMR spectra were recorded
by the Servei de Ressonància Magnètica Nuclear de la Universitat
Autònoma de Barcelona with a Bruker AM400 instrument. The
31P chemical shifts are reported in ppm up-field from external 85%
+
(SS)(P) coordination to 99mTc(CO)3 as the main product
because these signals were observed as minor products in
the reaction with the simultaneous addition of the dithio-
carbamate and the phosphane ligand.
1
H3PO4. The H and 13C chemical shifts are expressed in ppm up-
field from TMS.
4052
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
Eur. J. Inorg. Chem. 2005, 4048–4055

[Re(CO)3(SS)(P)] Complexes for 99mTc and 188Re Radiopharmaceuticals
FULL PAPER
Succinimidyl 3-diphenylphosphanylpropionate was provided by
Argus Spechem S.a.s. (Prato, Italy) and the precursor [NEt4]2-
[Re(CO3)Br3] was prepared by published procedures.[12] Micro-
analyses were performed at the Servei d’Anàlisi Química de la Uni-
versitat Autònoma de Barcelona. Electrospray ionisation mass
spectra (ESI-MS) were obtained with an Applied Mariner System
vacuum. The oily crude containing product L2 was purified by sil-
ica gel flash column chromatography (b) and concentrated to ob-
tain a pale-yellow oil. Yield: 368 mg (70%). TLC (b): Rf = 0.8.
HPLC: R = 9.90 min. FT-IR (KBr): ν = 1752 cm–1 (C=O, ester),
˜
t
1654 (C=O, amide). 1H NMR (CDCl3): δ = 2.31–2.41 (m, 4 H,
3
PCH2CH2), 3.72 (s, 3 H, OCH3), 3.98 (d, JCH,NH = 6.3 Hz, 2 H,
5220 mass spectrometer (PerSeptive Biosystems Inc., Framingham, -NHCH2), 6.12 (br., 1 H, NH), 7.30–7.45 (m, 10 H, ArH) ppm.
1
MA) in the positive-ion mode after dissolving the samples in aceto-
13C NMR (CDCl3, except phenyl resonances): δ = 23.3 (d, JC,P
2
nitrile (10–3 ).
= 10.6 Hz, PCH2), 32.5 (d, JC,P = 17.3 Hz, PCH2CH2), 41.5 (s,
3
CH2COOMe), 52.5 (s, OCH3), 170.3 (s, COOMe), 171.4 (d, JC,P
The diffraction measurements were recorded by the X-ray Diffrac-
tion Service of the Universitat Autònoma de Barcelona.
= 13.4 Hz, CONH) ppm. 31P NMR (CDCl3): δ = –13.9 ppm. ESI-
MS: m/z = 330 [M + H]+
Analytical thin-layer chromatography (TLC) was performed on
Merck (Darmstadt, Germany) silica gel 60-F254 plates using the
following elution systems: (a): n-hexane/EtOAc (3:2); (b): n-hexane/
AcOEt (1:3); visualisation was accomplished by UV detection at
254 nm. Flash chromatography was carried out using silica gel 230–
400 Mesh (Merck, Darmstadt, Germany) according to the method
of Still.[28]
Methyl [3-(Diphenylphosphanyl)propionylamino]propionate (L3):
Triethylamine (2.68 mmol) was added to a suspension of β-alanine
methyl ester hydrochloride (1.79 mmol) in anhydrous CH2Cl2
(50 mL). The resulting solution was stirred for 30 min and suc-
cinimidyl 3-(diphenylphosphanyl)propionate (1.79 mmol) was
added. The mixture was stirred for 4 h and the solvent was then
removed under vacuum. The oily crude residue containing product
L3 was purified by silica gel flash column chromatography (b) and
concentrated to obtain a pale-yellow oil. Yield: 442 mg (72%). TLC
RP-HPLC analyses were performed on a Waters chromatography
system (Waters, Milford, MA) controlled with a binary Waters 510
programmable gradient pump of the Department of Pharmaceuti-
cal Sciences, University of Padova. The analyses were monitored
with a Waters 486 tunable absorbance detector set at 215 nm and
a Bioscan-γ-detector B-FC 3200 (Milano, Italy). A Hamilton C18
reverse-phase column (10 µm, 250×4.6 mm, Alltech Italia, Sedri-
ano, Milano) was used and the solvents were water with 0.1% tri-
fluoroacetic acid (A) and acetonitrile with 0.05% trifluoroacetic
acid (B). The HPLC gradient system started at 50% A/50% B,
which was maintained for 5 min, rising to 100% B in 5 min with a
linear gradient. It was maintained at a maximum of B for 8 min
before returning to initial conditions in 2 min. The flow rate was
1 mLmin–1.
