Study on the formation of mixed ligand oxorhenium and oxotechnetium complexes (SNS/S combination)

Article abstract of DOI:10.1016/S0020-1693(99)00262-5

Theoretically, several complexes can be formed during the reaction between the tridentate aminedithiol ligand EtN(CH₂CH₂SH)₂, L1H₂, the monodentate thiol p-ClC₆H₄SH, L2H, and the Re^VOCl₃(PPh₃)₂. Three main possibilities are: (i) neutral mixed ligand complexes ReOL1L2, the syn isomer, complex 1 and the anti isomer, complex 2; (ii) binuclear complex of the tridentate ligand, (ReO)₂(L1)₃, complex 3 and (iii) anionic complex of the monothiol [ReO(L2)₄]^-, complex 4. When a mixture of L1H₂/L2H, 1/1 ratio, is applied, the major product of the reaction is the syn isomer 1. A small amount of the anti isomer 2 is also isolated (yield <2%) while none of the complexes 3 and 4 are formed under the above reaction conditions. The oxorhenium complexes 3 and 4 have been synthesized by the reaction of L1H₂ or L2H respectively with the precursor ReOCl₃(PPh₃)₂. The crystal structures of 1, 3, and 4 are determined by X-ray crystallography. The corresponding ^99mTc complexes have been prepared by exchange reaction using ^99mTc-glucoheptonate as precursor. Similarly the major reaction product is the syn isomer, complex 1′, while none of the other complexes are formed during the reaction at tracer level. The above studies demonstrate that simultaneous action of a tridentate SNS ligand and a monodentate thiol in equimolar quantities on Re^VOCl₃(PPh₃)₂ or ^99mTc-glucoheptonate leads to a single rhenium or technetium-99m species, the syn MOL1L2.

Full text of DOI:10.1016/S0020-1693(99)00262-5

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Inorganica Chimica Acta 295 (1999) 1–8
Study on the formation of mixed ligand oxorhenium and
oxotechnetium complexes (SNS/S combination)
Minas Papadopoulos a, Ioannis Pirmettis a, Charalabos Tsoukalas a, Berthold Nock a,
Theodosia Maina a, Catherine P. Raptopoulou b, Hans-Juergen Pietzsch c,
Matthias Friebe c, Hartmut Spies c, Bernd Johannsen c, Efstratios Chiotellis a,*
a Institute of Radioisotopes and Radiodiagnostic Products, NCSR ‘Demokritos’, PO Box 60228, Ag. Paraske6i, 153 10 Athens, Greece
b Institute of Materials Science, NCSR ‘Demokritos’, Ag. Paraske6i, 153 10 Athens, Greece
c Institute of Bioinorganic and Radiopharmaceutical Chemistry, Forschungszentrum Rossendorf, Dresden, Germany
Received 26 March 1999; accepted 21 June 1999
Abstract
Theoretically, several complexes can be formed during the reaction between the tridentate aminedithiol ligand
EtN(CH2CH2SH)2, L1H2, the monodentate thiol p-ClC6H4SH, L2H, and the ReVOCl3(PPh3)2. Three main possibilities are: (i)
neutral mixed ligand complexes ReOL1L2, the syn isomer, complex 1 and the anti isomer, complex 2; (ii) binuclear complex of
the tridentate ligand, (ReO)2(L1)3, complex 3 and (iii) anionic complex of the monothiol [ReO(L2)4]−, complex 4. When a mixture
of L1H2/L2H, 1/1 ratio, is applied, the major product of the reaction is the syn isomer 1. A small amount of the anti isomer 2
is also isolated (yield B2%) while none of the complexes 3 and 4 are formed under the above reaction conditions. The
oxorhenium complexes 3 and 4 have been synthesized by the reaction of L1H2 or L2H respectively with the precursor
ReOCl3(PPh3)2. The crystal structures of 1, 3, and 4 are determined by X-ray crystallography. The corresponding 99mTc complexes
have been prepared by exchange reaction using 99mTc-glucoheptonate as precursor. Similarly the major reaction product is the syn
isomer, complex 1%, while none of the other complexes are formed during the reaction at tracer level. The above studies
demonstrate that simultaneous action of a tridentate SNS ligand and a monodentate thiol in equimolar quantities on
ReVOCl3(PPh3)2 or 99mTc-glucoheptonate leads to a single rhenium or technetium-99m species, the syn MOL1L2. © 1999 Elsevier
Science S.A. All rights reserved.
Keywords: Crystal structures; Rhenium complexes; Technetium complexes; Mixed ligand complexes
1. Introduction
complexes containing the TcꢀO core based on two
linear tetradentate ligand systems: (a) the propylenedi-
amine dioxime (PnAO), N4 backbone, and (b) the
diaminedithiol (DADT), N2S2 system [1–7].
