Rhenium(I) and Technetium(I) tricarbonyl complexes with [NSO]-type chelators: Synthesis, structural characterization, and radiochemistry

Article abstract of DOI:10.1002/ejic.201200056

The reactions of the NSO ligands 2-[2-(pyridin-2-yl)ethylthio]acetic acid (HL1), 3-[2-(pyridin-2-yl)ethylthio]propanoic acid (HL2), 2-(carboxymethylthio)- 3-(1H-imidazol-4-yl)propanoic acid (H₂L3), and 2-(carboxyethylthio)- 3-(1H-imidazol-4-yl)propanoic acid (H₂L4) with [NEt₄] ₂[ReBr₃(CO)₃] are presented. Ligands HL1, H₂L3, and H₂L4 act as tridentate NSO chelators and readily generate the fac-[Re(NSO)(CO)₃]complexes Re-L1, Re-HL3, and Re-HL4. Ligand HL2 acts as NSO tridentate chelator only in the presence of base to give complex Re-L2, while without base it coordinates as a NS bidentate chelator to generate complex fac-[ReBr(NS)(CO)₃], Re-HL2. All complexes were isolated and characterized by elemental analysis, IR and ¹H, ¹³C NMR spectroscopy. Complex Re-L1, Re-HL2, and Re-HL3 were characterized also by X-ray crystallography. Furthermore, the analogous technetium complexes fac-[^99mTc(NSO)(CO)₃]⁺, ^99mTc-L1, ^99mTc-L2, ^99mTc-HL3, and ^99mTc-HL4 were synthesized by reacting ligands HL1-H₂L4 with the fac-[^99mTc(OH₂)₃(CO)₃] ⁺ precursor for 30 min at 75 °C. The tracer complexes ^99mTc-L1-^99mTc-HL4 were found to be stable in L-cysteine and L-histidine challenge experiments. The bifunctional chelating agents that bear a second carboxylate group are promising for the development of targeted ^99mTc radiopharmaceuticals.

Full text of DOI:10.1002/ejic.201200056

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
FULL PAPER
DOI: 10.1002/ejic.201200056
Rhenium(I) and Technetium(I) Tricarbonyl Complexes with [NSO]-Type
Chelators: Synthesis, Structural Characterization, and Radiochemistry
George Makris,[a,b] Ourania Karagiorgou,[b] Dionysia Papagiannopoulou,*[a]
Angeliki Panagiotopoulou,[c] Catherine P. Raptopoulou,[d] Aris Terzis,[d] Vassilis Psycharis,[d]
Maria Pelecanou,[c] Ioannis Pirmettis,[b] and Minas S. Papadopoulos[b]
Keywords: Rhenium / Technetium / Carbonyl ligands / Radiopharmaceuticals / NSO ligands
The reactions of the NSO ligands 2-[2-(pyridin-2-yl)ethyl-
thio]acetic acid (HL1), 3-[2-(pyridin-2-yl)ethylthio]propanoic
acid (HL2), 2-(carboxymethylthio)-3-(1H-imidazol-4-yl)-
propanoic acid (H2L3), and 2-(carboxyethylthio)-3-(1H-imid-
azol-4-yl)propanoic acid (H2L4) with [NEt4]2[ReBr3(CO)3] are
presented. Ligands HL1, H2L3, and H2L4 act as tridentate
NSO chelators and readily generate the fac-[Re(NSO)-
(CO)3]complexes Re-L1, Re-HL3, and Re-HL4. Ligand HL2
acts as NSO tridentate chelator only in the presence of base
to give complex Re-L2, while without base it coordinates as
a NS bidentate chelator to generate complex fac-[ReBr(NS)-
(CO)3], Re-HL2. All complexes were isolated and charac-
terized by elemental analysis, IR and 1H, 13C NMR spec-
troscopy. Complex Re-L1, Re-HL2, and Re-HL3 were charac-
terized also by X-ray crystallography. Furthermore, the anal-
ogous technetium complexes fac-[99mTc(NSO)(CO)3]+, 99mTc-
L1, 99mTc-L2, 99mTc-HL3, and 99mTc-HL4 were synthesized by
reacting ligands HL1–H2L4 with the fac-[99mTc(OH2)3(CO)3]+
precursor for 30 min at 75 °C. The tracer complexes 99mTc-
L1–99mTc-HL4 were found to be stable in
L-cysteine and L-
histidine challenge experiments. The bifunctional chelating
agents that bear a second carboxylate group are promising
for the development of targeted 99mTc radiopharmaceuticals.
onyl complexes with tridentate chelating agents are fully
coordinated, which results in in vivo stability and favorable
pharmacokinetic properties.[7] A variety of NSO chelators
has been developed that include an amine or aromatic N
atom, a thioether S atom, and a carboxylate group O atom,
which have been established as suitable systems for the
99mTc/[Re(CO)3]+ core.[8–12] These tridentate ligands form
[M(CO)3]+ complexes with either a linear or tripodal con-
figuration.[5–15] Interesting [M(CO)3]+ coordination chemis-
try has been reported with NSO ligands that offer more
than one possible mode of complexation, such as [(2-pyrid-
inyl)methyl]-S-cysteine, S-carboxymethyl-l-cysteine, and [2-
Introduction
Technetium (99mTc) radiopharmaceuticals are routinely
used in nuclear medicine as non-invasive diagnostic agents
for scintigraphic/tomographic (γ-camera/SPECT) imaging.
New generation 99mTc radiopharmaceuticals consist of a ra-
dionuclide unit (99mTc complex) and a pharmacophore
group as the vector that carries the radionuclide to the tar-
get site. The design of these compounds is mostly ac-
complished by using a suitable bifunctional chelating agent
(BFCA) for the chelation of the radionuclide and the conju-
gation of the target specific moiety. An ideal BFCA should
be able to form stable and inert 99mTc complexes in high
yield and at low concentration.[1–4]
(2-pyridinyl)ethyl]-S-homocysteine
derivatives.[9–11,16,17]
However, for radiopharmaceutical purposes, the formation
of a single stable product is an essential requirement, and
this becomes a challenge when more than one ligating pos-
sibility is available. In the case of bifunctional ligands de-
signed to be joined with pharmacophores of interest, and
therefore carry many active complexing groups, the genera-
tion of the desired product may be influenced by the experi-
mental conditions (e.g. pH) and also by other structural or
stereochemical factors such as the chelate ring size etc.