(b): R = 0.75. HPLC: R = 9.98 min. FT-IR (KBr): ν = 1738 cm–1
˜
f
t
(C=O, ester), 1652 (C=O, amide). 1H NMR (CDCl3): δ = 2.15–
3
2.23 (m, 2 H, PCH2), 2.32–2.35 (m, 2 H, PCH2CH2), 2.43 (t, J =
6.3 Hz, 2 H, CH2COOMe), 3.35–3.41 (dt, 3J = 6.3, JCH,NH
=
=
3
3
6.0 Hz, 2 H, -NHCH2), 3.59 (s, 3 H, OCH3), 6.03 (t, JCH,NH
6.0 Hz, 1 H, NH), 7.22–7.36 (m, 10 H, ArH) ppm. 13C NMR
1
(CDCl3, except phenyl resonances): δ = 23.1 (d, JC,P = 11.5 Hz,
PCH2), 32.4 (d, 2JC,P = 18.2 Hz, PCH2CH2), 33.5 (s, CH2COOMe),
3
34.7 (s, HNCH2), 51.5 (s, OCH3), 171.9 (d, JC,P = 13.2 Hz,
CONH), 172.1 (s, 1C, COOMe) ppm. 31P NMR (CDCl3): δ =
–14.3 ppm. ESI-MS: m/z = 344 [M + H]+.
Synthesis of Rhenium Complexes. Two-Step Method: A solution of
sodium N,N-dimethyldithiocarbamate (0.35 mmol) dissolved in
methanol (20 mL) was added dropwise to a solution of rhenium
tricarbonyl precursor [NEt4]2[Re(CO3)Br3] (0.35 mmol) in the same
solvent (20 mL). The obtained mixture was stirred for 30 min. A
methanolic solution (20 mL) of phosphane ligand (0.35 mmol) was
then added dropwise to the resulting pale yellow-green solution,
and stirred for 90 min. The solvent was removed under vacuum
and the oily residue containing the complex was purified by silica
gel flash column chromatography (elution system a for C1 and b
for C2 and C3). The solvents were then evaporated under vacuum.
The obtained oil was taken up with 5 mL of Et2O and then 50 mL
of n-hexane was added to precipitate the product. The white pow-
der was filtered off and dried under vacuum.
Na99mTcO4 was eluted from a commercial Drytec Sorin 99Mo/
99mTc Nycomed Amersham Sorin generator (Saluggia, Vercelli,
Italy) using a 0.9% saline solution. The radioactive precursor fac-
[
99mTc(H2O)3(CO)3]+ was prepared with an IsoLink kit purchased
from Mallinckrodt Med. B.V. (Pettern, Netherland).
All manipulations were carried out as approved for low-level radio-
activity use.