The widespread use of compounds of the g-emitting
radionuclide 99mTc in nuclear medicine for the scinti-
graphic imaging of internal organs, as well as the recent
introduction of the b-emitting radionuclides 188Re and
186Re in radiotherapy have led to a rapid development
of their chemistries, in order to produce novel useful
radiopharmaceuticals. Concerning the particular class
of brain perfusion agents, many efforts have been fo-
cused on the synthesis of neutral, small size, lipophilic
An alternative concept for the synthesis of neutral
oxotechnetium and oxorhenium complexes is based on
the ‘3+1’ mixed ligand approach [8–11] involving the
SNS+S donor atom set [12–17]. According to this
concept, the simultaneous action of a tridentate ligand
(SNS) and a monodentate thiol (S) as coligand on a
suitable [MꢀO]3+ (M=Tc, Re) precursor leads to the
formation of neutral lipophilic metal species. The major
advantage of the mixed ligand system lies in its flexibil-
ity. Thus, a great variety of tridentate/monodentate
ligand combinations becomes easily available by use of
* Corresponding author. Tel.: +30-1-651 3793; fax: +30-1-654
3526.
E-mail address: echiot@mail.demokritos.gr (E. Chiotellis)
0020-1693/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0020-1693(99)00262-5

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M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
this system, thereby facilitating the production of ho-
mologous series. So far, interesting radioagents have
been developed from this system and evaluated either
as brain perfusion agents [18] or even as specific radio-
pharmaceuticals for the mapping of brain receptors
[19].
In order to better understand the chemistry of the
SNS/S system, the complexes presented in Fig. 1 have
been synthesized and characterized by elemental analy-
sis and spectroscopic methods. Crystallographic analy-
tor set either at 254 or 382 nm and to a Steffi gamma
detector from Raytest (RSM Analytische Instrumente
GmbH, Germany). Separations were achieved on a
Merck Lichrospher 100 RP-18 (10 mm, 250×4 mm2)
column eluted with a binary gradient system at a 1.0 ml
min−1 flow rate. Mobile phase A consists of 2% tri-
ethylamine neutralized to pH 7.1 with 85% phosphoric
acid, while mobile phase B was pure ethanol. The
elution profile was 0–10 min isocratic with 60% A and
40% B, followed by a linear gradient to 30 and 70% B
at 25 min; this composition was held for another 10
min. After a column wash with 95% B for 5 min the
column was re-equilibrated with mobile phase A for 20
min prior to next injection. Rhenium complexes were
detected by a photodiode array detector, Waters 991
PDA, recording the UV–Vis spectrum of the eluting
complexes, and a Beckman 171 radioisotope detector.
All laboratory chemicals were reagent grade. The
4-chlorothiophenol used as coligand was purchased
from Fluka. The tridentate ligand, 2,2%-dimercaptotri-
ethylamine, was synthesized as described previously
[20,21] and the compound was purified by vacuum
distillation. ReOCl3(PPh3)2 was prepared according to
the literature [22].
sis
of
complexes
ReO[CH3CH2N(CH2CH2S)2]-
[p-SC6H4Cl] (1), [ReO]2[CH3CH2N(CH2CH2S)2]3 (3)
and [ReO(p-SC6H4Cl)4][PCH3(C6H5)3] (4), is reported.
Analogous technetium-99m complexes have been pre-
pared by exchange reaction using Tc-99m glucohepto-
nate as precursor.
2. Experimental
2.1. Materials and methods
IR spectra were recorded as KBr pellets in the range
4000–500 cm−1 on a Perkin–Elmer 1600 FT-IR spec-
trophotometer and were referenced to polystyrene. Ele-
mental analyses were performed on a Perkin–Elmer
2400/II automatic analyzer. High performance liquid
chromatography (HPLC) analysis was performed on a
Waters 600 Millennium Chromatography System cou-
pled to both a Waters 486 Tunable Absorbance Detec-
Na99mTcO4 was obtained in physiological saline from
a commercial 99Mo/99mTc generator (Cis International).
Commercial glucoheptonate kits containing
a
lyophilized mixture of 0.2 mg of SnCl2 and 200 mg of
calcium glucoheptonate (Gluco/Demoscan, NCSR,
‘‘Demokritos’’) were used.
Fig. 1. Possible complexes by joint action of L1H2+L2H on ReOCCl3(PPh3)2.

M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
3
2.2. Safety note
room temperature afforded the product as green crys-
tals. Yield: 60%.
Technetium-99m is a gamma emitter (141 keV) with
a half life of 6 h. Handling of solutions containing this
radionuclide always proceeds behind sufficient lead
shielding.
Complex 3. Rf: 0.7 (silica gel, CH3OH/CH2Cl2/Et3N,
8/1.5/0.5). FT-IR (cm−1, KBr pellet): 944 (ReꢀO). UV–
Vis (nm): 208, 265, 373. Anal. Calc. for
C18H39N3O2S6Re2·CH3OH·3H2O·C, 23.24; H, 5.03; N,
4.28; S, 19.55. Found: C, 23.65; H, 4.75; N, 4.32; S,
1
2.3. Synthesis of the rhenium complexes
20.00%. H NMR lH (250 MHz, CDCl3, Me4Si): 1.05
(3H, t, CH3CH2N), 1.30 (6H, t, CH3CH2N), 2.50 (4H,
m, exo, NCH2CH2SꢁRe), 2.68 (2H, q, CH3CH2N), 2.90
(4H, m, exo, NCH2CH2SꢁRe), 2.90 (4H, m,
NCH2CH2S), 3.20 (4H, m, endo, NCH2CH2SꢁRe), 3.49
(6H, m, endo, NCH2CH2SꢁRe), 3.85 (6H, m,
CH3CH2NꢁRe, NCH2CH2SꢁRe). Crystals suitable for
X-ray crystallography were obtained by recrystallization
from MeCN/MeOH/CH2Cl2.
