A 'preformed chelate approach' model for coupling amine-modified rhenium and technetium '3+1' mixed ligand complexes to carboxylate residues: Crystal structure of ReO[CH3SCH2CH2N(CH2CH 2S)2][p-SC6H4NH2]

Article abstract of DOI:10.1016/S0277-5387(99)00286-7

Selected '3+1' mixed ligand oxorhenium and oxotechnetium complexes containing the SNS/S donor atom set have been modified by introduction of a bifunctional amine anchor on the p-position of the thiophenolato monodentate ligand. A representative series of complexes containing several tridentate ligands was prepared both at macromolar (Re complexes) and nanomolar (^99mTc complexes) amounts. Coupling of these complexes to activated carboxylate groups was performed according to the 'preformed chelate approach' using benzoyl chloride as a model molecule. Coupling yields were high both at nanomolar and millimolar metal concentration, as revealed by high-performance liquid chromatographic analysis of ^99mTc and Re species adopting parallel radiometric and photometric detection modes. All Re compounds have been characterized by classical analytical methods. In addition, the structures of representative parent ReO[CH₃SCH₂CH₂N(CH₂CH ₂S)₂][p-SC₆H₄NH₂] and daughter ReO[CH₃SCH₂CH₂N(CH₂CH ₂S)₂][p-SC₆H₄NHCOC₆H ₅] complexes were solved by X-ray crystallography. Both compounds adopt a distorted trigonal bipyramidal geometry around rhenium, wherein the oxo group and the sulfur atoms of the SNS ligand occupy the equatorial plane and the nitrogen atom and the sulfur of the monothiol are located at the apical positions trans to each other. Elsevier Science Ltd.

Full text of DOI:10.1016/S0277-5387(99)00286-7

Polyhedron 18 (1999) 3545–3552
www.elsevier.nl/locate/poly
A ‘preformed chelate approach’ model for coupling amine-modified
rhenium and technetium ‘311’ mixed ligand complexes to carboxylate
residues
Crystal structure of ReO[CH3SCH2CH2N(CH2CH2S)2][p-SC6H4NH2] and
ReO[CH3SCH2CH2N(CH2CH2S)2][p-SC6H4NHCOC6H5]
Theodosia Mainaa, Charalambos Tsoukalasa, Georgios Patsisa, Ioannis Pirmettisa, Berthold Nocka,
Minas Papadopoulosa, Catherine Raptopouloub, Aris Terzisb, Efstratios Chiotellisa ,
*
aInstitute of Radioisotopes–Radiodiagnostic Products, NCSR ‘Demokritos’, 15310 Ag. Paraskevi Attikis, Athens, Greece
bInstitute of Materials Science, NCSR ‘Demokritos’, 15310 Ag. Paraskevi Attikis, Athens, Greece
Received 7 July 1999; accepted 8 September 1999
Abstract
Selected ‘311’ mixed ligand oxorhenium and oxotechnetium complexes containing the SNS/S donor atom set have been modified by
introduction of a bifunctional amine anchor on the p-position of the thiophenolato monodentate ligand. A representative series of
complexes containing several tridentate ligands was prepared both at macromolar (Re complexes) and nanomolar (99mTc complexes)
amounts. Coupling of these complexes to activated carboxylate groups was performed according to the ‘preformed chelate approach’
using benzoyl chloride as a model molecule. Coupling yields were high both at nanomolar and millimolar metal concentration, as revealed
by high-performance liquid chromatographic analysis of 99mTc and Re species adopting parallel radiometric and photometric detection
modes. All Re compounds have been characterized by classical analytical methods. In addition, the structures of representative parent
ReO[CH3SCH2CH2N(CH2CH2S)2][p-SC6H4NH2] and daughter ReO[CH3SCH2CH2N(CH2CH2S)2][p-SC6H4NHCOC6H5] complexes
were solved by X-ray crystallography. Both compounds adopt a distorted trigonal bipyramidal geometry around rhenium, wherein the oxo
group and the sulfur atoms of the SNS ligand occupy the equatorial plane and the nitrogen atom and the sulfur of the monothiol are
located at the apical positions trans to each other.
