Histidine derivatives as tridentate chelators for the fac-[M I(CO)3] (Re, 99mTc, 188Re) core: Synthesis, structural characterization, radiochemistry and stability

Article abstract of DOI:10.1016/j.ica.2011.08.062

The development of new rhenium(I)- and technetium(I)-tricarbonyl complexes can lead to potentially useful radiopharmaceuticals. In this work, the synthesis of the neutral rhenium complex fac-[Re(NSO)(CO)₃], Re-1, where NSO is the tridentate che

Full text of DOI:10.1016/j.ica.2011.08.062

Inorganica Chimica Acta 378 (2011) 333–337
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Note
Histidine derivatives as tridentate chelators for the fac-[MI(CO)3] (Re, 99mTc, 188Re)
core: Synthesis, structural characterization, radiochemistry and stability
Dionysia Papagiannopoulou a, , Charalambos Tsoukalas b, George Makris a,b, Catherine P. Raptopoulou c,
⇑
c
b
d
d
d
´
´
Vassilis Psycharis , Leondios Leondiadis , Ewa Gniazdowska , Przemyslaw Kozminski , Leon Fuks ,
Maria Pelecanou e, Ioannis Pirmettis b, Minas S. Papadopoulos b
a Department of Medicinal Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
b Institute of Radioisotopes-Radiodiagnostic Products, National Centre for Scientific Research ‘‘Demokritos’’, 15310 Ag. Paraskevi Athens, Greece
c Institute of Materials Science, National Centre for Scientific Research ‘‘Demokritos’’, 15310 Ag. Paraskevi Athens, Greece
d Radiochemistry Department, Institute of Nuclear Chemistry and Technology, Warsaw, Poland
e Institute of Biology, National Centre for Scientific Research ‘‘Demokritos’’, 15310 Ag. Paraskevi Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 April 2011
Received in revised form 28 July 2011
Accepted 31 August 2011
Available online 9 September 2011
The development of new rhenium(I)- and technetium(I)–tricarbonyl complexes can lead to potentially
useful radiopharmaceuticals. In this work, the synthesis of the neutral rhenium complex fac-
[Re(NSO)(CO)3], Re-1, where NSO is the tridentate chelating agent 3-(1H-imidazol-4-yl)-2-(p-methoxy-
benzylthio)propionic acid 1 was effected via reaction with (NEt4)2[ReBr3(CO)3] in the presence of
NaHCO3. Complex Re-1 crystallized from methanol/water and its structure was established by IR, 1H
and 13C NMR spectroscopies, ESI-MS analysis and X-ray crystallography. When the reaction took place
in the absence of base, HPLC analysis revealed the presence of a second product (yield 7%) that was
assigned by NMR and ESI analysis to be complex fac-[Re(NS)(CO)3Br] Re-2. At the tracer level, the anal-
ogous complexes fac-[99mTc(NSO)(CO)3], 99mTc-1 and fac-[188Re(NSO)(CO)3], 188Re-1, were synthesized
and their radiochemical stability in physiological conditions was determined. Both tracer complexes
99mTc-1 and 188Re-1 are stable in solution as well as in the presence of strongly coordinating agents like
histidine or cysteine.
Keywords:
Rhenium
Technetium
Tricarbonyl complexes
Histidine derivatives
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
with the fac-[99mTc(CO)3]+ core [6–8]. These agents may combine
an amine or an aromatic nitrogen N, an S thioether group and a car-
The chemistry of technetium and rhenium has been studied
extensively as a result of the significance of these radiometals in
the development of radiopharmaceuticals for imaging (99mTc)
and/or radiotherapy (188Re) in Nuclear Medicine. The design of tar-
geted radiopharmaceuticals by the conjugation of bioactive mole-
cules to technetium and rhenium, is currently a challenging field
of radiopharmaceutical research [1–4].
boxylate group O for charge-neutralizing purposes. In parallel,
therapeutic radiopharmaceuticals of 188Re can be developed by
using the same ligands designed for the fac-[99mTcL(CO)3]+ com-
plexes because of the similar chemical properties of technetium
and rhenium. The currently applied efficient method for the prep-
aration of the corresponding fac-[188Re(H2O)3(CO)3]+ precursor, in-
volves the use of BH3.NH3 as reducing agent and boranocarbonate
as a solid CO source [9].