2.3.1. ReO[CH3CH2N(CH2CH2S)2][p-SC6H4Cl] (1), (2)
To a stirred suspension of trichlorobis(triphenylphos-
phine)rhenium(V) oxide (166 mg, 0.2 mmol) in
methanol (10 ml), 1 M CH3COONa in methanol (2 ml,
2 mmol) was added. A mixture of 2,2%-dimercaptotri-
ethylamine (L1H2) (33 mg, 0.2 mmol) and 29 mg (0.2
mmol) of 4-chlorothiophenol (L2H) was added under
stirring. The solution was refluxed until the green–yel-
low color of the precursor turned to dark-green. After
cooling to room temperature, the reaction mixture was
diluted with CH2Cl2 (30 ml) and then washed with
water. The organic layer was separated from the mixture
and dried over MgSO4. The volume of the solution was
reduced to 5 ml and then 5 ml of methanol were added.
Analysis of the solution by HPLC (conditions are given
in the previous section) demonstrated the formation of
two complexes in a ratio of approximately 25/1. Slow
evaporation of the solvents at room temperature af-
forded the major product of the reaction as a green solid
(1, syn isomer, 50% yield). Crystals suitable for X-ray
crystallography were obtained by recrystallization from
MeOH/CH2Cl2. Only in some preparations was a small
amount of another complex isolated as an orange solid
from the filtrate (2, anti, yield B2%).
2.3.3. [ReO(p-SC6H4Cl)4][PCH3(C6H5)3] (4)
To a stirred suspension of trichlorobis(triphenylphos-
phine)rhenium(V) oxide (166 mg, 0.2 mmol) in
methanol (10 ml), 1 M CH3COONa in methanol (2 ml,
2 mmol) was added. Then, a solution p-HSꢁC6H4Cl,
(L2H), (116 mg, 0.8 mmol) in methanol (2 ml) was
added. The same procedure as above was followed and
HPLC analysis demonstrated the formation of mainly
one complex. Slow evaporation of the solvents at room
temperature afforded the product as green crystals.
Yield: 45%.
Complex 4. Rf: 0.9 (silica gel, CH3OH/CH2Cl2/Et3N,
8/1.5/0.5). FT-IR (cm−1, KBr pellet): 963 (ReꢀO). UV–
Vis (nm): 211, 367, 406. Anal. Calc. for
C43H34Cl4OPS4Re: C, 49.05; H, 3.26; S, 12.16. Found:
1
C, 48.59; H, 3.35; S, 12.10%. H NMR lH (250 MHz,
Complex 1 (syn). Rf: 0.8 (silica gel, CH3OH/CH2Cl2/
Et3N, 8/1.5/0.5). FT-IR (cm−1, KBr pellet): 940
(ReꢀO). UV–Vis (nm): 231, 294, 412. Anal. Calc. for
C12H17ClNOS3Re: C, 28.31; H, 3.37; N, 2.75; S, 18.19.
CDCl3, Me4Si): 2.45 (3H, d, PCH3), 6.95 (8H, dd,
o-PhꢁH), 7.32 (8H, dd, m-PhꢁH), 7.45 (6H, m, o-
PhꢁH), 7.65 (6H, m, m-PhꢁH), 7.78 (3H, m, p-PhꢁH).
Crystals suitable for X-ray crystallography were ob-
tained by recrystallization from EtOH/CH2Cl2.
1
Found: C, 28.35; H, 3.45; N, 2.67; S, 18.53%. H NMR
lH (250 MHz, CDCl3, Me4Si): 1.38 (3H, t, CH3CH2N),
2.50–2.90 (4H, m, exo, NCH2CH2S), 3.30 (2H, m,
endo, NCH2CH2S), 3.55 (2H, m, endo, NCH2CH2S),
3.95 (2H, q, CH3CH2NꢁRe), 7.35 (2H, dd, o-PhꢁH),
7.55 (2H, dd, m-PhꢁH).
Complex 2 (anti ). Rf: 0.85 (silica gel, CH3OH/
CH2Cl2/Et3N, 8/1.5/0.5), FT-IR (cm−1, KBr pellet): 963
(Re=O). UV–Vis (nm): 231, 257, 363.
2.4. Synthesis at tracer 99mTc le6el. General method
A Gluco/Demoscan kit was reconstituted with 10 ml
water, and then a 1.0 ml aliquot was mixed with 0.5–1.0
ml of 99mTc-pertechnetate solution (5–10 mCi). The
99mTc(V)Oglucoheptonate solution was added to a cen-
trifuge tube containing either (i) equimolar quantities
(0.02 mmol) of the tridentate ligand, L1H2, and the
monodentate ligand, L2H, complexes 1% and 2%; (ii) 0.02
mmol of the tridentate ligand, L1H2, complex 3% or (iii)
0.02 mmol of the monodentate ligand, L2H, complex 4%.