1999 Elsevier Science Ltd. All rights reserved.
Keywords: Mixed ligand approach; Oxotechnetium; Oxorhenium; Preformed chelate approach
1. Introduction
The dominance of 99mTc radiopharmaceuticals in nu-
clear medicine practice is based on its ideal nuclear
properties (t1 / 256 h, gamma photons 140 keV) on the one
hand, and its cost effectiveness and wide availability
through commercial 99Mo/ 99mTc generator systems on the
other [1–3,7]. Therefore, a main challenge in radiophar-
maceutical design today is the development of highly
specific, site-directed 99mTc probes. However, the incorpo-
ration of 99mTc into a small bioactive molecule is not an
easy task as it often requires tethering of a metal chelating
agent to its backbone [4–6,8,9]. This coupling proceeds
via a bifunctional anchor present on the ligand backbone –
often an amine or a carboxylate unit – either after
(‘preformed chelate approach’) or prior to (‘post-conjuga-
tion approach’) complex formation [6,9]. The introduction
of the bulky metal chelate has a drastic influence on the
The field of nuclear medicine is expanding toward the
early stage diagnosis and therapy of disease at the molecu-
lar level. As a result, the demand for effective site-directed
molecular probes, that labeled with the appropriate
radionuclide will carry the radioactivity selectively to
target tissues, is worldwide recognized. For this purpose,
efforts are currently focused on the development of novel
specific radiopharmaceuticals, e.g. labeled monoclonal
antibodies, receptor seeking peptides or bioactive drugs,
that can interact efficiently at the molecular level with high
affinity low capacity systems in vivo [1–6].
*Corresponding author. Tel.: 130-1-650-3908; fax: 130-1-654-3526.
E-mail address: mainathe@mail.demokritos.gr (E. Chiotellis)
0277-5387/99/$ – see front matter
PII: S0277-5387(99)00286-7
1999 Elsevier Science Ltd. All rights reserved.

3546
T. Maina et al. / Polyhedron 18 (1999) 3545–3552
physicochemical characteristics of the bioactive molecule,
which is usually small [6]. Several bifunctional chelating
agents have been used for coupling to specifically acting
compounds, mainly tetradentate ligands suitable for ox-
otechnetium and oxorhenium [10]. The time consuming
synthetic routes involved in the above strategy can be
facilitated by the application of bifunctional mixed ligand
systems.
In this work we propose the use of representative ‘311’
mixed ligand oxotechnetium and oxorhenium complexes of
the SNS/S type for coupling to activated carboxylate
groups via an amine bifunctional anchor introduced on
the common monothiolate ligand. The synthesis and
characterization is performed by variation of the trid-
entate SNS ligand for the following complexes:
IR spectra were recorded as KBr pellets in the range
4000–500 cm21 on a Perkin-Elmer 1600FT-IR spec-
trophotometer and were referenced to polystyrene. The H
1
NMR spectra were recorded on a Bruker FT-NMR/250
AF spectrometer using tetramethyl silane (TMS) as an
internal standard. Elemental analyses were performed on a
Perkin-Elmer 2400/II automated analyzer. For thin layer
chromatography silica gel coated aluminium F254 sheets
from Merck were used. High performance liquid chroma-
tography (HPLC) analyses were performed on a Waters
chromatograph equipped with the 600E solvent delivery
system. A LiChrospher 100 RP C-18 (10 mm, 4.03250
mm) column from Merck was eluted at a flow-rate of 1.0
ml min21 using 2% triethylammonium phosphate (TEAP)
buffer pH 7.4/EtOH as the eluent applying the following
gradient system: 3 to 20 min from 100 to 30% TEAP
buffer; 20 to 30 min 30% TEAP buffer isocratic. Detection
of complexes was accomplished by a Waters 991 photo-
diode array detector (UV trace for Re and the ligands) and
a Beckman 171 detector (gamma trace for 99mTc).
ReO[CH3SCH2CH2N(CH2CH2S)2][p-SC6H4NH2],
ReO[C2H5SCH2CH2N(CH2CH2S)2][p-SC6H4NH2],
1,
2,
ReO[(C2H5)2NCH2CH2N(CH2CH2S)2][p-SC6H4NH2], 3
and ReO[C2H5N(CH2CH2S)2][p-SC6H4NH2], 4, as well
as for their 99mTc analogs 19, 29, 39 and 49. Coupling of the
above complexes to activated carboxylate groups is then
investigated using C6H5COCl as a model molecule accord-
ing to the ‘preformed chelate approach’ at both millimolar
(Re) and nanomolar (99mTc) level. The daughter amide
complexes thereby formed are: ReO[CH3SCH2CH2N-
(CH2CH2S)2][p-SC6H4NHCOC6H5], 5, ReO[C2H5SCH2-
CH2N(CH2CH2S)2][p-SC6H4NHCOC6H5], 6, ReO-
[(C2H5)2NCH2CH2N(CH2CH2S)2][p - SC6H4NHCOC6-
H5], 7 and ReO[C2H5N(CH2CH2S)2][p-SC6H4NHCO-
C6H5], 8, as well as their 99mTc counterparts, complexes
59, 69, 79 and 89. The structure of complexes 1 and 5 as
elaborated by X-ray crystallography is also reported.