The radiopharmaceutical chemistry of 99mTc(I)–tricarbonyl
complexes primarily involves the substitution of the labile water
molecules of the fac-[99mTc(H2O)3(CO)3]+ precursor [5] with suit-
able bidentate or tridentate ligands in aqueous solution. Both
bidentate and tridentate ligands give complexes of high kinetic
and thermodynamic stability, with tridentate ligands exhibiting
faster reaction rates and better stabilizing the complex against
trans-chelation reactions. A series of suitable tridentate chelating
agents, including histidine, has been applied to produce complexes
In this work our interest focuses on the fac-[99mTc(NSO)(CO)3]
complexes where NSO is a suitable tridentate chelating agent,
combining a S thioether group, an aromatic N and a carboxylate
O [10–15]. These agents can be either linear [12] or tripodal like
methionine or S-substituted cysteine [10,14]. Within this frame-
work, a new neutral fac-[Re(NSO)(CO)3] complex (Re-1) with the
tripodal histidine derivative 3-(1H-imidazol-4-yl)-2-(p-methoxy-
benzylthio)propionic acid (1) was synthesized and fully charac-
terized by X-ray crystallography and other spectroscopic methods
(Fig. 1). Chemistry was successfully transferred to the 99mTc and
188Re tracer level to obtain the analogous to Re-1 radioactive
complexes 99mTc-1 and 188Re-1.
⇑
Corresponding author.
E-mail address: papagd@pharm.auth.gr (D. Papagiannopoulou).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.08.062

334
D. Papagiannopoulou et al. / Inorganica Chimica Acta 378 (2011) 333–337
COOH
HN
N
S
COOH
COOH
NH2
NaNO2/H2SO4
HCl
p-MeOBzSH
NaOH
HN
HN
N
N
Cl
1
O
[NEt4]2[ReBr3(CO)3]
[
99mTc(H2O)3(CO)3]+
188Re(H2O)3(CO)3]+
O
[
[NEt4]2[ReBr3(CO)3]
in the absence of NaHCO3
6
2
O
3
H
5
4
HN
N
9
10
12
S
14
1
OH
H
M
8
11
O
OC
O
7
CO
OC
13
Re-1
+
HN
OC
N
S
Re-1 M = Re
Re
O
99mTc-1 M = 99mTc
188Re-1 M = 188Re
Br
OC
CO
Re-2
Fig. 1. Synthesis of ligand 1 and of the Re-1, 99mTc-1, 188Re-1 complexes.
1:1 and 7 mL NaOH 2 M were added dropwise under N2. The mixture
was stirred for 18 h. Then the solvents were evaporated, the residue
was re-dissolved in 5 mL water and the pH was adjusted to ꢀ7 by
addition of HCl 5 M. The white solid formed was isolated and
washed with water. Yield: 754 mg, 45%.
2. Experimental
2.1. Materials
All chemicals were reagent grade and were used as such unless
otherwise noted. Rhenium was purchased from Aldrich as
Re2(CO)10 and was converted to (NEt4)2[ReBr3(CO)3] as reported
previously [16]. L-3-(1H-imidazol-4-yl)-2-chloropropionic acid
was synthesized according to a literature method [17].
1H and 13C NMR data are given in Table 1.
2.3. Synthesis of Re-1
For labeling with 99mTc a kit containing 5.5 mg NaBH4, 4 mg
Na2CO3 and 10 mg Na-K tartrate was purged with CO gas prior to
addition of Na99mTcO4, as described elsewhere [5]. For 188Re label-
ing, the Isolink™ kit in combination with a pre-reduction kit
(BH3ÁNH3 reagent) was used [9].
0.1 mmol (77 mg) of [NEt4]2[ReBr3(CO)3] reacted with 0.1 mmol
(29 mg) of 1 and 0.1 mmol NaHCO3 in refluxing methanol for 3 h
to generate one product as shown by HPLC. The solvent was evapo-
rated to dryness and the residue was crystallized by slow evapora-
tion from methanol–water. Yield: 35 mg (62%), tR: 19.9 min, IR
, KBr): 2029, 1907, 1875(sh), 1623. Anal. Calc. for
C17H15N2O6ReS: C, 36.36; H, 2.69; N, 4.99. Found: C, 36.06; H, 3.01;
N, 4.89%.