The mixture was agitated in a vortex mixer and left to
react at room temperature for 10 min. The complexes
were extracted with CH2Cl2 (3×1.5 ml) and the com-
bined organic extracts were dried over MgSO4 and
filtered. The extractions were nearly quantitative for all
three preparations.
2.3.2. (ReO)2[CH3CH2N(CH2CH2S)2]3 (3)
To a stirred suspension of trichlorobis(triphenylphos-
phine)rhenium(V) oxide (332 mg, 0.4 mmol) in
methanol (10 ml), 1 N CH3COONa in methanol (2 ml,
2 mmol) was added. Then, a solution of 2,2%-dimercap-
totriethylamine (L1H2) (99 mg, 0.6 mmol) in methanol
(2 ml) was added. The same procedure was followed as
above and HPLC analysis demonstrated the formation
of one complex. Slow evaporation of the solvents at

4
M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
The identity of the 99mTc complexes was established
range 2.3+h1h2 separation. For 3: 2qmax=130°, scan
speed 1.5° min−1, scan range 2.5+h1h2 separation.
Three standard reflections monitored every 97 reflec-
tions showed less than 3% variation and no decay.
Lorentz, polarization and psi-scan absorption correc-
tions were applied using the Crystal Logic software.
For 1, 2989 reflections were collected which averaged
with Rint=0.0125 to give 2755 independent; for 3,
collected symmetry equivalent data were averaged with
by comparative HPLC studies using as references sam-
ples of the well characterized corresponding Re com-
plexes. In all preparations for the mixed ligand
complexes, 1% and 2%, HPLC analysis of the organic
extracts (50 ml, 50–100 mCi) showed one major radioac-
tive peak (\95%) which was proved to be the syn
isomer, 1. Only in some preparations was a minor peak
(B2%) detected.
R
int=0.0179 to give 5713 independent reflections from
2.5. X-ray crystallography
a total of 6081 collected. For 4, 9826 reflections were
collected and the unique data were 9379 (Rint=0.0268).
The structures were solved by direct methods using
SHELXS-86 [23] and refined by full-matrix least-squares
techniques on F2 with SHELXL-93 [24]. Refinement de-
tails for complex 1: 2755 reflections were used to refine
240 parameters. All hydrogen atoms were located by
difference maps and refined isotropically; all non-hy-
drogen atoms were refined anisotropically. The final
values for R1, wR2 and GOF for all data are 0.0327,
0.0751 and 1.092, respectively. The maximum and min-
imum residual peaks in the final difference map were
A brown crystal of 1 with dimensions 0.25×0.25×
0.50 mm, and a dark red crystal of 4 with dimensions
0.10×0.30×0.50 mm were mounted in air while a
green crystal of 3 with dimensions 0.10×0.20×0.50
mm was mounted in glass fiber and covered with epoxy
glue. Diffraction measurements for 1 and 4 were made
on a Crystal Logic Dual Goniometer diffractometer
using graphite monochromated Mo Ka radiation, but
data collection for complex 3 was performed on a P21
Nicolet diffractometer with Ni-filtered Cu Ka radia-
tion. Unit cell dimensions were determined by using the
angular settings of 25 automatically centered reflections
in the range 11B2qB23° (for 1 and 4) and 24B2qB
54° (for 3) and they appear in Table 1. Intensity data
were recorded using a q–2q scan. For 1: 2qmax=50.7°,
scan speed 3.5° min−1, scan range 2.5+h1h2 separa-
tion. For 4: 2qmax=54°, scan speed 4.0° min−1, scan
0.942 and −0.905 e A−3. The largest shift/e.s.d. in the
,
final cycle was 0.002. Refinement details for complex 3:
5712 reflections were used to refine 345 parameters. All
hydrogen atoms were introduced at calculated positions
as riding on bonded atoms and refined isotropically; all
non-hydrogen atoms were refined anisotropically. The
final values for R1, wR2 and GOF for all data are
Table 1
Summary of crystal and refinement data for complexes 1, 3 and 4
1
3
4
Data/parameters refined
Formula
Formula weight
T (K)
C12H17NOS3ClRe
C12H17NOS3ClRe
509.10
C19H49N3O6S6Re2
C19H49N3O6S6Re2
980.41
C43H34OS4Cl4PRe
C43H34OS4Cl4PRe
1053.99
298
298
298
,
u (A)
Space group
Mo Ka (0.710730)
P21/n
7.392(3)
16.476(8)
13.323(7)
Cu Ka (1.5418)
Mo Ka (0.710730)
(
(
P1
R3
,
a (A)
b (A)
c (A)
h (°)
i (°)
k (°)
10.207(1)
13.839(2)
14.260(2)
104.729(4)
105.719(3)
109.924(3)
1683.9(3)
2
42.08(2)
42.08(2)
13.975(7)
,
,
105.09(1)
3
,
V (A )
1567(1)
4
2.158
8.317
976
21429.5(2)
18
1.470
3.015
9396
Z
dcalc. (g cm−3
)
1.934
16.13
956
v (mm−1
F(000)
)
Data/parameters refined
Goodness-of-fit
R1
wR2
2755/240
1.092
5712/345
1.052
9363/482
1.029
0.0279 a
0.0723 a
0.0418 b
0.1121 b
0.0442 c
0.0965 c
a For 2484 reflections: I\2|(I).
b For 5004 reflections: I\2|(I).
c For 6216 reflections: I\2|(I).