In our previous work, we described the syntheses of the
rhenium and technetium tricarbonyl complexes with the
NSO chelating agent, 2-(p-methoxybenzylthio)-3-(4-imid-
azolyl)propionic acid, as shown in Figure 1. This ligand was
shown to have high potency at low ligand concentration
(Ͻ10–5 m), and the complexes formed were stable at tracer
Currently, many efforts to design novel 99mTc-radiophar-
maceuticals focus on the fac-[99mTcI(CO)3]+-type com-
plexes, because of their high stability and their easy and
efficient preparation in aqueous media.[5,6] The Tc-tricarb-
[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 Athens, Greece
[c] Institute of Biology,
National Centre for Scientific Research “Demokritos”,
15310 Athens, Greece
[d] Institute of Materials Science,
National Centre for Scientific Research “Demokritos”,
15310 Athens, Greece
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
D. Papagiannopoulou et al.
FULL PAPER
level (99mTc, 188Re) in the presence of potent chelators.[18]
Currently, our interest lies in the design of bifunctional che-
lators based on the NSO donor atom system with a second
pendant carboxylate group for tethering to a pharmaco-
phore. Within this framework, and in order to investigate
the NSO coordination behavior, the tridentate ligands 2-[2-
(pyridin-2-yl)ethylthio]acetic acid (HL1) and 3-[2-(pyridin-
2-yl)ethylthio]propanoic acid (HL2) were synthesized and
complexed with the [M(CO)3]+ core. Following that, in or-
der to investigate the preference of this type of NSO ligand
bearing a second carboxylate group for linear vs. tripodal
coordination, the 2-(S-carboxymethylthio)-3-(1H-imidazol-
4-yl)propanoic acid (H2L3) and 2-(S-carboxyethylthio)-3-
(1H-imidazol-4-yl)propanoic acid (H2L4) were synthesized
and complexed with the [MI(CO)3]+ core. The results of this
study are presented herein.
Scheme 1. Synthesis of ligands HL1–H2L4.
Figure 1. Structure of complex [Re(NSO)(CO)3].
Results and Discussion
Synthesis and Characterization
Ligands HL1 and HL2 were prepared in high yields by
2-(pyridin-2-yl)ethylation,[19,20] and the pure products were
isolated by crystallization from THF (Scheme 1). The reac-
tion of the precursor [NEt4]2[ReBr3(CO)3] with an equi-
molar amount of ligand HL1 in methanol led to the ex-
pected NSO mode of complexation and the formation of
complex Re-L1 (Scheme 2). Reaction of HL2 with [NEt4]2-
Scheme 2. Syntheses of complexes Re-L1, Re-L2, Re-HL2, Re-HL3
and Re-HL4.
[ReBr3(CO)3] in methanol led to the isolation of complex forded only a very low yield for H2L3 (Ͻ10%) or were un-
Re-HL2 with the structure fac-[ReBr(HL2-NS)(CO)3] in successful for H2L4. However, the pure ligands were iso-
which the propionic acid chain remains free. When the reac- lated in moderate yields after esterification of the diacids
tion was carried out in the presence of 1 equiv. NaOH, the H2L3 and H2L4 to the ethyl esters Et2L3 and Et2L4. The
NSO mode of complexation prevailed, and complex Re-L2 purified diesters were then hydrolyzed by base, and the so-
was formed as a single product (Scheme 2). Both in the ab- dium salts of H2L3 and H2L4 were used directly for com-
sence and presence of base, the yields of complexes ob- plexation. Ligands H2L3 and H2L4 are soluble in water and
tained were quantitative, and the complexes were charac- DMSO and slightly soluble in methanol and ethanol.
terized by elemental analysis and IR and NMR spec-
Ligands H2L3 and H2L4 reacted with [NEt4]2[ReBr3-
troscopy. These results indicate that the formation of a 5- (CO)3] in water at pH 7. Analysis of the reaction mixture
membered ring (Re–S–C–C–O) is favored over that of a 6- by HPLC after 3 h of reflux indicated in both cases the
membered ring (Re–S–C–C–C–O) upon coordination of the formation of a single product Re-HL3 and Re-HL4, respec-
carboxylate group in complex Re-L1 and Re-L2, respec- tively. The complexes were characterized by elemental
tively. This fact has also been noted in the literature in a analysis and spectroscopic methods. In Re-HL3 coordina-
similar NSO system by He et al.[16]
tion takes place in a linear mode to form two chelate rings,
Ligands H2L3 and H2L4 were designed as NSO bifunc- one six-membered and one five-membered, as in the case
tional ligands carrying two carboxylic acid chains. They of Re-L1 (Scheme 2). Although coordination of the second
were prepared from α-chloro-l-histidine (Scheme 1).[18] Sev- carboxylate group is in principle possible, leading to a five-
eral efforts to isolate the pure ligands H2L3 and H2L4 by membered ring as well (Figure 2), it was not observed. In
multiple crystallizations from ethanol/water mixtures af- the case of Re-HL4, coordination takes place in the tripodal
2
www.eurjic.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 0000, 0–0

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
RhI and TcI Tricarbonyl Complexes with [NSO]-Type Chelators
mode with formation of three chelate rings, one six-mem- Table 1. 1H and 13C chemical shifts for complexes Re-L1, Re-HL2,
Re-L2 in [D6]DMSO at 25 °C. The numbering of the atoms is
shown in Figure 3.
bered, one five-membered, and one seven-membered, while
the alternative coordination of the S-carboxylate side chain
Re-L1
Re-HL2
Re-L2
(Figure 2) was not observed. As in the cases of Re-L1/Re-
HL2, formation of a five-membered carboxylate ring is pre-
ferred.
1-H
2-H
3-H
4-H
6-H
7-H
8-H
9-H
OH
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
8.74
7.57
8.10
7.69
3.47, 3.00
3.43, 2.64
2.96, 3.59
9.05
7.49
8.04
7.64
8.79
7.61
8.13
7.76
3.48, 2.54
3.56, 3.02
3.05, 2.31
2.18, 1.90
3.56, 3.16
3.12, 2.43
3.34, 3.18
2.75
12.57 broad
157.85
124.43
140.19
127.89
161.38
36.76
156.04
124.95
140.66
127.10
159.72
38.07
30.80
35.86
178.06
155.10
124.70
140.66
126.93
159.40
37.99
28.46
32.16
33.70
172.93
Figure 2. Possible complexation of H2L3 and H2L4 with
[M(CO)3]+.
26.29
34.41
32.73
171.95
Strong bands in the region 2029–1894 cm–1 in the IR
spectra of the complexes indicate the presence of three carb-
onyl ligands in a facial arrangement.[9–12,16–18,21,22] Further-
more, the bands for the coordinated carboxylate groups in
complexes Re-L1, Re-L2, Re-HL3, and Re-HL4 appear be-
tween 1639 and 1602 cm–1 and those for the uncoordinated
carboxylate of Re-HL2, Re-HL3, and Re-HL4 in the region
1739–1709 cm–1. All rhenium complexes are soluble in
DMSO, slightly soluble in methanol and ethanol, and insol-
uble in water and are stable in the solid state and in solution
for a period of months, as proven by HPLC and NMR
spectroscopy.