When reaction took place in the absence of NaHCO3 HPLC anal-
ysis of the reaction mixture showed the presence (7%) of a second
product peak with a retention time of 19.4 min. Attempts to isolate
the second product did not succeed in generating a pure sample;
ESI and NMR data of the mixture – enriched in the second product
by successive recrystallizations – were in agreement with the
structure Re(NS)Br(CO)3, Re-2 (Fig. 1).
(cmÀ1
Elemental analyses were performed on a Perkin-Elmer 2400
automated analyzer. IR spectra were recorded as KBr pellets on a
Perkin-Elmer 1600 FT-IR spectrophotometer in the region 500–
4000 cmÀ1. 1H NMR spectra were recorded in DMSO-d6 on a Bruker
Avance 500 MHz spectrometer. HPLC analysis was performed on
an Agilent HP 1100 series pump, connected both to a Gabi gamma
detector from Raytest and an HP 1100 multiple wavelength detec-
tor. Separations were achieved on an Agilent Eclipse XDB-C18 col-
umn (25 cm  4.6 mm, 5
lm) eluted with a binary gradient system
at 1 mL/min flow rate and composition 100% solvent A: 0.1% TFA in
water at 0 min, linearly converting to 75% solvent B: methanol over
15 min. ESI mass spectral analysis was performed on an AQA Nav-
igator, Finnigan mass spectrometer. Test solution in 50% aqueous
methanol was infused into an electrospray interface at a flow rate
of 0.1 mL/min, using a Harvant Syringe pump. Positive or negative
ion ESI spectra were acquired by adjusting the needle and cone
voltages accordingly. Hot nitrogen gas (Dominic-Hunter
UHPLCMS-10) was used for desolvation at 170 °C. Isotopic pattern
calculations were performed by List v.1.3.2. (Thermo Finnigan)
software.
2.4. Synthesis of 99mTc-1
About 1 mL of an aqueous mixture of [99mTc(OH2)3(CO)3]+
(ꢀ0.5 GBq/ml) and ligand 1 (10 nmoL, 10À5 M) at pH 7, reacted at
85 °C for 30 min. The reaction mixture was analyzed by RP HPLC
revealing the formation of only one product as in the case of Re-
1 tR: 20.1 min.
2.5. Synthesis of 188Re-1
2.2. Synthesis of 3-(1H-imidazol-4-yl)-2-(p-methoxybenzylthio)
propionic acid, 1
About 1 mL of an aqueous mixture of [188Re(OH2)3(CO)3]+
(ꢀ20 MBq) and ligand 1 (1.3 Â 10À3 M) at pH 6.5 reacted at 65 °C
for 30 min. The reaction mixture was analyzed by RP HPLC reveal-
ing the formation of only one product as in the case of Re-1 tR:
19.9 min.
In a modified method [18], L-3-(1H-imidazol-4-yl)-2-chloro-
propionic acid (5.75 mmol, 1 g) and p-methoxybenzylmercaptan
(6.89 mmol, 1.06 g) were mixed together in 30 mL of water:ethanol

D. Papagiannopoulou et al. / Inorganica Chimica Acta 378 (2011) 333–337
335
Table 1
1H and 13C chemical shifts (ppm) for ligand 1 and the complexes Re-1 and Re-2 in DMSO-d6 at 25 °C. The numbering of the atoms is shown in Fig. 1.
Ligand 1
7.52
6.74
Complex Re-1
8.34
7.15
Complex Re-2
8.63
Ligand 1
134.56
116.70
134.56
29.41
46.12
173.05
34.26
Complex Re-1
141.28
116.12
133.74
26.97
44.54
177.37
44.54
126.23
130.81
114.24
193.20
195.67
196.89
Complex Re-2
H-1
H-2
H-4
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
140.66
114.79
133.78
28.03
42.88
171.13
43.15
126.09
131.25
114.29
192.48
195.51
196.02
7.35
2.79
3.00
3.44
2J = 14.5 Hz
3J = 9.3 Hz
2.74
2J = 17.8 Hz
3J = 4.8 Hz
3.02
2J = 14.7 Hz
3J = not measurable
2.40
2J = 14.5 Hz
3J = 5.2 Hz
3.43
2J = 17.8 Hz
3J = 3.1 Hz
3.70
2J = 14.7 Hz
3J = 3.5 Hz
3.99
129.60
130.06
113.80
H-5
H-7
H-9,13
H-10,12
C-9,13
C-10,12
C„O
3.76
7.21
6.86
4.61, 3.92 2J = 13.0 Hz
7.33
3.97, 3.72 2J = 13.3 Hz
7.16
6.98
6.92
H-14
NH
3.73
13.02
3.77
13.12
3.74
13.25
L
-cysteine. The mixtures were incubated at 37 °C and were ana-
2.6. X-ray crystal structure determination of complex Re-1
lyzed by HPLC or TLC after 4 h and 24 h.