M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
5
0.0480, 0.1194 and 1.053, respectively. The maximum
and minimum residual peaks in the final difference map
are crystalline solids, soluble in CH2Cl2 and CHCl3,
slightly soluble in EtOH and MeOH and insoluble in
pentane and water. They are stable in the solid state as
well as in organic solutions for a period of months as
shown by HPLC. Their stability is not affected by the
presence of air or moisture.
When a mixture of L1H2/L2H 1/1 is applied, the
major product of the reaction is the syn isomer 1 as
demonstrated by crystal structure analysis. HPLC de-
tection of the crude reaction mixture showed that both
complexes 3 and 4 do not form during the reaction
under the above conditions. Only in some preparations
did HPLC analysis reveal the presence of a small
amount of an additional complex with lower retention
time in comparison to the syn isomer. It was isolated in
a small quantity and its spectroscopic data, IR and
UV–Vis show that it is the anti isomer [17].
The infrared spectra of compounds 1 and 2 exhibit
strong ReꢀO stretching bands at 940 cm−1 for the syn
isomer and 963 cm−1 for the anti isomer. This shift to
higher frequencies has been also reported for other syn
and anti mixed ligand complexes with the same donor
atom system. The infrared spectra of compounds 3 and
4 exhibit strong ReꢀO stretching bands at 944 and 963
cm−1, respectively. These values are consistent with
those reported for several other well-characterized
monooxo complexes of rhenium [25–28]. The electronic
absorption spectra of the compounds were determined
during HPLC analysis by using the photodiode array
detector.
were 0.815 and −1.578 e A−3. The largest shift/e.s.d.
,
in the final cycle was 0.211. Refinement details for
complex 4: 9363 reflections were used to refine 482
parameters. All non-hydrogen atoms were refined
anisotropically. One of the phenyl rings of the cation
phosphine was found slightly disordered and refined to
a regular hexagon. These atoms and the methyl group
of the cation were refined anisotropically, but restrained
so that their Uij components approximate isotropic
behavior. As a consequence, no hydrogen atoms for
these carbons were included in the refinement. All the
rest of the hydrogen atoms were located by difference
maps and refined isotropically. The final values for R1,
wR2 and GOF for all data are 0.0884, 0.1191, and
1.061, respectively. The maximum and minimum
residual peaks in the final difference map were 0.968
and −0.577 e A−3. The largest shift/e.s.d. in the final
cycle was 0.004.
,
3. Results and discussion
3.1. Chemistry
It is known that the combination of a dianionic
tridentate SNS, SOS or SSS ligand with a monodentate
thiolate produces a binary ligand system ‘3+1’ that
can bind to the MO3+ (M=Tc or Re) core and form
neutral, lipophilic, small-sized complexes which adopt
either a trigonal bipyramidal or a square pyramidal
geometry. However, during complexation the formation
of other complexes is also possible.
3.2. Description of the structures
An ORTEP diagram of complex 1 is shown in Fig. 2.
Thus, when a mixture of the tridentate aminedithiol
ligand, EtN(CH2CH2SH)2, L1H2, and the monodentate
As has already been mentioned, the formation of two
thiol,
p-ClC6H4SH,
L2H,
is
reacted
with
ReVOCl3(PPh3)2 in different L1H2/L2H/ReV molar ra-
tios the following complexes can be formed (Fig. 1).
1. L1H2/L2H/ReV, 1/1/1: neutral mixed ligand com-
plexes MOL1L2 (syn, complex 1 and anti, complex
2). Formation of two isomers, syn and anti, during
coordination of L1H2 and a monodentate thiol
L2H, is expected as a result of the different possible
orientations of N-ethyl substituent of the tridentate
ligand with respect to the ReO3+ core. However,
the anti isomer is not always formed.
2. L1H2/L2H/ReV, 3/0/2: binuclear complex of the tri-
dentate ligand, (MO)2(L1)3, complex 3.
3. L1H2/L2H/ReV, 0/1/4: anionic complex of the
monothiol [MO(L2)4]−, complex 4.
All of the above complexes have been synthesized by
exchange reaction using ReOCl3(PPh3)2 as precursor
and selectively monitoring reaction stoichiometry. The
complexes were extracted in dichloromethane and iso-
lated by recrystallization from CH2Cl2/MeOH. They
Fig. 2. ORTEP diagram of ReO[CH3CH2N(CH2CH2S)2][p-SC6H4Cl]
(1).

6
M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
instead of a monothiol. The calculated trigonality index
~ is 0.64 and 0.63 for Re(1) and Re(2), respectively.
,
Each rhenium atom lies 0.10 A out of the basal plane
towards the sulfur atom of the bridging bidentate lig-
and. The ethyl substituent on the nitrogen atom of the
tridentate ligand is in cis position with respect to the
oxo group resulting in syn configuration around each
rhenium but the ReꢀO groups are trans to each other.
