Synthesis and structure of novel sugar-substituted bipyridine complexes of rhenium and 99m-technetium

Article abstract of DOI:10.1002/chem.200700296

Novel ligands have been obtained from the reaction of 4.4′- dibromomethyl-2.2′-bipyridine with 2,3.4.6-tetra-O-acetyl-β-D- glucopyranosylthiol. 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthiol or 2,3,4,6-tetra-O-acetyl-α-D-thioacetylmannopyranoside in which the sugar residues are thioglycosidically linked to the bipyridinc in the 4,4′-position. Cleavage of the acetyl groups affords hydrophilic symmetric ligands with free hydroxyl groups. Reaction of the new glycoconjugated ligands (L) with [Re(CO)₅Cl] yields fluorescent complexes of general formula [Re(L)-(CO)₃Cl]. which were characterised by mass spectrometry, elemental analysis and ¹H and ¹¹CNMR. IR. UV/Vis and fluorescence spectroscopy. These complexes exhibit excellent solubility and stability in organic solvents or water, depending on the residues of the sugar. One complex, namely tricarbonyl-4,4′-bis[(2.3.4,6-tetra-O-acetyl-β-D- glycopyranosyl)thiomethyl]-2,2′-bipyridinerhe-niumtricarbonylo chloride, has been characterised by X-ray crystallography. A non-symmetric structure of the complexes could be assigned. Radio-labelling of the unprotected ligands with [^99mTc(H₂O)₃(CO)₃]⁺ affords the corresponding water-soluble technetium complexes (in quantitative yields), which were characterised by their HPLC radiation traces. The formed complexes are stable for several hours in the presence of histidine but show partial ligand-exchange after one day.

Full text of DOI:10.1002/chem.200700296

FULL PAPER
DOI: 10.1002/chem.200700296
Synthesis and Structure of Novel Sugar-Substituted Bipyridine Complexes of
Rhenium and 99m-Technetium
Michael Gottschaldt,*[a] Daniel Koth,[a] Dirk Müller,[b] Ingo Klette,[b] Sven Rau,[c]
Helmar Gçrls,[c] Bernhard Schäfer,[c] Richard P. Baum,[b] and Shigenobu Yano[d]
Abstract: Novel ligands have been ob-
tained from the reaction of 4,4’-dibro-
momethyl-2,2’-bipyridine with 2,3,4,6-
tetra-O-acetyl-b-d-glucopyranosylthiol,
2,3,4,6-tetra-O-acetyl-b-d-galactopyra-
nosylthiol or 2,3,4,6-tetra-O-acetyl-a-d-
thioacetylmannopyranoside in which
the sugar residues are thioglycosidically
linked to the bipyridine in the 4,4’-posi-
tion. Cleavage of the acetyl groups af-
fords hydrophilic symmetric ligands
with free hydroxyl groups. Reaction of
the new glycoconjugated ligands (L)
with [Re(CO)5Cl] yields fluorescent
complexes of general formula [Re(L)-
N
anosyl)thiomethyl]-2,2’-bipyridinerhe-
niumtricarbonylo chloride, has been
characterised by X-ray crystallography.
A non-symmetric structure of the com-
plexes could be assigned. Ra
labelling of the unprotected ligands
with [99mTc(H2O)3(CO)3]+ affords the
corresponding water-soluble techne-
tium complexes (in quantitative yields),
dio-
AHCTREUNG
AHCTREUNG
AHCTREUNG
which were characterised by their
HPLC radiation traces. The formed
complexes are stable for several hours
in the presence of histidine but show
partial ligand-exchange after one day.