2.2. Synthesis of rhenium complexes
2.2.1. ReO[CH3SCH2CH2N(CH2CH2S)2 ][p-SC6H4NH2 ], 1
To a 0.5-M AcONa solution in MeOH (4 ml)
ReVOCl3(PPh3)2
(166.6
mg,
0.2
mmol),
CH3SCH2CH2N(CH2CH2SH)2 (42 mg, 0.2 mmol) and
p-aminothiophenol (25 mg, 0.2 mmol) were suspended
under stirring. The mixture was refluxed until a clear
solution formed. After addition of CH2Cl2 the organic
phase was washed with H2O, dried and concentrated to a
small volume. Red crystals separated by slow evaporation
from CH2Cl2 /MeOH. Yield: 75 mg (70%). Rf
(SiO2:MeCN:MeOH:CH2Cl2:Et2NH; 75:3.5:15:6.5):0.7;
elemental analysis, % found: C, 29.50; H, 4.20; N, 5.65; S,
24.17; % calculated for C13H21N2OReS4: C, 29.14; H,
3.95; N, 5.23; S, 23.94; UV–Vis (lmax /nm): 259, 447; IR
(KBr, nmax /cm21): 3420, 3337, 2963, 2914, 1621, 1593,
1289, 947 (Re=O str), 823; 1H NMR dH (250 MHz,
2. Experimental
2.1. General
Reagent grade chemicals and HPLC solvents were
obtained from commercial sources (Fluka, or Aldrich
Chemicals), as well as p-aminothiophenol and ben-
*
CDCl3, Me4Si): 2.10 (3H, s, CH3 S) 2.86 (2 H, t,
*
*
*
CH2 CH2N–Re), 2.75–3.00 (4H, m, exo, NCH2 CH2 S),
zoylchloride.
Synthesis
and
purification
of
*
3.45 (2H, m, endo, NCH2 CH2S), 3.60 (2H, m, endo,
CH3SCH2CH2N(CH2CH2SH)2, C2H5SCH2CH2N(CH2C-
H2SH)2, (C2H5)2NCH2CH2N(CH2CH2SH)2 [11], and
C2H5N(CH2CH2SH)2 [12,13], ligands were performed
according to reported protocols. Rhenium was purchased
from Aldrich as KReO4 and was converted to the
ReVOCl3(PPh3)2 precursor according to a described meth-
od [14]. Complexes 3 and 4 were available from a previous
study [15].
*
*
NCH2CH2 S), 3.68 (2H, b, NH2), 3.93 (2H, t, CH2CH2 N–
Re), 6.70 (2H, dd, m-Ph-H), 7.45 (2H, dd, o-Ph-H).
2.2.2. ReO[C2H5SCH2CH2N(CH2CH2S)2 ][p-SC6H4NH2 ], 2
This complex was prepared by reacting equimolar
amounts of C2H5SCH2CH2N(CH2CH2SH)2 (45 mg, 0.2
mmol) and p-aminothiophenol (25 mg, 0.2 mmol) on the
ReVOCl3(PPh3)2 (166.6 mg, 0.2 mmol) precursor in a
similar manner as for 1. Red crystals separated by slow
evaporation from CH2Cl2 /MeOH. Yield: 82 mg (75%). Rf
(SiO2:MeCN:MeOH:CH2Cl2:Et2NH; 75:3.5:15:6.5):0.7;
elemental analysis, % found: C, 30.79; H, 4.39; N, 5.65; S,
22.95; % calculated for C14H23N2OS4Re: C, 30.58; H,
4.22; N, 5.10; S, 23.32; UV–Vis (lmax /nm): 258, 445; IR
[
99mTc]NaTcO4 was obtained in physiological saline as
a commercial 99Mo/ 99mTc generator eluate (Cis Interna-
tional). Commercial glucoheptonate kits containing a
lyophilized mixture of calcium glucoheptonate (200 mg)
and SnCl2 (0.2 mg) (Gluco/Demoscan, NCSR ‘Demok-
ritos’) were used.