CϵO 195.12, 193.21, 192.61 193.19, 191.69 196.54, 194.23, 193.18
Table 2. 1H and 13C NMR chemical shifts (ppm) for complexes Re-
HL3 and Re-HL4 in [D6]DMSO at 25 °C. The numbering of the
atoms is shown in Figure 3.
Re-HL3
Re-HL4
1-H
2-H
4-H
5-H
7-H
8-H
NH
OH
8.34
7.20
8.33
7.17
2
2
2.93, 3.19; J = 16.4 Hz
4.23
3.67, 3.60
3.47, 3.18; J = 17.7 Hz, 3J = 3.8 Hz
4.27; 3J = 3.8 Hz
3.23, 3.08
2.78
1
The H and 13C NMR assignments for the complexes
Re-L1, Re-L2, Re-HL2, Re-HL3, and Re-HL4 are based on
13.02
not visible
13.11
12.63 broad
141.35
116.31
133.61
27.38
45.60
178.01
35.68
the combined analysis of a series of 1H–1H and 1H–13C
correlation spectra and are presented in Tables 1 and 2. For C-1 141.99
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
116.47
132.78
26.36
47.77
169.53
35.49
complexes Re-L2 and Re-HL4 for which no X-ray structure
exists, structural characterization was based on their char-
acteristic NMR spectral patterns and on chemical shift
comparisons with structurally related complexes herein and
in the literature.[9–12,16–18] Upon complexation of the ligands
HL1–H2L4, the signal C-1 pyridinyl and imidazoyl carbon
atom adjacent to the coordinating nitrogen is shifted down-
field by approximately 7 ppm, while the signal for the corre-
sponding 1-H proton is shifted downfield by 0.4–0.7 ppm.
These downfield shifts are typical for the coordination of
heterocyclic aromatic nitrogen atoms. In addition, upon co-
ordination, differentiation of the previously equivalent pro-
tons of the methylene groups of the chelated NSO (Re-L1,
Re-L2, Re-HL3, Re-HL4) or NS backbone (Re-HL2) is
noted. In complexes Re-HL2 and Re-HL4 bearing the free
mercaptopropionic acid chain, the methylene protons close
to coordinated sulfur (8-H and 7-H) are also differentiated,
while those close to the carboxyl group (9-H and 10-H0)
appear together at approximately 2.75 ppm. In complexes
Re-L1, Re-L2, and Re-HL2, the 6-H protons are distin-
guished from the 7-H protons on the basis of the presence
of a NOESY correlation peak with the pyridinyl 4-H pro-
ton. The assignment is further confirmed through the ob-
178.03
32.29
171.97
193.17, 195.96, 196.67
CϵO 195.41, 193.22
Figure 3. 1H–13C long range correlation (HMBC) spectrum for
servation of the long-range heteronuclear coupling of 4-H complex Re-L1 in [D6]DMSO at 25 °C.
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
3

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
D. Papagiannopoulou et al.
FULL PAPER
and C-6 (Figure 3). It is of interest that the chemical shift remaining four atoms, and in molB, C26 and Re2 are dis-
of the carboxylate C=O group appears at δ = 178 ppm placed by 0.75 and 0.72 Å above the S–C–C–N plane. In the
when the carboxylate group participates in a five-membered crystal lattice of Re-L1, the molecules are linked through
ring (complexes Re-L1, Re-HL3, Re-HL4) and at δ = intermolecular S···S contacts and form dimers. In particu-
173 ppm when it participates in a six-membered ring (com- lar, molA is associated into molA–molA dimers through the
plex Re-L2), which indicates a weaker bonding to the metal, S1···S1Ј (1 – x, –y, 1 – z) [3.482 Å] contacts, and similarly
in agreement with the synthesis results that indicate a pref- molB is linked into molB–molB dimers through the
erence for formation of a five-membered chelate ring.
S2···S2ЈЈ (-x, 1 – y, 2 – z) [3.497 Å] contacts.
Description of the Structure
The structures of complexes Re-L1, Re-HL2, and Re-
HL3 were determined by X-ray crystallography. Important
crystallographic and refinement data are listed in Table 3.
¯
Complex Re-L1 crystallizes in the triclinic space group P1
with two crystallographically independent molecules in the
asymmetric unit, denoted as molA and molB respectively.
A labeled plot of molA is shown in Figure 4, and selected
bond lengths and angles are listed in Table 4. The structure
consists of neutral mononuclear entities in which the rhe-
nium ions are in a distorted octahedral geometry compris-
ing of three facially bound CO groups and the NSO donor
atom set of the tridentate L1 ligand. The Re–carbonyl bond
lengths, 1.912(6)–1.928(6) Å in molA and 1.902(5)–
1.928(5) Å in molB, are consistent with those found in other
Re-tricarbonyl complexes. The Re–(NSO) bonding dis-
tances are also in the ranges observed for other well-charac-
terized complexes, with Re–N bond lengths of 2.233(4) and
2.213(4) Å, Re–S bond lengths of 2.476(1) and 2.469(1) Å,
and Re–Ocarboxyl bond lengths of 2.126(3) and 2.128(3) Å,
for molA and molB, respectively. There is one five-mem-
bered ring, Re–S–C–C–O, and one six-membered ring, Re–
S–C–C–C–N, in the coordination sphere; the former is
planar and the latter adopts the less–stable, twist-boat con-
formation. In molA, atoms C6 and Re1 are displaced by
0.65 and 0.78 Å above the best mean plane defined by the
Figure 4. Labeled plot of one of the crystallographically indepen-
dent molecules in the asymmetric unit of Re-L1 with ellipsoids
drawn at the 30% probability level. Hydrogen atoms have been
omitted for clarity.
Table 4. Selected bond lengths [Å] and angles [°] for Re-L1.
Distances
Re1–C12
Re1–C11
Re1–C10
Re1–O1
Re1–N1
Re1–S1
1.912(6)
1.915(6)
1.928(6)
2.126(3)
2.233(4)
2.476(1)
Re2–C31
Re2–C30
Re2–C32
Re2–O21
Re2–N21
Re2–S2
1.902(5)
1.910(5)
1.928(5)
2.128(3)
2.213(4)
2.469(1)
Angles
C12–Re1–C11
C12–Re1–C10
C11–Re1–C10
C12–Re1–O1
C11–Re1–O1
C10–Re1–O1
C12–Re1–N1
C11–Re1–N1
C10–Re1–N1
O1–Re1–N1
C12–Re1–S1
C11–Re1–S1
C10–Re1–S1
O1–Re1–S1
88.6(3)
89.1(2)
86.1(2)
91.8(2)
178.2(2)
95.7(2)
91.6(2)
94.4(2)
179.1(2)
83.8(1)
171.9(2)
99.6(2)
91.9(2)
80.1(1)
87.4(1)
C31–Re2–C30
C31–Re2–C32
C30–Re2–C32
C31–Re2–O21
C30–Re2–O21
C32–Re2–O21
C31–Re2–N21
C30–Re2–N21
C32–Re2–N21
O21–Re2–N21
C31–Re2–S2
C30–Re2–S2
C32–Re2–S2
O21–Re2–S2
N21–Re2–S2
87.4(2)
88.3(2)
88.6(2)
176.1(2)
93.6(2)
95.5(2)
97.0(2)
175.6(2)
91.9(2)
82.0(1)
96.0(2)
91.5(2)
175.6(2)
80.1(1)
87.7(1)
Table 3. Crystallographic data for Re-L1, Re-HL2 and Re-HL3.