Methyl 3-Diphenylphosphanylpropionate (L1): A solution of suc-
cinimidyl 3-diphenylphosphanylpropionate (1.41 mmol) in meth-
anol (20 mL) was added dropwise to a stirred solution of (benzotri-
azol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate
(PyBOP, 1.41 mmol) in the same solvent (20 mL). The mixture was
left stirring for 6 h at room temperature, then the solvent was re-
moved under vacuum. The oily residue containing product L1 was
purified by silica gel flash column chromatography (a) and concen-
trated to obtain a pale-yellow oil. Yield: 268 mg (70%). TLC (a):
One-Step Method: A solution of N,N-dimethyldithiocarbamate
(0.28 mmol) and phosphane ligand (0.28 mmol) dissolved in meth-
anol (40 mL) was added dropwise to a solution of rhenium tricar-
bonyl precursor [NEt4]2[Re(CO3)Br3] (0.28 mmol) in the same sol-
vent (20 mL). The obtained mixture was stirred for 60 min and the
solvent was removed under vacuum. The crude product containing
the complex was purified by silica gel flash column chromatog-
raphy (elution system a for C1 and b for C2 and C3). The solvents
were evaporated under vacuum. The obtained oil was taken up with
5 mL of Et2O and then 50 mL of n-hexane was added to precipitate
the product. The white solid was filtered off and dried under vac-
uum.
R = 0.8. HPLC: R = 14.63 min. FT-IR (KBr): ν = 1744 cm–1
˜
f
t
(C=O, ester). 1H NMR (CDCl3): δ = 2.35–2.41 (m, 4 H,
PCH2CH2), 3.64 (s, 3 H, OCH3), 7.32–7.43 (m, 10 H, ArH) ppm.
1
13C NMR (CDCl3, except phenyl resonances): δ = 22.7 (d, JC,P
=
2
12.5 Hz, PCH2), 30.3 (d, JC,P = 19.2 Hz, PCH2CH2), 52.5 (s,
OCH3), 173.2 (d, JC,P = 15.3 Hz, COOMe) ppm. 31P NMR
3
(CDCl3): δ = –14.4 ppm. ESI-MS: m/z = 273 [M + H]+.
Methyl [3-(Diphenylphosphanyl)propionylamino]acetate (L2): Tri-
ethylamine (2.39 mmol) was added to a suspension of glycine
methyl ester hydrochloride (1.59 mmol) in anhydrous CH2Cl2
(50 mL). The solution was stirred for 30 min and then succinimidyl
3-(diphenylphosphanyl)propionate (1.59 mmol) was added. The
mixture was stirred for 3 h and the solvent was then removed under
[Re(CO)3(L1)(N,N-dimethyldithiocarbamate)]
method: Yield: 172 mg (76%). One-step method: Yield: 132 mg
(73%). TLC (a): R = 0.4. HPLC: R = 14.94 min. FT-IR (KBr): ν
(C1):
Two-step
˜
f
t
= 2016 cm–1, 1921, 1890 (CϵO), 1733 (C=O, ester), 1523 (C–N,
Eur. J. Inorg. Chem. 2005, 4048–4055
www.eurjic.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4053

M. Riondato, D. Camporese, D. Martín, J. Suades, A. Alvarez-Larena, U. Mazzi
N 3.82, S 8.74; found C 40.87, H 3.93, N 3.71, S 8.70. ESI-MS:
FULL PAPER
S2CNMe2). 1H NMR (CDCl3): δ = 2.31–2.39 (m, 2 H, PCH2), 2.86
[s, 6 H, N(CH3)2], 2.89–2.97 (m, 2 H, PCH2CH2), 3.61 (s, 3 H, m/z = 735 [M + H]+.
OCH3), 7.26–7.55 (m, 10 H, ArH) ppm. 13C NMR (CDCl3, except
Synthesis of Technetium-99m Complexes. General Procedure: Tech-
1
phenyl resonances): δ = 22.7 (d, JC,P = 28.7 Hz, PCH2), 30.1 (d,
netium-99m labelling was performed by addiction of 15 µL of an
ethanolic solution of N,N-dimethyldithiocarbamate (0.8 m,
0.012 µmol) and phosphane ligand (0.2 m, 0.003 µmol) to 85 µL
2JC,P = 43.3 Hz, PCH2CH2), 38.2 [s, N(CH3)2], 51.6 (s, OCH3),
3
172.6 (d, JC,P = 16.4 Hz, COOMe), 190.1–193.6 [m, Re(CO)3],
206.6 (s, NCS2) ppm. 31P NMR (CDCl3):
δ = 5.2 ppm.