Introduction
diation, the nuclides 99mTc and 186/188Re form a so-called di-
agnostic and therapeutic pair, with the g-emitter 99mTc used
for imaging and the corresponding 186Re or 188Re complexes,
which have a high b-component in their radioactive decay,
used for therapy. In addition to their interesting radioactive
properties, rhenium(I) polypyridine complexes have been
employed as ion sensors,[1] intercalators or photocleavage
agents for nucleic acid[2] and boronic acid esters and as
sugar sensors.[3] It has been shown that the excited state of
these complexes has MLCT character and that appropriate
substitution of the bipyridine ligands influences the photo-
physical properties.[4] Rhenium(I) complexes have also been
used in the photochemical and electrochemical reduction of
carbon dioxide.[5] Various technetium complexes with differ-
ent oxidation states containing bipyridyl ligands diazo-cou-
pled to 4-amino-1-naphthalenesulfonic or salicylic acid
(analogous to Congo Red or chrysamin G dyes) have been
used to localise and quantify amyloidal fibrils in mammals
for diagnosing the degree of progression of Alzheimerꢀs dis-
ease;[6] many other complexes have been successfully syn-
thesised and their structure determined.[7] In addition, poly-
pyridyl ligands, including unmodified 2,2’:6’,2’’-terpyridine
and 1,10-phenanthroline systems, have been synthesised,
Radiolabelled metal complexes are very important substan-
ces for diagnosis and therapy in nuclear medicine. Because
of their closely related chemical properties but differing ra-
[a] Dr. M. Gottschaldt, D. Koth
Institute for Organic and Macromolecular Chemistry
Friedrich Schiller University of Jena
Humboldtstrasse 10, 07743 Jena (Germany)
Fax : (+49)3641-948202
E-mail: Michael.Gottschaldt@uni-jena.de
[b] Dr. D. Müller, I. Klette, Prof. R. P. Baum
Department of Nuclear Medicine, Zentralklinik Bad Berka GmbH
Robert-Koch-Allee 9, 99437 Bad Berka (Germany)
[c] Dr. S. Rau, Dr. H. Gçrls, Dr. B. Schäfer
Institute for Inorganic and Analytical Chemistry
Friedrich Schiller University of Jena
Lessingstrasse 8, 07743 Jena (Germany)
[d] Prof. S. Yano
Division of Materials Science, Graduate School of Human Culture
Nara Womenꢀs University
Kitauoyanishimachi, Nara 630–8506 (Japan)
Chem. Eur. J. 2007, 13, 10273 – 10280
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10273

characterised and the influence of additional ligands stud-
ied.[8]
feryl glycosides are used in the fluorometric detection of
cleaving enzymes.[23] Only two compounds with a thioether
linkage between a bipyridine and cyclodextrin exist in the
chemical literature to date.[24] In comparison to O-glycosy-
lated compounds, S-glycosyl bonds are resistant to endoge-
nous hydrolysis catalysed by glycosidases,[25] therefore we
have attempted to connect different monosaccharides to
2,2’-bipyridine S-glycosidically in order to obtain biologically
stable ligands and complexes of Re and Tc and now report
our first results in this area.
Polypyridines functionalised with carbohydrates combine
the useful properties of both basic functionalities. Thus, the
polypyridyl residues provide not only versatile and stable
complexation of metal ions but also analytically useful prop-
erties like fluorescence of the corresponding metal com-
plexes. Addition of a carbohydrate to the polypyridine scaf-
fold has the added advantage of reducing the toxicity and
improving the solubility, and opens up the possibility of mo-
lecular targeting of carbohydrate binding domains in cells
and tissues. IrIII, RhIII, RuII and ReI complexes of 2,2’-bipyri-
dine-functionalised cyclodextrins have been synthesised as
potential photo- and electroactive receptors following this
strategy.[9] Europium complexes of terpyridines substituted
with saccharides have also been employed as target cell
markers in time-resolved fluorometric assays.[10] Complexes
of Ru or Fe with sugar-containing terpyridines have been
shown to be stable against enzymatic cleavage by b-glucosi-
dase, in contrast to their free ligands,[11] and Ru complexes
containing cyclodextrins have been studied as cyclometallat-
ed luminescent probes and for the detection of photoin-
duced intercomponent processes; related iron complexes
have been employed for modelling cyclodextrin recognition
sites.[12] Metal complexes of N-acetylgalactosamine- and
-glucosamine-substituted 2,2’-bipyridines have also been syn-
thesised and structurally characterised and their binding
properties for NAcGal-specific lectins determined.[13]
Results and Discussion
The dibromide 1 was synthesised from 4,4’-dimethyl-2,2’-bi-
pyridine according to a literature procedure.[26] However,
only a 1:1 mixture with isomeric 4’-(dibromomethylene)-4-
methyl-2,2’-bipyridine was obtained after chromatographic
separation from the tri- and monobromo products. Reaction
of the crude product containing 1 with 2,3,4,6-tetra-O-
acetyl-b-d-glucopyranosylthiol (2) or 2,3,4,6-tetra-O-acetyl-
b-d-galactopyranosylthiol (3)[27] in a mixture of DMF and
sodium carbonate led to the acetyl-protected ligands 5 and
6, respectively, after chromatographic purification. The cor-
responding mannose derivative 7 was synthesised in a one-
pot reaction in DMF starting from 2,3,4,6-tetra-O-acetyl-a-
d-thioacetylmannopyranose (4).[28] This was achieved by hy-
drolysis of the thioacetyl group in situ by stirring with dieth-
ylamine at 08C and subsequent addition of sodium carbon-
ate and the dibromide 1 (Scheme 1).