Re-L1
Re-HL2
Re-HL3
Formula
Fw
Space group
a [Å]
b [Å]
c [Å]
C12H10NO5ReS C13H13BrNO5ReS C12H13N2O8ReS
466.47
P1
561.41
P1
531.51
P21/n
7.655(3)
19.703(7)
10.781(4)
90
¯
¯
7.732(2)
13.255(4)
13.806(4)
88.93(1)
82.84(1)
83.16(1)
1393.9(7)
4
8.531(4)
9.319(4)
10.842(5)
81.81(1)
85.20(1)
75.866(9)
826.3(6)
2
α [°]
β [°]
93.88(2)
90
γ [°]
N1–Re1–S1
V [Å3]
Z
1622.3(10)
4
Complex Re-HL2 crystallizes in the triclinic space group
T [°C]
Radiation
ρcalcd. [gcm–3]
μ [mm–1]
25
Mo-Kα
2.223
25
Mo-Kα
2.257
9.917
2693
25
¯
P1 with one molecule in the asymmetric unit. A labeled
plot of Re-HL2 is shown in Figure 5, and selected bond
lengths and angles are listed in Table 5. The structure con-
sists of neutral mononuclear rhenium(I) entities in which
the metal ion is in a distorted octahedral environment com-
prising of three facially bound CO groups, the NS donor
atom set of L2, and a bromide ion. The carboxylate group
of L2 remains protonated and is directed away from the
Mo-Kα
2.176
7.662
2543
8.884
Reflections with 4341
IϾ2σ(I)
[a]
R1
0.0231
0.0576
0.0343
0.0947
0.0299
0.0782
[a]
wR2
[a] w = 1⁄[σ2(Fo2) + (αP)2 + bP] and P = [max(Fo ,0) + 2Fc ]/3, R1
2
2
= Σ(|Fo| – |Fc|)/Σ(|Fo|) and wR2 = {Σ[w(Fo – Fc ) ]/Σ[w(Fo2)2]}1/2
.
2
2 2
4
www.eurjic.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 0000, 0–0

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
RhI and TcI Tricarbonyl Complexes with [NSO]-Type Chelators
coordination sphere of the metal ion. The observed Re–CO, methanol molecule are in the asymmetric unit. A labeled
Re–N, and Re–S bond lengths fall in the ranges found in plot of Re-HL3 is shown in Figure 6, and selected bond
analogous rhenium(I) complexes. The Re–S–C–C–C–N six- lengths and angles are listed in Table 5. The structure con-
membered ring in the coordination sphere adopts the less– sists of neutral mononuclear rhenium(I) entities comprising
stable, twist-boat conformation in which atoms C6 and Re1 the fac-[Re(CO)3] group and the NSO donor atom set of
lie 0.71 and 0.55 Å above the best mean plane defined by the tridentate L3 ligand. The second carboxylate group of
the remaining four atoms. In the crystal lattice, the mole- L3 remains protonated and is directed away from the metal
cules of Re-HL2 are associated into dimers through inter- ion. The imidazole ring of L3 is also protonated and coor-
molecular O–H···Br hydrogen-bonding interactions be- dinates to rhenium(I) through the second nitrogen atom.
tween the protonated carboxylate of HL2 and the coordi- The Re–carbonyl bond lengths, 1.902(6)–1.935(6) Å, are
nated Br– of a neighboring molecule [O1···Br (1 – x, –y, consistent with those found in other Re-tricarbonyl com-
–z) 3.323 Å, H1O···Br 2.382 Å, O1–H1O···Br 165.9°].
plexes, with the longest being the one opposite to Nim and
[5,8–12,13,18]
the shortest opposite to Ocarboxyl
.
The Re–(NSO)
bonding distances are also in the ranges observed for other
well-characterized complexes, with a Re–Nim bond length
of 2.174(4) Å, Re–S bond length of 2.486(2) Å, and Re–
O
carboxyl bond length of 2.154(4) Å.[8–12,18,23] The Re–S–C2–
C1–O1 five-membered ring in the coordination sphere
adopts the envelope conformation in which the atom S is
0.65 Å above the mean plane of the remaining four atoms.
There is also a six-membered ring in the coordination
sphere defined by the atoms Re–S–C3–C5–C6–N, whose
conformation cannot be easily described in terms of the
known conformations of cyclohexane. The best way to de-
scribe this particular six-membered ring is to define the
mean plane passing through Re–S–C3–N (largest deviation
0.03 Å for C3) from which atoms C6 and C5 are displaced
by 0.61 and 1.15 Å, respectively. This thus suggests a con-
formation “frozen” between half-chair and twist-boat with
regard to the displacement of C6 and the orientation of
the imidazole ring. The observed intermolecular hydrogen-
bonding interactions of the O–H···O and N–H···O type in-
volving the protonated carboxylate group and the imidazole
nitrogen atom of L3, as well as the solvate methanol, are
very likely to contribute to the stability of the above inter-
mediate conformation of the six-membered ring. In the
crystal lattice, the molecules of Re-HL3 form two-dimen-
sional sheets parallel to the ac plane as a result of their
linkage through hydrogen bonds [O4···O2 (–0.5 + x, 0.5 – y,
0.5 + z) 2.570 Å, H4O···O2 1.927 Å, O4 – H4O···O2 167.3°;
N2···O1m (–1 + x, y, –1 + z) 2.866 Å, H2N···O1m 2.183 Å,
Figure 5. Labeled plot of Re-HL2 with ellipsoids drawn at the 30%
probability level. Only the H atom of the carboxylate moiety is
shown, the rest have been omitted for clarity.
Table 5. Selected bond lengths [Å] and angles [°] for Re-HL2 and
Re-HL3.