The molecular structure of the anionic complex 4 is
given in Fig. 4. The coordination of rhenium is dis-
torted square pyramidal with four sulfur atoms in the
basal plane and the oxo group at the apex. Rhenium
,
lies 0.74 A out of the mean plane of the sulfur atoms
towards the apical oxygen. The angle between the
S1S2S3 and S2S3S4 planes is 10.6° and its value was
used previously as a measure of the distortion of the
square pyramid. Blower et al. [30] reported that in
complex [ReO(SPh)4]− this angle takes the value of 3.8°
and in complexes [ReO(TMT)4]− and [ReO(DIPT)4]−
with more substituted thiophenols as ligands, the calcu-
lated values are 13.6 and 5.4°, respectively. They also
concluded that the distortion of the square pyramid
may be due to intermolecular and crystal packing ef-
fects. McDonell et al. [31] reported that the anion
[ReO(SPh)4]− is distorted significantly from C4 symme-
try (‘turbine’ conformation) by measuring the dihedral
angles OꢁReꢁSꢁC (67–108°) and the angles between the
plane of the four sulfur atoms of the square pyramid
and those of the phenyl rings of the thiophenol ligands
(82–114°). In our case, the variation in the OꢁReꢁSꢁC
dihedral angles is small (71.3–79.5°), but the range in
the angles of the S1S2S3S4 mean plane with the mean
planes of the phenyls is large (53.8–87.7°) and this
leads to significant distortion from C4 symmetry. Fi-
Fig. 3. ORTEP diagram of (ReO)2[CH3CH2N(CH2CH2S)2]3 (3).
isomers, syn and anti, is possible. Complex 1 is the syn
isomer with the N-ethyl substituent and the oxo group
pointing in the same direction. The coordination geo-
metry around rhenium(V) is distorted trigonal bipyra-
midal, as has been observed previously for a series of
oxotechnetium and oxorhenium complexes. The basal
plane of the trigonal bipyramid is formed by the atoms
S(1) and S(2) of the tridentate ligand and the oxo group
while the apical positions are occupied by the nitrogen
atom of the ligand (N(1)) and the sulfur atom of the
monodentate thiol (S(3)). The angles between the atoms
of the basal plane range from 116.9(2) to 121.5(1)°,
values close to the ideal 120°, but the distortion of the
trigonal bipyramid comes from the NꢁReꢁS(3) angle of
160.3(1)o. The calculated trigonality index ~ (~=(€1–
€2)/2, €1, € the largest angles in the coordination
2
sphere, ~=0 for perfect s.p., ~=1 for perfect t.bp.) is
0.65 showing a degree of distortion [29]. Rhenium lies
,
0.10 A out of the basal plane of the trigonal bipyramid
towards the monodentate thiol. These features have
been also observed in analogous oxorhenium complexes
with syn configuration.
The crystal structure of the binuclear complex 3 is
given in Fig. 3. The tridentate ligand is coordinated to
the metal through two different modes: as the usual
chelating tridentate agent through the SNS donor set
and as a bridging bidentate one through the sulfur
atoms. Although we have widely used this type of
tridentate ligands, it is the first time that this bridging
bidentate mode is observed. The coordination geometry
around each rhenium atom is distorted trigonal bipyra-
midal. As in the case of the monomer complex 1, the
basal plane is defined by the sulfur atoms of the triden-
tate chelating ligand and the oxo group while the apical
positions are occupied by the nitrogen of the chelating
ligand and the sulfur atom of the bridging ligand,
Fig. 4. ORTEP diagram of ReO(SC6H4Cl)4][PH(C6H5)3] (4).

M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
7
Table 2
Selected bond distances (A) and angles (°) for complexes 1 and 4
,
1
4
ReꢁO
ReꢁN
ReꢁS(1)
ReꢁS(2)
ReꢁS(3)
ReꢁS(4)
1.692(4)
2.199(4)
2.266(2)
2.281(2)
2.314(2)
1.678(4)
2.358(2)
2.363(2)
2.319(2)
2.324(2)
OꢁReꢁN
95.0(2)
116.9(2)
83.7(1)
120.8(2)
82.9(1)
121.5(1)
104.7(1)
160.3(1)
85.8(1)
OꢁReꢁS(1)
NꢁReꢁS(1)
OꢁReꢁS(2)
NꢁReꢁS(2)
S(1)ꢁReꢁS(2)
OꢁReꢁS(3)
NꢁReꢁS(3)
S(1)ꢁReꢁS(3)
S(2)ꢁReꢁS(3)
OꢁReꢁS(4)
S(3)ꢁReꢁS(4)
S(1)ꢁReꢁS(4)
S(2)ꢁReꢁS(4)
104.6(2)
104.6(2)
150.7(1)
112.0(2)
84.7(1)
85.3(1)
113.1(2)
134.9(1)
82.9(1)
85.0(1)
88.4(1)
nally, the trigonality index ~ is 0.26. The bond distances
ReꢀO and ReꢁS (Table 2) are consistent with those
found in analogous thiophenolato oxorhenium
complexes.
3.3. Comparison by HPLC of analogous 99mTc and rhe-
nium complexes
In order to establish the structure of the 99mTc com-
plexes prepared at tracer level with the respective rhe-
nium complexes prepared in macroscopic amounts,
comparison by HPLC applying parallel radiometric
and photometric detection was pursued.
Thus, by co-injection of complexes 1 and 1%, identical
retention times (tR: 18.6 min) were exhibited, while the
recovery through the column was quantitative (Fig. 5).