of
a
freshly prepared solution of fac-[99mTc(H2O)3(CO)3]+
C22H23NO5PReS2: calcd. C 39.77, H 3.50, N 2.11, S 9.68; found C
(15 MBq), pH 7.4. The mixture was incubated at 80 °C and stirred
for 1 h. Analysis by HPLC equipped with a γ-radiometric detector
showed a main peak for all experiments. Data are expressed as
means of SD of three experiments.
39.66, H 3.65, N 2.08, S 9.42. ESI-MS: m/z = 664 [M + H]+.
[Re(CO)3(L2)(N,N-dimethyldithiocarbamate)]
(C2):
Two-step
method: Yield: 165 mg (68%). One-step method: Yield: 146 mg
(75%). TLC (b): R = 0.5. HPLC: R = 13.39 min. FT-IR (KBr): ν
˜
f
t
Comparative fac-[99mTc(H2O)3(CO)3]+ labelling reactions with the
only presence of N,N-dimethyldithiocarbamate or phosphane li-
gand were carried out under the same conditions and analysed by
HPLC.
= 2016 cm–1, 1919, 1890 (CϵO), 1750 (C=O, ester), 1654 (C=O,
1
amide) 1522 (C–N, S2CNMe2). H NMR (CDCl3): δ = 2.25–2.33
(m, 2 H, PCH2), 2.85 [s, 6 H, N(CH3)2], 2.94–3.02 (m, 2 H,
3
PCH2CH2), 3.74 (s, 3 H, OCH3), 3.96 (d, JCH,NH = 5.1 Hz, 2 H,
99mTc(CO)3(L2)(N,N-dimethyldithiocarbamate)] (C4): HPLC: Rt =
-NHCH2), 5.88 (br., 1 H, NH), 7.37–7.55 (m, 10 H, ArH) ppm.
[
1
13C NMR (CDCl3, except phenyl resonances): δ = 24.1 (d, JC,P
=
13.27 min. Labelling yield = 83 1.7%. (HPLC: Rt [99mTc(CO)3
with DMTC] = 14.29 min, Rt [99mTc(CO)3 with L2] = 10.98 min,
11.57 min).
2
28.7 Hz, PCH2), 30.2 (d, JC,P = 43.0 Hz, PCH2CH2), 38.2 [s,
N(CH3)2], 41.4 (s, CH2COOMe), 52.4 (s, OCH3), 170.16 (s, CO-
3
OMe), 171.48 (d, JC,P = 14.7 Hz, CONH), 189.2–193.3 [m,
99mTc(CO)3(L3)(N,N-dimethyldithiocarbamate)] (C5): HPLC: Rt =
Re(CO)3], 212.4 (s, NCS2) ppm. 31P NMR (CDCl3): δ = 6.7 ppm.
C24H26N2O6PReS2: calcd. C 40.05, H 3.64, N 3.89, S 8.91; found
C 39.97, H 3.75, N 3.65, S 8.62. ESI-MS: m/z = 721 [M + H]+.
[
13.44 min. Labelling yield = 83 1.7%. (HPLC: Rt [99mTc(CO)3
with DMTC] = 14.29 min, Rt [99mTc(CO)3 with L3] = 11.38 min,
12.12 min).