Re-HL2
Re-HL3
Distances
Re1–C12
Re1–C13
Re1–C11
Re1–N1
Re1–S1
1.912(8)
1.914(8)
1.920(7)
2.225(6)
2.490(2)
2.626(1)
Re–C10
Re–C11
Re–C12
Re–O1
Re–N1
Re–S
1.902(6)
1.930(6)
1.935(6)
2.154(4)
2.174(4)
2.487(2)
Re1–Br1
Angles
C12–Re1–C13
C12–Re1–C11
C13–Re1–C11
C12–Re1–N1
C13–Re1–N1
C11–Re1–N1
C12–Re1–S1
C13–Re1–S1
C11–Re1–S1
N1–Re1–S1
C12–Re1–Br1
C13–Re1–Br1
C11–Re1–Br1
N1–Re1–Br1
S1–Re1–Br1
89.4(3)
88.8(3)
89.5(3)
92.2(3)
93.9(3)
176.5(3)
175.2(2)
94.9(2)
89.0(2)
89.7(2)
91.2(2)
178.7(2)
91.7(3)
84.9(1)
84.7(1)
C10–Re–C11
C10–Re–C12
C11–Re–C12
C10–Re–O1
C11–Re–O1
C12–Re–O1
C10–Re–N1
C11–Re–N1
C12–Re–N1
O1–Re–N1
C10–Re–S
88.7(2)
88.2(2)
89.4(2)
173.6(2)
94.4(2)
97.4(2)
91.7(2)
91.1(2)
179.5(2)
82.7(2)
97.8(2)
173.4(2)
90.0(2)
79.2(1)
89.6(1)
C11–Re–S
C12–Re–S
O1–Re–S
N1–Re–S
Figure 6. Labeled plot of Re-HL3 with ellipsoids drawn at the 30%
probability level. Only significant H atoms are shown; the rest have
Complex Re-HL3 crystallizes in the monoclinic space
group P21/n in which one complex molecule and a solvate been omitted for clarity.
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
5

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
D. Papagiannopoulou et al.
FULL PAPER
N2 – H2N···O1m 161.8°; O1m···O3 (1 + x, y, z) 2.907 Å, that carries two carboxylate groups with coordinating po-
H1m···O3 2.257 Å, O1m–H1m···O3 167.8°].
tential demonstrates that coordination in the linear mode is
preferred over the tripodal mode, since only the linear com-
plex is formed even though coordination of either carboxyl-
ate group would lead to formation of a five-membered ring
(Figure 2). The study with H2L4 confirms the preference
for the formation of a five-membered ring over the six-
membered ring, a preference that apparently overcomes
that for linear coordination.
With technetium, the ligands HL1–H2L4 behave in an
analogous way with the generation of single, stable com-
plexes. In particular ligands H2L3 and H2L4, which react
at very low concentrations with 99mTc, could be used for
the conjugation of a pharmacophore group of interest to-
ward the development of novel diagnostic and therapeutic
radiopharmaceuticals.
Radiochemistry
The fac-[99mTc(NSO)(CO)3] complexes 99mTc-L1, 99mTc-
HL3 and 99mTc-HL4 were synthesized in high yield (Ͼ95%)
by the reaction of the fac-[99mTc(H2O)3(CO)3]+ precursor
with ligand HL1, H2L3 or H2L4 (10–4 m) at 75 °C for
30 min at pH 6–7. HPLC analysis of the reaction mixture
showed the formation of a single product, the same as that
for the rhenium analogues. The identity of the tracer com-
plexes was established by HPLC γ-detection after co-injec-
tion with the rhenium complexes Re-L1 (tR: 16.3 min), Re-
HL3 (tR: 15.6 min), and Re-HL4 (tR: 14.9 min). It was
found that 99mTc-L1 elutes with tR = 16.7 min, 99mTc-HL3,
tR = 15.7 min and 99mTc-HL4, tR = 15.1 min. A representa-
tive HPLC co-injection chromatogram is shown in Figure 7.
The formation of the fac-[99mTc(NSO)(CO)3] 99mTc-L2
complex was quantitative only at a higher HL2 ligand con-
centration of 10–3 m. The radiochemical yield of 99mTc-L2
at lower HL2 concentrations was low, and many products
were observed in the chromatogram. All 99mTc complexes
were challenged against 1 mm histidine and cysteine, and
the analysis showed that they were ≈85–95% stable after
24 h. In particular, analysis of the complexes with bifunc-
tional ligands showed that the percentage of intact 99mTc-
HL3 was 83% after 24 h in histidine and 98% after 24 h in
Experimental Section
General: All chemicals were reagent grade and were used as such
unless otherwise noted. Re2(CO)10 was purchased from Aldrich and
was converted to (NEt4)2[ReBr3(CO)3] as previously reported.[24]
Solvents for high-performance liquid chromatography (HPLC)
were HPLC grade. They were filtered through membrane filters
(0.22 μm, Millipore, Milford, MA) and degassed.
For the 99mTc labeling, a kit containing 5.5 mg of NaBH4, 4 mg of
Na2CO3, and 10 mg of Na-K tartrate was purged with CO gas
prior to addition of Na99mTcO4, as described in the literature.[13]
cysteine, while 99mTc-HL4 was about 93% and 99% intact Elemental analyses were performed on a Perkin–Elmer 2400 auto-
mated analyzer. IR spectra were recorded as KBr pellets on a Per-
kin–Elmer 1600 FTIR spectrophotometer in the region 4000–
500 cm–1. 1H and 13C NMR spectra were recorded on a Bruker
300 MHz or 500 MHz Avance DRX spectrometer and by using
(CH3)4Si as the internal reference. 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
detector. Separations of the rhenium and technetium-99m com-
plexes were achieved on an Agilent Eclipse XDB-C18 column
(25 cmϫ4.6 mm, 5 μm) eluted with a binary gradient system at a
1 mL/min flow rate and with a composition of 100% solvent A:
0.1% trifluoroacetic acid in water at 0 min, linearly converting to
75% solvent B: methanol, over 15 min.
after 24 h in histidine and cysteine, respectively. These re-
sults indicate that the tracer complexes will be stable in bio-
logical fluids where histidine and cysteine are present.
Ligand Syntheses
Figure 7. Comparative HPLC analysis of Re-HL3 (UV) and the
2-[2-(Pyridin-2-yl)ethylthio]acetic Acid (HL1): 2-vinylpyridine
(3.26 g, 31 mmol) freshly distilled under vacuum was added drop-
wise in a solution of mercaptoacetic acid (2.86 g, 31 mmol) in
methanol (50 mL). The reaction mixture was heated under reflux
for 4 h. Methanol was then removed on a rotary evaporator, and
the residue was dissolved in ethanol (5 mL) and kept at –20 °C for
24 h. The white precipitate formed was recrystallized from tetra-
labeling mixture of 99mTc-HL3 (γ detection) co-injected.