A crystal with approximate dimensions 0.18 Â 0.20 Â 0.22 mm
was mounted in air and covered with epoxy glue. Diffraction mea-
surements were made on a P21 Nicolet diffractometer upgraded by
Crystal Logic using graphite monochromated Cu radiation. Unit cell
dimensions were determined and refined by using the angular set-
tings of 25 automatically centered reflections in the range
22 < 2h < 54° and they appear in Table 2. Intensity data were re-
corded using a h À 2h scan. Three standard reflections monitored
every 97 reflections showed less than 3% variation and no decay.
Lorentz, polarization corrections were applied using Crystal Logic
software. The structure was solved by direct methods using SHEL-
XS-97 [19] and refined by full-matrix least-squares techniques on
F2 with SHELXL-97 [20]. Further experimental crystallographic de-
tails for Re-1: 2hmax = 118°; reflections collected/unique/used,
2.8. Lipophilicity studies
About 50 l
L of purified 99mTc-1 complex were mixed with
1.95 mL PBS pH 7.4 and 2.0 mL of octanol-1 in triplicates. The mix-
tures were shaken for 3 min and centrifuged for 5 min and then
50 lL aliquots of each phase were withdrawn and measured in a
NaI scintillation counter. The remaining organic phase was re-
extracted with equal volume of aqueous phase and the procedure
was repeated until the counts measured in both phases reached
a stable value. The ratios of the extractions were averaged as D7.4
values.
3. Results and discussion
3270/2706 [Rint = 0.0380]/2706; parameters refined;
(D/
r)
max = 0.001; (
D
q)max/(D
q)
min = 0.815/À1.308 e/Å3; R1/wR2 (for
3.1. Synthesis
all data), 0.0335/0.0892. Hydrogen atoms were either located by
difference maps and were refined isotropically or were introduced
at calculated positions as riding on bonded atoms. All non-hydro-
gen atoms were refined anisotropically.
Complex Re-1 was synthesized in refluxing methanol by react-
ing the (NEt4)2[ReBr3(CO)3] precursor with ligand 1 in the presence
of 1 equiv. of NaHCO3. HPLC analysis of the reaction mixture
showed one product peak in the chromatogram with 19.9 min elu-
tion time. Even though two diastereomers are expected due to the
fact that the coordinating S-atom is a prochiral center, only one
species was observed in HPLC and NMR analysis. The complex
was collected as crystals suitable for X-ray crystallography by slow
crystallization from methanol–water. When the reaction took
place in the absence of the NaHCO3 two peaks appeared in the
HPLC chromatogram a major one (>90%) at tR = 19.9 min and a
minor one (ꢀ7%) at 19.4 min. The identity of the minor product
was assigned as being Re(NS)Br(CO)3, Re-2 by NMR and ESI-MS
analysis of an enriched in the minor product sample, obtained
through multiple crystallizations. It should be noted that when
NaHCO3 was added in the mixture of Re-1 and Re-2 complete con-
version of Re-2 to Re-1 was effected as witnessed by HPLC
analysis.
The chemical shifts for the complexes Re-1 and Re-2 as well as
the ligand 1 are presented in Table 1. In both complexes upon coor-
dination downfield shifts are noted for the protons on C-1, C-5 and
C-7 directly attached to the donor N and S atoms. The effect of
coordination is especially dramatic for the benzyl group; e.g. in
complex Re-1 the previously equivalent benzyl H-7 protons appear
as two well separated doublets shifted downfield by ꢀ0.5 ppm on
average, while the benzyl carbon C-7 is downfield shifted by
ꢀ10 ppm compared to its position in ligand 1. In complex Re-2,
the chemical shift of the carbonyl carbon C-6 at 171.13 ppm
2.7. Stability studies of 99mTc-1 and 188Re-1
About 0.1 mL of the isolated by HPLC pure 99mTc-1 or 188Re-1
complex was mixed with 0.9 mL of saline or 1 mM L-histidine or
Table 2
Crystallographic data for complex Re-1.