[Re(CO)3(L3)(N,N-dimethyldithiocarbamate)]
(C3):
Two-step
method: Yield: 192 mg (77%). One-step method: Yield: 147 mg
X-ray Crystallography: Colourless single crystals were obtained
from methanol at –30°C (C1) or by slow diffusion of n-hexane into
a solution of the compound in ethyl acetate at room temperature
(73%). TLC (b): R = 0.5. HPLC: R = 13.54 min. FT-IR (KBr): ν
˜
f
t
= 2015 cm–1, 1920, 1889 (CϵO), 1734 (C=O, ester), 1652 (C=O,
1
amide) 1526 (C–N, S2CNMe2). H NMR (CDCl3,): δ = 2.20–2.27 (C3). Crystal data and selected information on data collection and
(m, 2 H, PCH2CH2), 2.40 (t, 3J = 6.1 Hz, 2 H, Ala-CH2-COOMe), structure determination are given in Table 2. Data were collected
2.85 [s, 6 H, N(CH3)2], 2.93–3.00 (m, 2 H, PCH2CH2), 3.42–3.49
on a Bruker SMART CCD area-detector diffractometer at room
temperature. Graphite-monochromated Mo-Kα radiation (λ =
3
3
(dt, J = 6.3, JCH,NH = 5.0 Hz, 2 H, Ala-NH-CH2), 3.70 (s, 3 H,
3
OCH3), 5.97 (t, JCH,NH = 5.0 Hz, 1 H, NH), 7.41–7.57 (m, 10 H, 0.71073 Å) was used. Lorentz-polarisation and absorption correc-
ArH) ppm. 13C NMR (CDCl3, except phenyl resonances): δ = 24.3
tions were applied using Bruker SAINT and SADABS software.
The structures were solved by direct methods and refined by full-
matrix least-squares on F2 for all unique measured data with
1
2
(d, JC,P = 28.8 Hz, PCH2), 30.0 (d, JC,P = 47.0 Hz, PCH2CH2),
31.9 (s, CH2COOMe), 34.9 (s, HNCH2), 38.4 [s, N(CH3)2], 51.5 (s,
OCH3), 171.5 (d, JC,P = 14.4 Hz, CONH), 172.5 (s, COOMe),
weighting w–1 = σ2(Fo2) + (aP)2 + bP, where P = (Fo2 + 2Fc )/3.[29]
3
2
189.2–193.4 [m, Re(CO)3], 212.2 (s, NCS2) ppm. 31P NMR
(CDCl3): δ = 7.7 ppm. C25H28N2O6PReS2: calcd. C 40.92, H 3.85,
Non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were included with riding model constraints and isotropic displace-
Table 2. Crystal data and structure refinement parameters for C1 and C3.
C1
C3
Empirical formula
Formula mass
Crystal system
Space group
C22H23NO5PReS2
662.70
monoclinic
C2/c
C25H28N2O6PReS2
733.78
monoclinic
P21/c
a [Å]
b [Å]
c [Å]
22.6340(16)
10.6284(7)
21.2346(14)
103.212(1)
4973.1(6)
10.6473(8)
29.191(2)
9.1776(7)
92.566 (2)
2849.6(4)
β [°]
V [Å3]
Z
8
4
ρcalcd. [Mgm–3]
Absorption coefficient [mm–1]
F(000)
1.770
5.152
2592
1.710
4.508
1448
Crystal size [mm]
Theta range for data collection
Reflections collected/unique
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
R(F), Rw(F2) [I Ͼ 2σ(I)]
R(F), Rw(F2) (all data)
0.22×0.18×0.08
1.85 to 28.26
15196/5601 (Rint = 0.0445)
0.66 and 0.32
5601/12/292
1.056
0.22×0.10×0.05
1.40 to 28.22
17896/6380 (Rint = 0.0560)
0.80 and 0.37
6380/12/337
1.068
0.0457, 0.0899
0.0636, 0.0960
0.0603, 0.1120
0.0989, 0.1275
4054
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
Eur. J. Inorg. Chem. 2005, 4048–4055

[Re(CO)3(SS)(P)] Complexes for 99mTc and 188Re Radiopharmaceuticals
FULL PAPER
[10] G. W. Anderson, J. E. Zimmerman, F. M. Callahan, J. Am.
Chem. Soc. 1964, 86, 1839–1842.