Conclusions
The HL1–H2L4 ligands employed, which contain an aro-
matic N, a thioether S and a carboxylate O atom, led to the
formation of a single, stable complex with a Re-tricarbonyl
core. Our results allow for some conclusions to be reached
with regard to the coordination behavior of this type of
SNO ligand. Specifically, the study with ligands HL1 and
HL2 show that formation of a five-membered ring by the
S-carboxylate chain is preferred over formation of a six-
hydrofuran. Yield 5.86 g (96%). IR (KBr): ν = 1703 (COOH) cm–1.
˜
1H NMR (300 MHz, [D6]DMSO): δ = 8.56 (1 H, py) 8.36 (1 H,
py), 7.82 (1 H, py) 7.70 (1 H, py), 3.24 (t, 2 H, CH2), 3.18 (t, 2 H,
CH2), 2.95 (t, 2 H, CH2) ppm. C9H11NO2S (197.25): calcd. C 54.82,
H 5.62, N 7.10; found C 55.00, H 5.70, N 7.14.
3-[2-(Pyridin-2-yl)ethylthio]propanoic Acid (HL2): Ligand HL2 was
prepared following the same method as that for HL1 by using 3-
mercaptopropionic acid (3.29 g, 31 mmol) in place of mercaptoace-
membered ring. In addition, the study with ligand H2L3 tic acid. Yield: 6.22 g (95%). IR (KBr): ν = 1704 (COOH) cm–1.
˜
6
www.eurjic.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 0000, 0–0

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
RhI and TcI Tricarbonyl Complexes with [NSO]-Type Chelators
1H NMR (300 MHz, [D6]DMSO): δ = 8.60 (1 H, py), 8.35 (1 H,
suitable for X-ray analysis were isolated by dissolving the precipi-
py), 7.85 (1 H, py), 7.75 (1 H, py), 3.25 (t, 2 H, CH2), 3.00 (t, 2 H, tate in CH2Cl2/MeOH and by allowing the solvent mixture to
CH2), 2.70 (t, 2 H, CH2), 2.45 (t, 2 H, CH2) ppm. C10H13NO2S slowly evaporate. Yield: 95 mg (85%). tR = 16.46 min. IR (KBr): ν
˜
(211.28): calcd. C 56.85, H 6.20, N 6.63; found C 56.59, H 6.55, N
6.60.
= 2023, 1901, 1739 cm–1. 1H and 13C NMR data in Table 1.
C13H13BrNO5ReS (561.41): calcd. C 27.81, H 2.33, N 2.49; found
C 27.58, H 2.55, N 2.34.
Ethyl 2-(2-Ethoxy-2-oxoethylthio)-3-(1H-imidazol-4-yl)propanoate
(Et2L3): Ligand L3 was synthesized according to the following
procedure.[18] 2-Chloro-3-(1H-imidazol-4-yl)propanoic acid[25]
(500 mg, 2.88 mmol) and mercaptoacetic acid (396 mg, 4.3 mmol)
were mixed in water/ethanol (1:1 v/v, 10 mL), and 2 m NaOH
(6 mL) was added dropwise under N2. The mixture was stirred for
3 d. The pH was then adjusted to 5 by addition of 5 m HCl, and
the solvents were evaporated to dryness. The residue was slurried
in dry ethanol (25 mL), and thionyl chloride (3 mL, 40 mmol) was
added dropwise at 0 °C under N2. The mixture was heated under
reflux for 12 h and concentrated in vacuo. The oily residue was
purified by silica gel column chromatography by eluting with 5%
methanol in dichloromethane. Yield: 303 mg (37%). 1H NMR
(300 MHz, CDCl3): δ = 9.0 (br. s, 1 H, NH), 7.64 (s, 1 H, 1-H),
6.88 (s, 1 H, 2-H), 4.13–4.21 (m, 4 H, CH2CH3), 3.78 (t, J = 7.4 Hz,
1 H, 5-H), 3.47 (d, J = 15.7 Hz, 1 H, 7-H), 3.36 (d, J = 15.7 Hz, 1
H, 7-H), 3.22 (dd, J = 15.1, 8.1 Hz, 1 H, 4-H), 3.02 (dd, J = 15.0,
6.7 Hz, 1 H, 4-H), 1.26 (t, 3 H, CH2CH3), 1.24 (t, 3 H, CH2CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 171.72 (COOEt), 170.01
(COOEt), 134.75 (C-1), 132.80 (C-3), 118.35 (C-2), 61.63
(CH2CH3), 61.42 (CH2CH3), 46.57 (C-5), 33.26 (CH2), 28.68
(CH2), 14.01 (CH2CH3) ppm (the NMR numbering is shown in
Scheme 2, with the exception of the ethyl esters).
C12H18N2O4S·(0.5H2O) (286.35): calcd. C 48.80, H 6.48, N 9.48;
found C 49.00, H 6.12, N 9.52.
Synthesis of fac-[ReBr(L2-NSO)(CO)3] (Re-L2): [NEt4]2[ReBr3-
(CO)3] (154 mg, 0.2 mmol) was dissolved in methanol (10 mL), and
a solution of ligand HL2 (42 mg, 0.2 mmoL) in methanol (5 mL)
and 1 m NaOH (0.2 mL) were added. The mixture was heated un-
der reflux for 2 h. Yield: 74 mg (77%). tR = 17.78 min. IR (KBr):
ν = 2020, 1900, 1626 cm–1. 1H and 13C NMR data in Table 1.
˜
C13H12NO5ReS (480.50): calcd. C 32.49, H 2.52, N 2.91; found C
32.20, H 2.68, N 2.95.
Synthesis of fac-[Re(HL3-NSO)(CO)3] (Re-HL3) and fac-[Re(HL4-
NSO)(CO)3] (Re-HL4): The esterified ligands Et2L3 (28.6 mg,
0.1 mmol) or Et2L4 (29.8 mg, 0.1 mmol) was stirred in water
(2 mL) with 6 equiv. 2 m NaOH (0.3 mL) for 2 h, until complete
hydrolysis was confirmed by HPLC. The pH was then adjusted to
7 with 1 m HCl, and [NEt4]2[ReBr3(CO)3] (77 mg, 0.1 mmol) was
subsequently added. The mixture was heated under reflux for 3 h.
The solvent was evaporated to dryness, and the residue was crys-
tallized by slow evaporation from methanol/water. Crystals suitable
for X-ray crystallography were obtained for complex Re-HL3.
Re-HL3: Yield: 22 mg (41%). tR = 15.6 min. IR (KBr): 2028, 1918,
1709, 1611 cm–1. 1H and 13C NMR data in Table 2.
C11H9N2O7ReS·CH3OH (531.5): calcd. C 27.12, H 2.47, N 5.27;
found C 26.75, H 2.77, N 5.20.
Re-HL4: Yield: 17 mg (33%). tR = 14.9 min IR (KBr): ν = 2029,
˜
1896, 1718, 1602 cm–1. 1H and 13C NMR data in Table 2.