Formula
Formula weight
Space group
a (Å)
b (Å)
c (Å)
C17H15N2O6ReS
561.57
P212121
15.272(9)
10.632(5)
11.556(6)
90
a
(°)
b (°)
90
c
(°)
90
V (Å3)
1876.4(17)
4
Z
T (°C)
25
Radiation
CuKa
1.988
14.044
2604
0.0324
0.0881
qcalc (g cmÀ3
)
l
(mmÀ1
)
Reflections with I > 2
r(I)
a
R1
a
wR2
a
w = 1/[
r
2(Fo2) + (
a
P)2 + bP] and P = [max (Fo2,0) + 2Fc2]/3, R1
=
R
(|Fo| À |Fc|)/
2
R
(|Fo|) and wR2 = {
R
[w(Fo À Fc2)2]/
R .
[w(Fo2)2]}1/2

336
D. Papagiannopoulou et al. / Inorganica Chimica Acta 378 (2011) 333–337
Table 3
(6.2 ppm upfield compared to Re-1) as well as the presence of a hy-
droxyl peak at 13.0 ppm in spectra obtained in CDCl3 is suggestive
of the presence of an uncoordinated carboxyl group. In this case,
the presence of a bromine in the coordination sphere of Re-2 is ex-
pected, a hypothesis that was confirmed with ESI-MS analysis.
ESI analysis of the mixture in the positive mode generated
(M+H)+ charged states at m/z 563.3, in perfect agreement to the
molecular mass calculated for Re-1 (C17H15N2O6ReS, M = 562) on
the basis of the complex primary structure. In the ESI negative
mass spectrum of the mixture, the major ion observed was again
the (MÀH)À charged state at m/z 561.3. In addition, a second minor
ion was also observed at m/z 641.3, in agreement to the structure
Re-2 (C17H16BrN2O6ReS, M = 642) confirmed by isotopic pattern
calculation by the List software.
Selected bond distances (Å) and angles (°) for Re-1.
Distances
Re(1)–C(23)
Re(1)–C(21)
Re(1)–C(22)
1.866(10)
1.896(9)
1.910(10)
Re(1)–O(1)
Re(1)–N(1)
Re(1)–S(1)
2.132(5)
2.186(7)
2.473(2)
Angles
C(23)–Re(1)–C(22)
C(23)–Re(1)–C(21)
C(22)–Re(1)–C(21)
C(23)–Re(1)–O(1)
C(22)–Re(1)–O(1)
C(21)–Re(1)–O(1)
C(23)–Re(1)–N(1)
C(22)–Re(1)–N(1)
90.9(4)
86.3(4)
88.2(4)
175.9(3)
92.3(3)
96.3(3)
95.5(3)
173.4(3)
C(21)–Re(1)–N(1)
O(1)–Re(1)–N(1)
C(23)–Re(1)–S(1)
C(22)–Re(1)–S(1)
C(21)–Re(1)–S(1)
O(1)–Re(1)–S(1)
N(1)–Re(1)–S(1)
93.7(3)
81.2(2)
97.8(3)
94.2(3)
175.2(3)
79.5(1)
83.5(2)
Infrared spectroscopy of complex Re-1 reveals the characteris-
tic stretching bands of facially coordinated CO with
m
(CO) at
2029, 1907 and 1875(sh) cmÀ1
. Furthermore, the band at
2.13 respectively, fall well in the ranges observed in analogous
complexes [10–15]. The bond angles around rhenium are also con-
sistent with those of analogous complexes found in the literature
[10–15].
1623 cmÀ1 indicates the complexation of the carboxylate group
of the ligand. The complex is soluble in CH2Cl2, CHCl3 and metha-
nol and insoluble in ether, hexane and water. It is stable in solution
for a period of months as shown by HPLC and NMR.