Enhanced luminescence and recognition of 2,2’-bipyridine
complexes of Ru and Fe by lectins has been achieved by O-
glycosidic coupling of mono- and disaccharides via long-
chain spacers and diamide functions.[14] Ribose derivatives
bound to 2,2’-bipyridines by different spacers in the 4,4’- or
5-position have also been prepared and tested for chiral in-
duction during iron complexation or as building blocks for
intra-duplex metal complexes of modified DNA.[15]
In addition to the single set of signals for the sugar resi-
due and the pyridine ring expected for a C2-symmetric com-
1
pound, the H NMR spectra of these ligands show two sig-
nals for the non-equivalent CH2 protons of the thio-substi-
tuted methylene group at d=4.0 and 3.8 ppm with a large
coupling constant of 13 Hz. Cleavage of the acetyl esters
was carried out under basic conditions with sodium methox-
ide in methanol to give the unprotected ligands 8–10 as
white solids. These compounds, which are the first bipyri-
dines with thioglycosidically linked saccharides, precipitate
as partial sodium alkoxides and were characterised by high-
resolution mass spectrometry (HRMS) and NMR spectros-
copy. They do not dissolve in common organic solvents but
are readily soluble in water.
Complexation to the rhenium carbonyl core was achieved
by refluxing a methanolic suspension of the corresponding
ligand (5–10) with [Re(CO)5Cl] (Scheme 2). The resulting
yellow-orange raw products were purified by column chro-
matography over silica gel. Complexes 11–13 were found to
be very soluble in organic solvents such as ethyl acetate or
chloroform. Complexes 14–16 exhibit very good water solu-
bility and stability, since even arduous treatment in aqueous
solutions caused no change in their spectra. Complexes 11–
13 show absorption maxima at 299 and 393 nm in dichloro-
methane in their UV/Vis spectra, with the absorption
maxima of complexes 14–16 appearing at 323 and 389 nm,
respectively, in water. The low-energy absorption band at
Metal complexes functionalised with carbohydrates but
containing other cores for metal complexation are increas-
ingly being studied in medicinal inorganic chemistry; exam-
ples include Re and Tc complexes for use as radiotracers.[16]
2,2’-Dipicolylamine,[17] 3-hydroxypyridone[18] and 2-hydroxy-
benzyl[19] derivatives of different monosaccharides, for exam-
ple, have been used as chelators for Tc and Re carbonyl
cores, and similar complexes have been reported from 1,3-
diamines of sugars.[20] Saccharide-functionalised bis(quinoli-
nolyl)amino acids have also been complexed to a rhenium
tricarbonyl core,[21] and glucose and 2-deoxyglucose have
been functionalised at C-1 with iminodiacetic acid and the
resulting ligands complexed with Re and Tc.[22] In all of
these examples the linkage between the saccharides and the
metal complexing units was accomplished by employing
amido or O-glycosidic linkers, although procedures for the
fluorometric or colourimetric determination of sugar and
protein processing enzymes reveal they may be not stable in
vivo. For instance X-gal (5-bromo-4-chloro-3-indoyl-b-d-gal-
actoside) is a well known histochemical substrate that is
used to detect b-galactosidase, and several 4-methylumbelli-
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Chem. Eur. J. 2007, 13, 10273 – 10280

Sugar-Substituted Bipyridine Complexes of Re and 99mTc
FULL PAPER
Scheme 1. Synthesis of the ligands: i) Na2CO3, DMF, room temp.; ii) HNEt2, DMF, 08C, 15 min and then Na2CO3, 12 h, room temp.; iii) NaOMe, MeOH,
12 h, room temp.
strong signals at 1740 cmÀ1 for
the carboxyl groups that are
absent for the non-protected
complexes 14–16.