T. Maina et al. / Polyhedron 18 (1999) 3545–3552
3547
(KBr, nmax /cm21): 3424, 3338, 2953, 2916, 1611, 1593,
1289, 941 (Re=O str), 821; 1H NMR dH (250 MHz,
2.2.5. ReO[(C2H5 )2NCH2CH2N(CH2CH2S)2 ][p-
SC6H4NHCOC6H5 ], 7
*
CDCl3, Me4Si): 1.30 (3H, t, CH3 CH2S), 2.50–2.90 (6H,
This
complex
was
prepared
by
reacting
*
*
*
m, CH3CH2 S, exo, NCH2 CH2 S), 3.20–3.55 (4H, m,
ReO[C2H5NCH2CH2N(CH2CH2S)2][p-SC6H4NH2] (112
mg, 0.2 mmol) and C6H5COCl (112 mg, 0.8 mmol) in a
similar manner as for 5. Green crystals separated by slow
evaporation from CHCl3 /EtOH. Yield: 113 mg (85%). Rf
(SiO2:MeCN:MeOH:CH2Cl2:Et2NH, 75:3.5:15:6.5):0.8;
elemental analysis, % found: C, 41.77; H, 5.00; N, 6.21; S,
14.33%; calculated for C23H32N3O2ReS3: C, 41.55; H,
4.85; N, 6.32; S, 14.42%; UV–Vis (lmax /nm): 271, 427,
3259, 2963, 2929, 2800, 1641, 1586, 1288, 942 (Re=O
str), 830, 703, 643, 1H NMR dH (250 MHz, CDCl3,
*
*
endo, NCH2 CH2 S), 3.67 (2H, b, NH2), 3.88 (2H, t,
*
SCH2CH2 N–Re), 6.65 (2H, dd, m-Ph-H), 7.40 (2H, dd,
o-Ph-H).
2.2.3. ReO[CH3SCH2CH2N(CH2CH2S)2 ][p-
SC6H4NHCOC6H5 ], 5
To a solution of ReO[CH3SCH2CH2N(CH2CH2S)2][p-
SC6H4NH2] (107 mg, 0.2 mmol) and diisopropylethyl-
amine (77.5 mg, 0.6 mmol) in CHCl3 a solution of
C6H5COCl (112 mg, 0.8 mmol) in CHCl3 was added
dropwise under stirring. After 5 min, aliquots of this
*
Me4Si): 1.05 (6H, t, CH3 CH2N), 2.57 (4H, q,
*
*
CH3CH2 N), 2.85 (2H, t, CH2 CH2N–Re), 2.75–3.00 (4H,
*
*
m, exo, NCH2 CH2 S), 3.38–3.70 (4H, m, endo,
*
*
*
NCH2 CH2 S), 3.90 (2H, t, CH2CH2 N–Re), 7.50–7.90
mixture
were
analyzed
by
TLC
(SiO2;
(9H, m, aromatic).
MeCN:MeOH:CH2Cl2:Et2NH; 75:3.5:15:6.5) for follow-
ing the completion of the reaction. The organic phase was
washed with H2O, dried, and concentrated to a small
volume. After addition of some EtOH and slow evapora-
tion of the solvents at ambient temperature the product
separated as green crystals. Yield: 102 mg (80%). Rf
(SiO2:MeCN:MeOH:CH2Cl2:Et2NH; 75:3.5:15:6.5):0.8;
m.p. (from MeOH/CH2Cl2): 209–2108C; elemental analy-
sis, % found: C, 37.81; H, 3.72; N, 4.26; S, 19.85; %
calculated for C20H25N2O2ReS4: C, 37.54; H, 3.94; N,
4.38; S, 20.04; UV–Vis (lmax /nm): 271, 423; IR (KBr,
nmax /cm21): 3373, 2974, 2919, 1664, 1580, 1305, 943
(Re=O str), 831, 707; 1H NMR dH (250 MHz, CDCl3,
2.2.6. ReO[C2H5N(CH2CH2S)2 ][p-SC6H4NHCOC6H5 ], 8
The
complex
was
prepared
by
reacting
ReO[C2H5N(CH2CH2S)2][p-SC6H4NH2] (98 mg, 0.2
mmol) and C6H5COCl (112 mg, 0.8 mmol) in a similar
manner as for 5. Green crystals separated by slow evapora-
tion from CHCl3 /EtOH. Yield: 95 mg (80%). Rf
(SiO2:MeCN:MeOH:CH2Cl2:Et2NH; 75:3.5:15:6.5):0.8;
elemental analysis, % found: C, 38.15; H, 3.10; N, 4.35; S,
16.30; % calculated for C19H23N2O2ReS3: C, 38.43; H,
3.90; N, 4.72; S, 16.20; UV–Vis (lmax /nm): 271, 425; IR
(KBr, nmax /cm21): 3291, 2971, 2960, 2927, 1645, 1578,
1
*
*
Me4Si): 2.20 (3H, s, CH3 S), 2.92 (2H, t, SCH2 CH2NRe),
1288, 941 (Re=O str), 816, 740, 696; H NMR dH (250
*
*
2.6–3.0 (4H, m, exo, NCH2 CH2 S), 3.3–3.6 (4H, m, endo,
*
MHz, CDCl3, Me4Si): 1.40 (3H, t, CH3 CH2N), 2.60–2.95
*
*
*
NCH2 CH2 S), 4.0 (2H, t, SCH2CH2 NRe), 7.5–7.8 (9H,
*
*
(4H, m, exo, NCH2 CH2 S), 3.12–3.65 (4H, m, endo,
m, aromatic).