3.3. Radiochemistry
3.2. Description of crystallographic structure
Complex 99mTc-1 was synthesized by reaction of fac-
[
99mTc(H2O)3(CO)3]+ precursor with ligand 1 after heating at
Compound Re-1 crystallizes in the orthorhombic space group
with one crystallographically independent molecule in the asym-
metric unit. The molecular structure of Re-1 is given in Fig. 2 and
selected bond distances and angles are listed in Table 3. The coor-
dination geometry about rhenium is distorted octahedral com-
prised by the NSO donor atom set of the tridentate ligand and
the three carbonyl groups. The apical positions of the octahedron
are occupied by the carboxylate oxygen atom of the tridentate li-
gand and one of the carbonyl groups. Rhenium lies 0.09 Å above
the equatorial plane. The five-membered ring in the coordination
sphere, defined by the S–C–C–O chelating atoms of the tridentate
ligand and the metal ion, adopt the envelope configuration with
S1 displaced by 0.82 Å out of the best mean plane of the remaining
four atoms. The six-membered ring in the coordination sphere, de-
fined by the S–C–C–C–N chelating atoms of the tridentate ligand
and the metal ion, adopt the half-chair or envelope configuration
with S1 displaced by 1.21 Å out of the best mean plane of the
remaining five atoms. The angles around the metal within the
tetragonal plane of the octahedron range from 83.5(2)° to
94.2(3)° whereas those involving the apical atoms range from
79.5(1)° to 97.8(3)°. The Re–carbonyl bond distances (1.87–1.91)
are consistent with those found in other Re–tricarbonyl complexes
[10–15]. The Re–S, Re–N and Re–O bond distances 2.47, 2.19 and
85 °C for 30 min at pH 7. The reaction yield was greater than 95%
at low ligand concentration (10À5 M). Complex formation could
also be observed (yield approximately 40%) even at the lower con-
centration of 10À6 M of 1. The identity of tracer complex 99mTc-1
was established by HPLC c-detection and comparison of its reten-
tion time to that of the authentic well-characterized complex Re-1.
Distribution coefficient of 99mTc-1 was calculated to be log
D7.4 = 1.6 0.2. Complex 188Re-1 was synthesized by reacting the
fac-[188Re(H2O)3(CO)3]+ precursor with ligand 1 (1.3 mM) at 65 °C
for 30 min. The identity of the tracer complex 188Re-1 was estab-
lished in the same way as 99mTc-1 and its radiochemical yield
was about 80%.
99mTc-1 was incubated in saline as well as in 1 mM histidine
and 1 mM cysteine solutions at 37 °C and was found to be >95%
stable in all these conditions for 24 h, with no decomposition or
trans-chelation being observed. The stability of 188Re-1 was also
evaluated and was found to be greater than 95% under the above
experimental conditions. The longer half-life of 188Re allowed sta-
bility tests at longer incubation times in which 188Re-1 proved in-
tact even after 48 h. Therefore, both tracer complexes 99mTc-1 and
188Re-1 are expected to be stable in the physiological
and -cysteine concentrations [21].
L-histidine
L
4. Conclusions
The histidine derivative ligand 1 proved to be an efficient NSO
chelator for the M(CO)3+ (M = Re, 99mTc, 188Re) core generating sta-
ble neutral complexes of the fac-[M(NSO)(CO)3] type. In these com-
plexes the ligand forms three (five-, six-, and seven-membered)
bridged chelate rings as is the case with plain histidine. For the
[Re(CO)3]+ core in the absence of any base, ligand 1 also acted as
a bidentate NS ligand generating a fac-[Re(NS)Br(CO)3] complex
in which one of the three bromines of the precursor is present in
the coordination sphere while the carboxylate group remains free.
Both tracer complexes 99mTc-1 and 188Re-1 are stable in solu-
tion as well as in the presence of strongly coordinating agents like
histidine or cysteine. Since the NSO chelating system 1 is prepared
in a facile two-step synthesis by nucleophilic attack of a thiol on a
suitable intermediate halide derived from histidine, in principle
any bioactive thiol can be used to generate target-specific com-
plexes for diagnostic or therapeutic applications.
Fig. 2. Labeled plot of the molecular structure of Re-1 with thermal ellipsoids
drawn at 40% probability.

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337
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Papastaikoudi, R. Alberto, I. Pirmettis, M. Papadopoulos, Inorg. Chem. 44
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This project was conducted in part under a Marie Curie Fellow-
ship for Transfer of Knowledge-MTKD-CT-2004-509224 (POL-RAD-
PHARM). The Isolink™ and rhenium pre-reduction kits were kindly
provided by Dr. Hector Knight, Mallinckrodt Medical B.V. (Petten,
The Netherlands).
Appendix A. Supplementary material
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Pelecanou, I. Pirmettis, M.S. Papadopoulos, Polyhedron 29 (2010) 876.
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CCDC 820715 contains the supplementary crystallographic data
for Re-1. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.ica.2011.08.062.
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