Similarly, co-injection of compounds 4 and 4% lead to
identical tR for both complexes (tR: 23 min), revealing
their structural analogy. However, aliquots of the label-
ing reaction mixture of 4% led to poor column recoveries
and a high radioactivity background, an indication of
complex 4% instability and decomposition to hydrolyzed
technetium species. Eventually, the labeling reaction
mixture containing the tridentate ligand alone (complex
3%), when co-injected with complex 3 revealed a 2 min
difference in their respective tR (tR for 3: 13.5 min and
for 3%: 15.6 min) under the applied conditions. More-
over, poor column recoveries indicated the formation of
unidentified technetium species retained by the column.
In fact, 2 h after labeling none of the complexes 3% and
4% survived in their respective labeling reaction mix-
tures. Therefore, it can be concluded, that the 99mTc
binuclear complex analogous to 3 is not formed at
Fig. 5. HPLC profiles. A: g-trace of the reaction mixture of the 99mTc
preparation of complex 1%. B, C, D, E: UV–Vis trace at 254 nm of
complexes 1, 2, 3, and 4, respectively.

8
M. Papadopoulos et al. / Inorganica Chimica Acta 295 (1999) 1–8
Table 3
[5] B.L. Holman, R.S. Hellman, S.J. Goldsmith, I.G. Mena,
J. Leveille, P.G. Gherardi, J.-L. Moretti, A. Bischof-Delaloye,
T.C. Hill, P.M. Rigo, R.L. Van Heertum, P.J. Ell, U. Buell,
M.C. De Roo, R.A. Morgan, J. Nucl. Med. 30 (1989) 1018.
[6] R.C. Walovitch, T.C. Hill, S.T. Garrity, E.H. Cheesman, B.A.
Burgess, D.H O’Leary, A.D. Watson, M.V. Ganey, R.A. Mor-
gan, S.J. Wiliams, J. Nucl. Med. 30 (1989) 1892.
[7] J. Leveille, G. Demonceau, M. De Roo, P. Rigo, R. Taillefer,
R.A. Morgan, D. Kupranick, R.C. Walovitch, J. Nucl. Med. 30
(1989) 1902.
[8] H.-J. Pietzsch, H. Spies, S. Hoffmann, J. Stach, Inorg. Chem.
Acta 161 (1989) 15.
[9] H. Spies, H.-J. Pietzch, R. Syhre, S. Hoffmann, Isotopenpraxis
26 (1990) 159.
[10] H.-J. Pietzch, H. Spies, S. Hoffmann, D. Scheller, Appl. Radiat.
Isot. 41 (1990) 185.
[11] H. Spies, Th. Fietz, M. Glaser, H.J. Pietzsch, B. Johannsen, in:
M. Bandoli, G. Mazzi, U. Nicolini (Eds.), Technetium and
Rhenium in Chemistry and Nuclear Medicine 4, SGE, Padua,
1995, p. 243.
,
Selected bond distances (A) and angles (°) for complex 3
Re(1)ꢁO(1)
Re(1)ꢁN(1)
Re(1)ꢁS(1)
Re(1)ꢁS(2)
Re(1)ꢁS(3)
1.694(5)
2.231(7)
2.281(2)
2.278(2)
2.305(2)
Re(2)ꢁO(2)
Re(2)ꢁN(3)
Re(2)ꢁS(4)
Re(2)ꢁS(5)
Re(2)ꢁS(6)
1.684(5)
2.216(7)
2.312(2)
2.277(2)
2.277(2)
O(1)Re(1)ꢁN(1)
O(1)ꢁRe(1)ꢁS(2)
N(1)ꢁRe(1)ꢁS(2)
O(1)ꢁRe(1)ꢁS(1)
N(1)ꢁRe(1)ꢁS(1)
S(1)ꢁRe(1)ꢁS(2)
O(1)ꢁRe(1)ꢁS(3)
N(1)ꢁRe(1)ꢁS(3)
S(3)ꢁRe(1)ꢁS(2)
S(1)ꢁRe(1)ꢁS(3)
96.1(3)
121.4(2)
82.5(2)
116.7(2)
83.3(2)
121.2(1)
104.0(2)
159.8(2)
88.5(1)
O(2)Re(2)ꢁN(3)
O(2)ꢁRe(2)ꢁS(5)
N(3)ꢁRe(2)ꢁS(5)
O(2)ꢁRe(2)ꢁS(6)
N(3)ꢁRe(2)ꢁS(6)
S(5)ꢁRe(2)ꢁS(6)
O(2)ꢁRe(2)ꢁS(4)
N(3)ꢁRe(2)ꢁS(4)
S(5)ꢁRe(2)ꢁS(4)
S(6)ꢁRe(2)ꢁS(4)
96.0(3)
117.8(2)
83.7(2)
120.2(2)
83.0(2)
121.4(1)
104.5(2)
159.4(2)
84.3(1)
86.0(1)
89.0(1)
[12] S.G. Mastrostamatis, M.S. Papadopoulos, I.C. Pirmettis,
E. Paschali, A.D. Varvarigou, C.I. Stassinopoulou, C.P. Rapto-
poulou, A. Terzis, E. Chiotellis, J. Med. Chem. 37 (1994) 3212.