*
*
*
NCH2 CH2 S), 3.95 (2H, q, CH3CH2 N–Re), 7.50–7.85
(9H, m, aromatic).
2.2.4. ReO[C2H5SCH2CH2N(CH2CH2S)2 ][p-
2.3. Synthesis of 99mTc complexes
SC6H4NHCOC6H5 ], 6
The analogous complexes: 19 99mTcO[CH3SCH2CH2N-
(CH2CH2S)2][p-SC6H4NH2], 29 99mTc[C2H5SCH2CH2N-
(CH2CH2S)2][p-SC6H4NH2], 39 99mTc[(C2H5)2NCH2-
CH2N(CH2CH2S)2] [p-SC6H4NH2] and 49 99mTcO-
[C2H5N(CH2CH2S)2][p-SC6H4NH2] were prepared at the
tracer level as previously described for 39 and 49 [15]. Briefly,
to a centrifuge tube CH3SCH2CH2N(CH2CH2SH)2 (4.2
mg, 0.02 mmol) and p-aminothiophenol (2.5 mg, 0.2
mmol) were placed and a solution of 99mTc-glucoheptonate
(1.0 ml, 3–10 mCi) was added. The mixture was stirred
vigorously on a vortex mixer and was then exctracted in
CH2Cl2 (331.5 ml). The combined organic extracts were
dried over MgSO4, which was then filtered off. The
radioactivity content of both the aqueous and organic
phases was measured separately [Yield (as determined by
organic extraction): .85%].
To a solution of ReO[C2H5SCH2CH2N(CH2CH2S)2]-
[p-SC6H4NH2] (110 mg, 0.2 mmol) and diisopropyl-
ethylamine (77.5 mg, 0.6 mmol) in CHCl3 a solution
of C6H5COCl (112 mg, 0.8 mmol) in CHCl3 was added
and the reaction proceeded in a similar manner as for
5. Green crystals separated by slow evaporation from
CHCl3 /EtOH.
Yield:
104
mg
(80%).
Rf
(SiO2:MeCN:MeOH:CH2Cl2:Et2NH; 75:3.5:15:6.5):0.8;
elemental analysis, % found: C, 38.77; H, 4.23; N, 4.01; S,
19.22; % calculated for C21H27N2O2ReS4: C, 38.57; H,
4.16; N, 4.28; S, 19.61; UV–Vis (lmax /nm): 271, 423; IR
(KBr, nmax /cm21): 3424, 2964, 2925, 2867, 1641, 1584,
943 (Re=O str), 827, 704; H NMR dH (250 MHz, CDCl3,
Me4Si): 1.2 (3H, t, CH3 CH2S), 2.6 (2H, q, CH3CH2 S),
2.7–3.0 (4H, mm, exo, NCH2 CH2 S), 2.95 (2H, t,
1
*
*
*
*
*
*
*
SCH2 CH2NRe), 3.2–3.5 (4H, mm, endo, NCH2 CH2 S),
3.95 (2H, t, SCH2CH2 NRe), 7.50–7.90 (9H, m, aromatic).
The 99mTc coupled complexes 59, 69, 79and 89 were
*

3548
T. Maina et al. / Polyhedron 18 (1999) 3545–3552
prepared as follows for 59: Complex 19 was first prepared
as described above and then purified by HPLC. The eluent
was concentrated to a small volume under a mild stream of
nitrogen and transfered into a centrifuge tube, to which
C6H5COCl (1 mg) was added. The mixture was stirred
vigorously on a vortex mixer for 5 min and was then
analyzed by HPLC.