The NMR spectra of com-
plexes 11–16 show that, in con-
trast to the C2-symmetric free
ligands, each sugar residue and
pyridine unit in the complex
now exhibits a separate set of
signals in the 13C NMR spectra.
The 1H NMR chemical shifts
Scheme 2. Synthesis of the rhenium complexes: i) methanol, 10 h, reflux.
are also affected. The most pro-
nounced effect is observed for
the signals of the protons at-
around 390 nm for all these complexes is typical for the
MLCT transition of rhenium(I) diimines (Table 1). The
emission of the Re compounds 11–13 upon excitation at
400 nm occurs at around 610 nm (dichloromethane) and for
complexes 14–16 upon excitation at 350 nm emission occurs
between 600 and 640 nm (water). These values are typical
for the phosphorescence derived from the triplet rhenium-
to-ligand charge transfer (3MLCT) excited state.[3d]
tached to the anomeric carbons: in compound 11, for in-
stance, they appear as two doublets with the same coupling
constant (J1,2 =9.8 Hz) but at different positions (d=4.51
and 4.49 ppm). These results indicate a non-symmetric met-
allocomplex structure.
Crystallisation of 11 from methanol resulted in yellow
needles which were suitable for X-ray structure analysis
(Figure 1).
The rhenium atom is coordinated to the bipyridyl nitro-
gen atoms, three carbonyl groups and one axial chloride.
The sugar residues are located outside the coordination
sphere. A closer look at the bond lengths and angles at the
rhenium centre (Table 2) provides additional support for the
conclusions derived from the IR and NMR spectra. Thus,
the different angles at the rhenium centre, for instance N1-
Re-Cl1 (83.3(2)8) and N2-Re-Cl1 (90.5(2)8), confirm that
the structure is not symmetric and explain the separate sig-
nals observed for every part of the molecule, such as the
pyridine rings of the bipyridine unit.
Table 1. Absorption and emission of the rhenium complexes.
Compd[a]
UV/Vis
[nm]
Emission
[nm][b]
Compd[c]
UV/Vis
[nm]
Emission[d]
[nm]
11
12
13
298, 389
298, 390
299, 394
609
612
615
14
15
16
323, 345
323, 349
321, 358
643
597
642
[a] In dichloromethane. [b] Excitation at 400 nm. [c] In water. [d] Exci-
tation at 350 nm.
The IR spectra of the complexes are consistent with the
proposed structures since bands attributable to the
[Re(CO)3Cl] core and the residues of the sugar moieties are
present. The single absorption at 2020 cmÀ1 can be assigned
to the axial CO group, whereas the absorption at 1880 cmÀ1
for the equatorial carbonyl ligands splits into two peaks in
most cases. The acetyl-protected complexes 11–13 exhibit
Technetium is the most widely used isotope in nuclear
medicine. Its nuclear properties (t1/2 =6.01 h and g=
142.7 keV) allow the decay process to be conveniently mea-
sured by single photon emission computed tomography
(SPECT). Due to the similar chemical properties of Re and
Tc, rhenium complexes are good structural models for tech-
netium complexes. The [99Tc(CO)3(H2O)3]+ cation was gen-
A
Chem. Eur. J. 2007, 13, 10273 – 10280
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10275

M. Gottschaldt et al.
As an example of these 99mTc
compounds we determined the
in vitro stability of compound
17 following standard proce-
dures (incubation with solutions
of histidine in PBS buffer at
378C).[29] The susceptibility of
the complex to undergo ligand-
exchange reactions with this
amino acid was followed over a
24-h period (Figure 2).
The results clearly show that
complex 17 possesses good sta-
bility over the first 4.5 h, after
which time two additional sig-
nals indicative of more lipophil-
ic complexes appear in the
HPLC trace. Complete ligand
Figure 1. ORTEP view (50% probability) of one of the molecules in the structure of 11. H atoms have been
omitted for clarity.