[13] C.I. Stassinopoulou, M. Pelecanou, S. Mastrostamatis, E.
Chiotellis, Magn. Reson. Chem. 32 (1994) 532.
[14] D. Spyriounis, M. Pelecanou, C.I. Stassinopoulou, C.P. Rapto-
poulou, A. Terzis, E. Chiotellis, Inorg. Chem. 34 (1995) 1077.
[15] I.C. Pirmettis, M.S. Papadopoulos, S.G. Mastrostamatis, C.P.
Raptopoulou, A. Terzis, E. Chiotellis, Inorg. Chem. 35 (1996)
1685.
tracer level, as was expected anyway from statistical
considerations [32]. Under these conditions, it is difficult
to unequivocally assign a structure to complex 3% (Table
3).
This study has demonstrated that, by simultaneous
action of a tridentate aminedithiolate (L1H2) and a
monothiolate (L2H) ligand on a suitable rhenium or
99mTc precursor the major reaction product is the syn
MO(L1L2) isomer which is important for radiopharma-
ceutical applications.
[16] M.S. Papadopoulos, M. Pelecanou, I.C. Pirmettis, D.M. Spyri-
ounis, C.P. Raptopoulou, A. Terzis, C.I. Stassinopoulou, E.
Chiotellis, Inorg. Chem. 35 (1996) 4478.
[17] M.S. Papadopoulos, I.C. Pirmettis, M. Pelecanou, C.P. Rapto-
poulou, A. Terzis, C.I. Stassinopoulou, E. Chiotellis, Inorg.
Chem. 35 (1996) 7377.
[18] I.C. Pirmettis, M.S. Papadopoulos, E. Chiotellis, J. Med. Chem.
40 (1997) 2539.
[19] B. Johannsen, M. Scheunemann, H. Spies, P. Brust, J. Wober,
B. Syhre, J.H. Pietzsch, Nucl. Med. Biol. 23 (1996) 429.
[20] F. Mann, J. Chem. Soc. (1934) 461.
[21] J. Harley-Mason, J. Chem. Soc. (1947) 320.
[22] J. Chatt, G.A. Rowe, J. Chem. Soc. (1962) 4019.
[23] G.M. Sheldrick, SHELXS-86, Structure Solving Program, Univer-
sity of Go¨ttingen, Germany, 1986.
4. Supplementary material
Tables of crystallographic data, fractional atomic
coordinates and anisotropic thermal parameters and a
full listing of bond distances and angles are available
upon request. A CIF in ASCII format is also available.
Acknowledgements
[24] G.M. Sheldrick, SHELXL-93, Crystal Structure Refinement, Uni-
versity of Go¨ttingen, Germany, 1993.
[25] T.N. Rao, D. Adhikesavalu, A. Camerman, A.R. Fritzberg, J.
Am. Chem. Soc. 112 (1990) 5798.
[26] L.C. Francesconi, G. Graczyk, S. Wehrli, N. Shaikh, D. Mc-
Clinton, S. Liu, J. Zubieta, H.F. Kung, Inorg. Chem. 32 (1993)
3114.
We are grateful to John Boutaris and the Agricultural
Bank of Greece (ATE) for financial support to C.P.R.
References
[27] J. O’Neil, S. Wilson, J. Katzenellenbogen, Inorg. Chem. 33
(1994) 319.
[28] K.S. Meegalla, K. Plossl, M.-P. Kung, A. Stevenson, L. Liable-
Sands, A. Rheingold, H.F. Kung, J. Am. Chem. Soc. 117 (1995)
11037.
[29] A.W. Addison, T.N. Rao, J. Reedijk, J. van Rijh, C.G. Ver-
schoor, J. Chem. Soc., Dalton Trans. (1984) 1349.
[30] P.J. Blower, J.R. Dilworth, J. Hutchinson, T. Nicholson, J.
Zubieta, Inorg. Chim. Acta 90 (1984) L27.
[1] R.D. Neirinckx, L.R. Canning, I.M. Piper, D.P. Nowotnik, R.D.
Pickett, R.A. Holmes, W.A. Volkert, A.M. Forster, P.S. Weisner,
J.A. Marriot, S.B. Chaplin, J. Nucl. Med. 28 (1987) 191.
[2] I. Podreka, E. Suess, G. Goldenberg, M. Steiner, T. Brucke, Ch.
Muller, W. Lang, R.D. Neirinckx, L. Deecke, J. Nucl. Med. 28
(1987) 1657.
[3] P.F. Sharp, F.W. Smith, H.G. Gemmell, D. Lyall, N.T.S. Evans,
D. Gvozdanovic, J. Davidson, D.A. Tyrrell, R.D. Pickett, R.D.
Neirinckx, J. Nucl. Med. 27 (1986) 171.
[31] A.C. McDonell, T.W. Hambley, M.R. Snow, A.G. Wedd, Aust.
J. Chem. 36 (1983) 253.
[4] J.P. Leonard, D.P. Nowotnik, R.D. Neirinckx, J. Nucl. Med. 27
(1986) 1819.
[32] J. Steigman, W.C. Eckelman, The Chemistry of Technetium in
Medicine, National Academy Press, Washington, DC, 1992.
.