HPLC analysis was performed as described above. After
co-injection of analogous Re and 99mTc complexes the
corresponding UV/Vis and gamma HPLC profiles were
compared.
were located by difference maps and refined isotropically,
while all non-H atoms were refined anisotropically. For 1:
reflections
collected/unique/used,
3325/3196[Rint 5
0.0255]/3196; parameters refined, 274; [D/s] max5
0.020; [Dr] max/[Dr] min50.622/ 20.768 e A23; R1/
˚
wR2 (all data)50.0327/0.0656. For 5: reflections col-
lected/unique/used, 4207/4011[Rint 50.0080]/4011; pa-
rameters refined, 362; [D/s] max50.005; [Dr] max/
[Dr] min50.518/ 20.703 e A23; R1/wR2 (all data)5
˚
0.0171/0.0496.
2.4. X-ray diffraction data and crystal structure
3. Results and discussion
determination and refinement
In this work representative bifunctional oxometal ‘311’
mixed ligand complexes of the SNS/S combination were
synthesized and characterized both at millimolar (Re
complexes 1 and 2) and nanomolar (99mTc complexes
19–49) concentration. In these compounds a bifunctional
amine anchor is introduced on the para position of the
phenylthiolate coligand. In this way coupling to activated
carboxylate residues was pursued using C6H5COCl as a
model molecule. Thus, the daughter Re complexes 5–8
were easily generated under mild conditions from their
respective parents (Re complexes 1–4) in millimolar
amounts and characterized by classical methods of analy-
sis. Similarly, their 99mTc counterparts 59–89 were gener-
ated at tracer level from their respective parents and their
structure assigned after HPLC chromatographic compari-
son to the respective Re analogs after adopting parallel
radiometric and photometric detection.
The oxorhenium complexes 1, 2, 3 and 4 were syn-
thesized by reacting equimolar amounts of tridentate and
p-aminophenylthiol ligands with ReVOCl3(PPh3)2 precur-
sor, as shown in Scheme 1. Given that the thiolate groups
are deprotonated upon binding to the MO31 core, neutral
complexes are finally produced. Complexes 1 and 2, are
newly synthesized, while the synthesis and chemical
characterization of complexes 3 and 4 has been reported
elsewhere [15]. Compounds 1 and 2 were purified by
extraction in CH2Cl2 and slow crystallization from
CH2Cl2 /MeOH. They are crystalline solids, soluble in
CH2Cl2 and CHCl3, slightly soluble in EtOH and MeOH
and insoluble in pentane and water. They are stable in solid
state as well as in organic solutions for a period of months.
Coupling of complexes 1, 2, 3 and 4 with C6H5COCl
affords the daughter compounds 5–8 in high yields, as
shown in Scheme 1. The latter were purified by crys-
tallization from CHCl3 /EtOH. They are crystalline solids
with physicochemical properties similar to those of their
parent analogs.
A red (0.1030.2030.40 mm) crystal of 1 and a green
(0.1030.1530.40 mm) of 5 were mounted in air. Diffrac-
tion measurements were made on a Crystal Logic Dual
Goniometer diffractometer using graphite monochromated
Mo Ka radiation. Unit cell dimensions were determined
and refined by using the angular settings of 25 auto-
matically centered reflections in the range 118,2u,238
and they appear in Table 1. Intensity data were recorded
using a u-2u scan. For 1: 2u max5508, scan speed
3.58 min21, scan range 2.41a1a2 separation; For 5: 2u
max5508, scan speed 3.28 min21, scan range 2.41a1a2
separation. Three standard reflections monitored every 97
reflections showed less than 3% variation and no decay.
Lorentz, polarization and c-scan absorption corrections
were applied using Crystal Logic software. The structures
were solved by direct methods using SHELXS-86 [16] and
refined by full-matrix least-squares techniques on F2 with
SHELXL-93 [17]. All hydrogen atoms, in both structures,
Table 1
Summary of crystal, intensity collection and refinement data
Complex 1
Complex 5
Formula
C13H21N2OReS4
535.76
13.197(7)
9.695(4)
C20H25N2O2ReS4
639.86
Formula weight
˚
a (A)
9.370(5)
10.403(6)
12.883(7)
83.58(2)
88.82(2)
66.21(2)
1142(1)
˚
b (A)
˚
c (A)
14.657(7)
a (8)
b (8)
g (8)
104.69(1)
3
˚
V (A )
1814(1)
Z
4
2
Dcalcd /Dmeasd (mg m23
Space group
Temperature (K)
)
)
1.962/1.94
P21 /n
298
Mo Ka (0.71073)
7.159
1.861/1.84
P-1
298
Mo Ka (0.71073)
5.708
˚
Radiation, l (A)
Abs. coeff, m, (mm21
Octants collected
GoF on F2
6h, 2 k, 2 l
1.056
6h, 6k, l
1.048
Formation of complexes 1, 2 and 5–8 was established
by elemental analysis, IR, UV–Vis and 1H NMR spec-
troscopies. Thus, they all show an intensive band at 941–
947 cm21 assigned to the Re=O stretching vibration. These
R1/wR2
0.0246/0.0609a
0.0160/0.0486b
a For 2727 reflections with I . 2s(I).
b For 3840 reflections with I . 2s(I).