[11] R. Visentin, R. Rossin, M. C. Giron, A. Dolmella, G. Bandoli,
U. Mazzi, Inorg. Chem. 2003, 42, 950–959.
[12] R. Alberto, R. Schibli, P. A. A. Egli, P. A. Schubiger, W. A.
Hermann, G. Artus, U. Abram, T. A. Kaden, J. Organomet.
Chem. 1995, 493, 119–127.
ment parameters 1.5 (methyl H) or 1.2 (the rest) times the Ueq
values of the corresponding carbon or nitrogen atoms.
CCDC-258371 (for C1) and -258372 (for C3) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] a) C. J. Davidson, L. Lock, in Comprehensive Coordination
Chemistry, vol. 4 (Eds.: H. G. Wilkinson, R. D. Gillard, J. A.
McCleverty), Pergamon Press, Oxford 1987; b) R. Dilworth,
S. J. Parrott, Chem. Soc. Rev. 1998, 27, 43–55.
[14] D. A. Blinn, R. S. Button, V. Farazi, M. K. Neeb, C. L. Tapley,
T. E. Trehearne, S. D. West, T. L. Kruger, B. N. Storhoff, J. Or-
ganomet. Chem. 1990, 393, 143–152.
Acknowledgments
The authors would like to thank the COST action B12, the
C.I.R.C.MSB. (Bari, Italy), the Italian Ministero dellЈUniversitá e
della Ricerca Scientifica e Tecnologica and the Spanish Dirección
General de Investigación for financial support.
[15] K. Heesche-Wagner, T. N. Mitchell, J. Organomet. Chem. 1994,
468, 99–106.
[16] D. Osella, P. Pollone, M. Ravera, M. Salmain, G. Jaouen,
Bioconjugate Chem. 1999, 10, 607–612.
[17] R. Schibli, K. V. Katti, W. A. Volkert, C. L. Burnes, Inorg.
Chem. 2001, 40, 2358–2362.
[18] K. R. Benak, B. N. Storhoff, J. Coord. Chem. 1995, 36, 303–
309.
[1] a) K. Schwochau, Technetium, Chemistry and Radiopharmaceu-
tical Application, Wiley-VCH, Weinheim, Germany, 2000; b)
J. Steigman, W. C. Eckelman, The Chemistry of Technetium in
Medicine, Nuclear Science Series, National Academic Press,
Washington DC, 1992.
[2] a) S. Jurisson, D. Berning, W. Jia, D. Ma, Chem. Rev. 1993, 93,
1137–1156; b) F. F. Knapp Jr., A. L. Beet, S. Guhlke, Antican-
cer Res. 1997, 17, 1783–1796.
[3] a) C. J. Smith, G. L. Sieckman, N. K. Owen, D. L. Hayes, D. G.
Mazuru, R. Kannan, W. A. Volkert, T. J. Hoffman, Cancer Res.
2003, 63, 4082–4088; b) R. La Bella, E. Garcia-Garayoa, M.
Langer, P. Bläuenstein, A. G. Beck-Sickinger, P. A. Schubiger,
Nucl. Med. Biol. 2002, 29, 553–560.
[19] J. D. G. Correia, A. Domingos, I. Santos, R. Alberto, K.
Ortner, Inorg. Chem. 2001, 40, 5147–5151.
[20] a) T. Kniess, J. D. G. Correia, A. Domingos, E. Palma, I. San-
tos, Inorg. Chem. 2003, 42, 6130–6135; b) E. Palma, J. D. G.
Correia, A. Domingos, I. Santos, R. Alberto, A. Spies, J. Or-
ganomet. Chem. 2004, 689, 4811–4819.
[21] A. A. Marti, G. Mazei, L. Maldonado, G. Paralitici, R. G.
Raptis, J. L. Colon, Eur. J. Inorg. Chem. 2005, 1, 118–124.