C12H11N2O7ReS (513.49): calcd. C 28.07, H 2.16, N 5.46; found C
28.37, H 2.33, N 5.58.
Ethyl 2-(3-Ethoxy-3-oxopropylthio)-3-(1H-imidazol-4-yl)propanoate
(Et2L4): Ligand L4 was prepared according to the procedure given
above for L3; 3-mercaptopropanoic acid (456 mg, 4.3 mmol) was
1
used in the place of mercaptoacetic acid. Yield: 350 mg (41%). H
X-ray Crystal Structure Determination: Diffraction measurements
were made on a Crystal Logic Dual Goniometer diffractometer by
using graphite monochromated Mo-Kα radiation. Unit cell dimen-
sions were determined and refined by using the angular settings
of 25 automatically centered reflections in the range 11Ͻ2θϽ23°.
Intensity data were recorded by using a θ–2θ scan. Three standard
reflections monitored every 97 reflections showed less than 3%
variation and no decay. Lorentz, polarization and ψ-scan absorp-
tion corrections were applied by using the Crystal Logic software.
The structure was solved by direct methods with SHELXS-97[26]
and refined by full-matrix least-squares techniques on F with
SHELXL-97.[27]
NMR (300 MHz, CDCl3): δ = 9.15 (br. s, 1 H, NH), 7.57 (s, 1 H,
1-H), 6.86 (s, 1 H, 2-H), 4.09–4.24 (m, 4 H, CH2CH3), 3.64 (dd, J
= 8.5, 6.4 Hz, 1 H, 5-H), 3.22 (dd, J = 14.9, 8.6 Hz, 1 H, 4-H),
2.99 (dd, J = 14.8, 6.4 Hz, 1 H, 4-H), 2.86–2.94 (m, 2 H, 8-H),
2.56–2.65 (m, 2 H, 7-H), 1.26 (t, 3 H, CH2CH3), 1.25 (t, 3 H,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.36 (COOEt),
171.67 (COOEt), 134.77 (C-1), 133.63 (C-3), 118.18 (C-2), 61.27
(CH2CH3), 60.71 (CH2CH3), 46.64 (C-5), 34.51 (CH2), 29.18
(CH2), 26.56 (CH2), 14.12 (CH2CH3), 14.04 (CH2CH3) ppm (the
NMR numbering is shown in Scheme 2, with the exception of the
ethyl esters). C13H20N2O4S (300.37): calcd. C 51.98, H 6.71, N 9.33;
found C 51.69, H 6.87, N 9.21.
Re-L1: 2θmax = 50°; reflections collected/unique/used, 5307/4907
Syntheses of the Rhenium Complexes
[Rint = 0.0087]/4907; parameters refined, 441; Δ/σ = 0.002; [Δρ]max
/
Synthesis of fac-[Re(L1-NSO)(CO)3] (Re-L1): [NEt4]2[ReBr3(CO)3]
(154 mg, 0.2 mmol) was dissolved in methanol (10 mL), and a solu-
tion of ligand HL1 (40 mg, 0.2 mmol) in methanol (5 mL) was
added. The mixture was heated under reflux for 2 h. The solvent
was evaporated to dryness, and the residue was crystallized by slow
evaporation from methanol/water. Crystals suitable for X-ray crys-
tallography were obtained by slow evaporation from CH2Cl2/
[Δρ]min = 1.511/–0.665 e/Å3; R1/wR2 (all data) = 0.0284/0.0603. All
hydrogen atoms were located by difference maps and were refined
isotropically; all non-hydrogen atoms were refined anisotropically.
Re-HL2: 2θmax = 50°; reflections collected/unique/used, 3109/2896
[Rint = 0.0128]/2896; parameters refined, 251; Δ/σ = 0.001; [Δρ]max
/
[Δρ]min = 1.820/–1.309 e/Å3; R1/wR2 (all data) = 0.0374/0.0980. All
hydrogen atoms were located by difference maps and were refined
isotropically; all non-hydrogen atoms were refined anisotropically.
MeOH. Yield: 75 mg (81%). tR = 16.30 min. IR (KBr): ν = 2025,
˜
1926, 1894, 1639 cm–1. 1H and 13C NMR data in Table 1.
C12H10NO5ReS (466.47): calcd. C 30.90, H 2.16, N 3.00; found C
30.69, H 2.22, N 2.98.
Re-HL3: 2θmax = 50°; reflections collected/unique/used, 3006/2849
[Rint = 0.0428]/2849; parameters refined, 258; Δ/σ = 0.004; [Δρ]max
/
Synthesis of fac-[Re(HL2-NS)(Br)(CO)3] (Re-HL2): [NEt4]2[ReBr3-
(CO)3] (154 mg, 0.2 mmol) was dissolved in methanol (10 mL), and
a solution of ligand HL2 (42 mg, 0.2 mmol) in methanol (5 mL)
was added. The mixture was heated under reflux for 2 h. Crystals
[Δρ]min = 1.213/–1.362 e/Å3; R1/wR2 (all data) = 0.0352/0.0820. All
hydrogen atoms were located by difference maps and were refined
isotropically, except those of the methyl group of the methanol
solvate, which were introduced at calculated positions as riding on
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
7

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
D. Papagiannopoulou et al.
FULL PAPER
[9] H. He, M. Lipowska, X. Xu, A. T. Taylor, M. Carlone, L. G.
Marzilli, Inorg. Chem. 2005, 44, 5437–5446.
bonded atoms; all non-hydrogen atoms were refined anisotropi-
cally.
[10] O. Karagiorgou, G. Patsis, M. Pelecanou, C. P. Raptopoulou,
A. Terzis, T. Siatra-Papastaikoudi, R. Alberto, I. Pirmettis, M.
Papadopoulos, Inorg. Chem. 2005, 44, 4118–4120.
[11] D. Papagiannopoulou, G. Makris, C. Tsoukalas, C. P. Rapto-
poulou, A. Terzis, M. Pelecanou, I. Pirmettis, M. S. Papado-
poulos, Polyhedron 2010, 29, 876–880.
[12] O. Karagiorgou, D. Papagiannopoulou, P. Kyprianidou, G.
Patsis, A. Panagiotopoulou, C. Tsoukalas, C. P. Raptopoulou,
M. Pelecanou, I. Pirmettis, M. Papadopoulos, Polyhedron 2009,
28, 3317–3321.
[13] R. Schibli, R. La Bella, R. Alberto, E. Garcia-Garayoa, K.
Ortner, U. Abram, P. A. Schubiger, Bioconjugate Chem. 2000,
11, 345–351.
[14] L. G. Luyt, H. M. Bigott, M. J. Welch, J. A. Katzenellenbogen,
Bioorg. Med. Chem. 2003, 11, 4977–4989.