T. Maina et al. / Polyhedron 18 (1999) 3545–3552
3549
Scheme 1. Preparation of Re and 99mTc complexes and coupling to C6H5COCl.
values are consistent with those reported for several other
well-characterized syn monooxo complexes of rhenium
[18–24]. The aromatic monothiolate coligand is present in
the final complexes, as evidenced by the peaks between
821 and 819 cm21. Complexes 1 and 2 show a double
peak in the region 3337–3422 cm21, characteristic of the
primary amine. The presence of the C6H5CO-fragment in
5–8 complexes is demonstrated on the one hand by the
signals between 643 and 742 cm21 and on the other hand
by those between 1641 and 1665 cm21 originating from
the amide bond. The UV–Vis spectra show maxima at 445
and 448 nm for the parent rhenium complexes and at the
range 424–430 nm for the respective amide compounds,
characteristic of ReVO–S charge transfer band(s), as re-
ported for analogous rhenium complexes [15–21].
deshielding effect compared to the exo protons, as being
closer to the core. By coordination the amine substituent
may be locked in either a syn or an anti configuration in
respect to the oxometal core and consequently two isomers
1
are theoretically expected. However, correlation of the H
NMR data to that of reported SNS/S rhenium analogs is
easily achieved and is consistent with the formation of
only the syn isomers in a trigonal bipyramidal array around
the metal [15–21]. Complexes 5–8 display a more compli-
cated pattern in the aromatic region than the characteristic
double of doublets of complexes 1 and 2, due to the added
aromatic ring.
X-ray structure analysis has been performed for com-
plexes 1 and 5 and the pertinent ORTEP diagrams are
shown in Figs. 1 and 2, respectively, whereas selected
bond distances and angles are listed in Table 2. The
coordination geometry about the rhenium atom, in both
complexes, is distorted trigonal bipyramidal with the oxo
group and the sulfur atoms of the tridentate ligand forming
the basal plane and the apical positions occupied by the
nitrogen atom and the sulfur of the monodentate thiol. The
two complexes correspond to the syn isomer with the
N-substituent positioned cis to the oxo group. The tri-
gonality index, t, calculated for both compounds is 0.61
1
The H NMR spectra show the expected signals, which
can be unambiguously assigned. In particular, all parent
ligand peaks – except the three thiolate protons – are
found shifted downfield. The deshielding effect of the
ReO31 core, due to the anisotropy caused by the circulat-
ing electrons of the ReO bond, is related to the distance
from the core. Accordingly, the peaks of the vicinal
protons are strongly shifted downfield. Moreover the
protons, that are endo to the ReO core, display a stronger

3550
T. Maina et al. / Polyhedron 18 (1999) 3545–3552
Table 2
˚
Selected bond distances (A) and angles (8)
Complex 1
Complex 5
Bond distances
Re–O(1)
Re–N(1)
Re–S(1)
Re–S(2)
Re–S(4)
1.691(4)
2.205(4)
2.266(2)
2.286(2)
2.299(2)
1.704(2)
2.224(3)
2.267(1)
2.290(2)
2.306(1)
Bond angles
O(1)–Re–N(1)
O(1)–Re–S(1)
N(1)–Re–S(1)
O(1)–Re–S(2)
N(1)–Re–S(2)
S(1)–Re–S(2)
O(1)–Re–S(4)
N(1)–Re–S(4)
S(1)–Re–S(4)
S(2)–Re–S(4)
96.6(2)
118.4(2)
83.5(1)
119.0(1)
83.0(1)
122.1(1)
104.7(1)
158.5(1)
83.8(1)
94.9(1)
119.8(1)
83.3(1)
119.6(1)
83.5(1)
119.9(1)
104.8(1)
160.3(1)
88.3(1)
89.1(1)
85.3(1)
Fig. 1. ORTEP diagram of 1.
˚
and 0,67 A for 1 and 5, respectively. Rhenium is almost
displaced from the mean plane of the remaining four atoms
(displacements 0.57 and 0.65 A for C2 and C3, respective-
ly, in both structures).