[4] a) S. Liu, D. S. Edwards, Chem. Rev. 1999, 99, 2235–2268; b) [22] a) J. F. Rowbottom, G. Wilkinson, J. Chem. Soc., Dalton Trans.
S. S. Jurisson, J. F. Lydon, Chem. Rev. 1999, 99, 2205–2218.
[5] a) R. Alberto, K. Ortner, N. Wheatley, R. Schibli, A. P. Schu-
biger, J. Am. Chem. Soc. 2001, 123, 3135–3136; b) R. Schibli,
R. Schwarzbach, R. Alberto, K. Ortner, H. Schmalle, C.
Dumas, A. Egli, P. A. Schubiger, Bioconjugate Chem. 2002, 13,
750–756.
[6] a) R. Alberto, R. Schibli, R. Waibel, U. Abram, A. P. Schu-
biger, Coord. Chem. Rev. 1999, 190–192; R. Alberto, R. Schibli,
R. Waibel, U. Abram, A. P. Schubiger, Coord. Chem. Rev. 1999,
901–919; b) W. A. Volkert, T. J. Hoffman, Chem. Rev. 1999, 99,
2269–2292.
1974, 1, 684–689; b) E. Lindner, R. Grimmer, J. Organomet.
Chem. 1970, 25, 493–501.
[23] J. D. Dilworth, D. V. Griffiths, S. J. Parrott, Y. Zheng, J. Chem.
Soc., Dalton Trans. 1997, 17, 2931–2936.
[24] D. L. Nosco, A. J. Tofe, T. J. Dunn, L. R. Lyle, R. G. Wolfan-
gel, M. J. Bushman, G. D. Grummon, D. E. Helling, M. E.
Marmion, K. M. Miller, D. W. Pipes, T. W. Strubel, D. W.
Wester, in Technetium and Rhenium in Chemistry and Nuclear
Medicine, 3 (Eds.: M. Nicolini, G. Bandoli, U. Mazzi), Cortina
International, Verona, Raven Press, New York, pp. 381–392,
1990.
[7] a) J. K. Pak, P. Benny, B. Spingler, K. Ortner, R. Alberto,
Chem. Eur. J. 2003, 9, 2053–2061; b) R. Schibli, K. V. Katti, C.
Higginbotham, W. A. Volkert, R. Alberto, J. Nucl. Med. Biol.
1999, 26, 711–716; c) J. Bernard, K. Ortner, B. Spingler, H. J.
Pietzsch, R. Alberto, Inorg. Chem. 2003, 42, 1014–1022.
[8] a) R. Alberto, Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 1299–
1302; b) S. Mundwiler, M. Kündig, K. Ortner, R. Alberto, Dal-
[25] K. K. Kothari, N. K. Pillarsetty, K. V. Katti, W. A. Volkert,
Radiochim. Acta 2003, 91, 53–57.
[26] C. J. Smith, G. L. Sieckman, N. K. Owen, D. L. Hayes, D. G.
Mazuru, R. Kannan, W. A. Volkert, T. J. Hoffman, Cancer Res.
2003, 63, 4082–4088.
[27] Wüst, M. B. Skaddan, P. Leibnitz, H. Spies, J. A. Katzenellen-
bogen, B. Johannsen, Bioorg. Med. Chem. 1999, 7, 1827–1835.
ton Trans. 2004, 9, 1320–1328; c) R. Alberto, J. K. Pak, D. [28] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
Van Staveren, S. Mundwiler, P. Benny, Biopolymers 2004, 76,
324–333.
2925.
[29] G. M. Sheldrick, SHELXS97/SHELXL97, University of
Göttingen, Germany.
[9] N. I. Gorshkov, R. Schibli, A. P. Schubiger, A. A. Lumpov,
A. E. Miroslavov, D. N. Suglobov, J. Organomet. Chem. 2004,
689, 4757–4763.
Received: March 22, 2005
Published Online: September 8, 2005
Eur. J. Inorg. Chem. 2005, 4048–4055
www.eurjic.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4055