[15] Y. Liu, J. K. Pak, P. Schmutz, M. Bauwens, J. Mertens, H.
Knight, R. Alberto, J. Am. Chem. Soc. 2006, 128, 15996–
159967.
[16] H. He, J. E. Morley, B. Twamley, R. H. Groeneman, D.-K. Bu-
car, L. R. MacGillivray, P. D. Benny, Inorg. Chem. 2009, 48,
10625–10634.
CCDC-862474 (for Re-L1), -862475 (for Re-HL2), and -862476
(for Re-HL3) contains the supplementary 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.
Synthesis of Technetium Complexes 99mTc-L1–99mTc-HL4: A freshly
prepared solution of the fac-[99mTc(CO)3(H2O)3]+ precursor
(450 μL, 5–10 mCi/mL) at pH 7 was added to a vial containing a
solution of ligands HL1, H2L3, H2L4 (50 μL, 10–3 m or 10–4 m), or
a solution of HL2 (50 μL, 10–2 m). The vial was sealed, flushed
with N2 for 5 min and heated for 30 min at 75 °C. The reaction
mixture was analyzed by HPLC, which revealed the formation of a
single product: 99mTc-L1, tR = 16.7 min; 99mTc-L2, tR = 18.48 min;
99mTc-HL3, tR = 15.7; 99mTc-HL4, tR = 15.1 min. The ligand con-
centrations in the labeling mixture that led to quantitative forma-
tion (Ն95%) of 99mTc-L1, 99mTc-HL3 and 99mTc-HL4 were as low
as 10–4 m, and at concentration of 10–5 m, a radiochemical yield
(RCY) of approximately 80–90% was achieved. The RCY for
99mTc-L2 was 95% at 10–3 m ligand concentration in the reaction
mixture.
[17] H. He, M. Lipowska, X. Xu, A. T. Taylor, L. G. Marzilli, Inorg.
Chem. 2007, 46, 3385–3394.
[18] D. Papagiannopoulou, C. Tsoukalas, G. Makris, C. P. Rapto-
poulou, V. Psycharis, L. Leondiadis, E. Gniazdowska, P. Koz´-
min´ski, L. Fuks, M. Pelecanou, I. Pirmettis, M. S. Papado-
poulos, Inorg. Chim. Acta 2011, 378, 333–337.
[19] R. H. Fish, J. J. Windle, W. Gaffield, J. R. Scherer, Inorg. Chem.
1973, 12, 855–859.
[20] R. Alsfasser, R. Vaneldik, Inorg. Chem. 1996, 35, 628–636.
[21] S. Alves, A. Paulo, J. D. G. Correia, Â. Domingos, I. Santos,
J. Chem. Soc., Dalton Trans. 2002, 4714–4719.
[22] Vitor, S. Alves, J. D. G. Correia, A. Paulo, I. Santos, J. Or-
ganomet. Chem. 2004, 689, 4764–4774.
[23] P. Kyprianidou, C. Tsoukalas, G. Patsis, D. Papagiannopoulou,
N. Nikolic, D. Jankovic, D. Djokic, C. P. Raptopoulou, M. Pe-
lecanou, M. Papadopoulos, I. Pirmettis, Polyhedron 2009, 28,
3171–3176.
[24] R. Alberto, A. Egli, U. Abram, K. Hegetschweiler, V. Gram-
lich, P. A. Schubiger, J. Chem. Soc., Dalton Trans. 1994, 2815–
2820.
In Vitro Histidine and Cysteine Challenge of 99mTc Complexes: The
procedure was the same for all 99mTc complexes; the HPLC-puri-
fied 99mTc complex (0.2 mL) was mixed with a solution of 1 mm
histidine or cysteine in 0.1 m PBS, pH 7.4 (0.8 mL), and the mixture
was incubated at 37 °C for 24 h. The mixture was analyzed by
HPLC at 1, 4 and 24 h intervals.
[1] M. D. Bartholomä, A. S. Louie, J. F. Valliant, J. Zubieta,
Chem. Rev. 2010, 110, 2903–2920.
[2] S. S. Jurisson, J. D. Lydon, Chem. Rev. 1999, 99, 2205–2218.
[3] A. Mahmood, A. G. Jones in Handbook of Radiopharmaceuti-
cals: Radiochemistry and Applications (Eds M. J. Welch, C. S.
Redvanly), John Wiley and Sons Ltd., Chichester, W. Sussex,
2003, pp. 323–362.
[4] R. K. Hom, J. A. Katzenellenbogen, Nucl. Med. Biol. 1997, 24,
485–498.
[25] S. Edlbacher, H. von Bidder, Z. Physiol. Chem. 1942, 276, 126–
[5] R. Alberto, R. Schibli, A. Egli, P. A. Schubiger, U. Abram,
T. A. Kaden, J. Am. Chem. Soc. 1998, 120, 7987–7988.
[6] R. Alberto, Top. Curr. Chem. 2005, 252, 1–44.
[7] R. Schibli, P. A. Schubiger, Eur. J. Nucl. Med. 2002, 29, 1529–
1542.
[8] D. R. Van Staveren, P. D. Benny, R. Waibel, P. Kurz, J.-K. Pak,
R. Alberto, Helv. Chim. Acta 2005, 88, 447–460.
129.
[26] G. M. Sheldrick, SHELXS-97, Structure Solving Program,
University of Göttingen, Germany, 1997.
[27] G. M. Sheldrick, SHELXS-97, Crystal Structure Refinement,
University of Göttingen, Germany, 1997.
Received: January 19, 2012
Published Online: ᭿
8
www.eurjic.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 0000, 0–0

Job/Unit: I20056
/KAP1
Date: 04-04-12 16:14:11
Pages: 9
RhI and TcI Tricarbonyl Complexes with [NSO]-Type Chelators
Re/Tc Radiochemistry
G. Makris, O. Karagiorgou,
D. Papagiannopoulou,*
A. Panagiotopoulou, C. P. Raptopoulou,
A. Terzis, V. Psycharis, M. Pelecanou,
I. Pirmettis, M. S. Papadopoulos ...... 1–9
fac-[Re(NSO)(CO)3] complexes were syn-
thesized with varying chelate ring size and
geometry. The order of complex formation
preference is: linear (6,5-membered rings)
linear (two six-membered rings). The anal-
ogous fac-[99mTc(NSO)(CO)3] complexes
were prepared in high yield and were stable
in solution.
Rhenium(I) and Technetium(I) Tricarbonyl
Complexes with [NSO]-Type Chelators:
Synthesis, Structural Characterization, and
Radiochemistry
Ͼ
tripodal (6,5,7-membered rings) Ͼ
Keywords: Rhenium / Technetium / Carb-
onyl ligands / Radiopharmaceuticals / NSO
ligands
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
9