˚
coplanar with the atoms of the basal plane of the trigonal
bipyramid, lying 0.087 and 0.100 A out of the plane
˚
toward the monodentate thiol, in 1 and 5, respectively. The
torsion angles of the tridentate chelating agent (S1–C1–
C2–N1 and N1–C3–C4–S2) are 44.52 and 52.498 for 1
and 44.22 and 53.788 for 5. The two five-membered rings
in the coordination sphere adopt the stable envelope
configuration with the carbon atoms adjacent to N1
A feature, which should be examined in 5, is the
planarity of the amide unit, which is defined by the torsion
angles v1 5C–C–N–C, v2 5O–C–N–H and v3 5O–C–
N–C and the values of the calculated parameters t 5 (v1 1
v2)/2(uv1 2 v2u , p), xN 5 (v2 2 v3 1 p) mod 2p and
xC 5 (v1 2 v3 1 p) mod 2p, where xN and xC represent
the out-of-plane bending at the amide nitrogen or carbon,
respectively [25]. In our case, the three torsion angles
v1 5C15–C14–N2–C11, v2 5O2–C14–N2–HN2 and
v3 5O2–C14–N2–C11 take the values 2167.74,
2168.80 and 12.008, respectively. Thus, the calculated
parameters are: t52168.278, xN 520.88 and xC 50.268,
indicating that the trans amide group is planar.
The pendant amine group of the monothiol in 1 is
H-bonded to the sulfur atoms S2 and S3 of the tridentate
ligand (Table 3) of neighboring complexes and as a result,
layers parallel to the diagonal of the ac plane are formed.
In 5, the amide hydrogen atom interacts with S2, the
coordinated sulfur of the tridentate ligand of a neighboring
Table 3
Hydrogen bond parameters for complexes 1 and 5a
Interaction
D–H
(A)
H . . . A
(A)
D . . . A
(A)
D–H . . . A
(8)
˚
˚
˚
Complex 1
N2–HN2 . . . S3(i)
N2–HN2 . . . S2(ii)
1.112
0.843
2.617
2.871
3.697
3.599
163.5
145.7
Complex 5
N2–HN2 . . . S2(iii)
0.828
3.024
3.839
168.9
a Symmetry transformations: (i) 2 0.5 1 x, 0.5 2 y, 2 0.5 1 z, (ii)
2 0.5 1 x, 0.5 1 y, 0.5 2 z, (iii) x, 2 1 1 y, z.
Fig. 2. ORTEP diagram of 5.

T. Maina et al. / Polyhedron 18 (1999) 3545–3552
3551
complex, resulting in the formation of polymeric chains
(Table 3).
clearly identified single metal species. As a result, this
strategy can be applied for efficiently tagging 99mTc to
pharmacologically interesting target molecules carrying
activated carboxylate residues.
The analogous 99mTc complexes 19–49 were prepared at
tracer level by a ligand exchange reaction via 99mTc-
glucoheptonate, as shown in Scheme 1. Labelling yields,
as calculated by CH2Cl2 extraction of the aqueous reaction
mixture, exceeded 85%. The radiochemical purity of the
organic extracts was tested by HPLC. Given that the
chemistry of Tc and Re are quite similar, corroboration of
structure of 99mTc and Re analogs was achieved by HPLC.
By coinjection of respective samples on a reverse phase
column both radioactivity (for 99mTc) and UV–Vis (for Re)
traces were identical, demonstrating the formation of
isostructural metal species (Fig. 3A,B for complexes 39
and 3, respectively).
Supplementary data
Supplementary data are available from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK on request, where two CIFs have been
deposited with deposition numbers CCDC 127939 and
CCDC 127940 for compounds 1 and 5, respectively.
In order to investigate the efficiency of this method for
coupling the above bifunctional 99mTc complexes to acti-
vated carboxylate residues according to the ‘preformed
chelate approach’, C6H5COCl was used as a model
molecule. Simple incubation of purified parent 99mTc
complexes 19–49 with C6H5COCl in organic medium at
ambient temperature resulted in quantitative and rapid
formation of daughter compounds, 59–89, respectively.
Formation of amide complexes was pursued by RP-HPLC
as well and a representative radiochromatogram for 79 is
shown in Fig. 3C. The structure of daughter compounds
59–89 was assigned by coinjection with their respective Re
analogs (5–8) and application of parallel radiometric and
photometric detection. As shown in Fig. 3C,D for com-
plexes 7 and 79 and the pertinent chromatographic profiles
are identical, revealing the structural analogy of the
compounds.
Acknowledgements
We are grateful to the Agricultural Bank of Greece
(ATE) and John Boutaris for financial support to AT and
CR.
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