Table 2. Selected bond lengths [Š] and angles [8] for 11.
exchange, which would result in the formation of the 99mTc
histidine carbonyl complex [99mTc
AHCTREUNG
À
Re N1
2.168(6)
2.182(6)
1.912(8)
1.924(7)
2.005(18)
2.387(7)
C41-Re-N2
C42-Re-N1
C43-Re-Cl1
N1-Re-Cl1
N2-Re-Cl1
C41-Re-C42
173.6(3)
169.8(3)
175.2(6)
83.3(2)
90.5(2)
90.3(3)
À
Re N2
synthesised under the same conditions for comparison, was
not detected. Exchange of only the H2O ligand at the tech-
netium centre with histidine could, in principle, be possible
with the complex core remaining intact. This has been ob-
served, for example, for related Re complexes containing
imidazole- or pyridine-based ligands.[30]
À
Re C41
À
Re C42
À
Re C43a
À
Re Cl1
À
erated in 0.9% saline solution from the 99mTcO4 anion by
using the Isolink kit from TYCO; the pH was adjusted with
phosphate buffer. Complexation of ligands 8–10 was carried
out under neutral conditions by addition of this technetium-
containing solution to the appropriate ligand (Scheme 3). In-
creased formation of by-products upon heating the reaction
mixtures to 1008C was not detected and the complexes
formed (17–19) were found to be stable for several hours in
this aqueous solution. HPLC analysis showed no retransfor-
Conclusion
We have developed a general synthetic pathway for obtain-
ing novel sugar-substituted bipyridines. The carbohydrate
residues are coupled thioglycosidically to bipyridine to
obtain biologically stable ligands. Complexation of the li-
gands with [Re(CO)5Cl] affords the expected luminescent
rhenium complexes, whose properties and structures were
determined by NMR, UV/Vis, IR and fluorescence spectros-
copy and mass spectrometry. In addition, the solid-state
structure of one complex has been elucidated by X-ray
structure analysis. The solubility of these complexes is
strongly influenced by the residues on the sugar units. For
example, the protected complexes 11–13 are soluble in or-
ganic solvents whereas the unprotected compounds 14–16
exhibit very good solubility in
À
mation into 99mTcO4 anion (Rf =7.8 min). The [99mTc(CO)3-
(H2O)3]+ ion (Rf =3.2 min) reacted completely and the ra-
A
N
need for an additional purification step. The retention times
of the formed compounds 17–19 are between 11.9 and
12.4 min using a triethylamine phosphate solution/methanol
gradient and an RP-18 column.
water. The corresponding radio-
labelled 99mTc complexes of the
unprotected ligands have been
synthesised
in
quantitative
[
yields using
99mTc(CO)3-
(H2O)3]+ as the metal ion
source and characterised by
their HPLC radiation traces.
These results show that lumi-
nescent probes based on the
rhenium(I) centre with periph-
eral sugar substitution can be
obtained and that the observed
Scheme 3. Synthesis of the 99mTc complexes using the Isolink kit.
10276
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Chem. Eur. J. 2007, 13, 10273 – 10280

Sugar-Substituted Bipyridine Complexes of Re and 99mTc
FULL PAPER
moval of the solvent the residue was
extracted with ethyl acetate and water,
dried over sodium sulfate and evapo-
rated. TLC (ethyl acetate/hexane, 3:2)
showed two spots (Rf =0.22 and 0.26)
along with that of the disulfide (Rf =
0.38). Chromatographic separation
(ethyl acetate/hexane, 3:1) gave
800 mg (86% with respect to the 50%
purity of the starting material) of the
desired product as
a white foam.
1H NMR (400 MHz, CDCl3): d=8.61
(d, 3J6’’,5’’ =4.9 Hz, 2H; H-6’’), 7.30 (d,
2H; H-5’’), 8.39 (s, 2H; H-3’’), 4.37 (d,
3
3J1,2 =9.8 Hz, 2H; H-1), 5.16 (t, J2,3
=
3
9.0 Hz, 2H; H-2), 5.10 (t, J3,4 =9.5 Hz,
2H; H-3), 5.09 (t, 3J4,5 =9.5 Hz, 2H;
3
H-4), 3.69 (ddd, 3J5,6 =4.2 Hz, J5,6’
=
2.9 Hz, 2H; H-5), 4.19–4.27 (m, 4H;
2
H-6, H-6’), 4.04, 3.85 (2d, JH,H
=
13.4 Hz, 4H; CH2), 2.10, 2.04, 2.02,
1.99 ppm (4 s, 24H; CH3-acetyl);
13C NMR (CDCl3): d=170.4, 169.8,
169.1 (CO-acetyl), 155.8 (C2’’), 149.3
(C6’’), 147.0 (C4’’), 124.0 (C5’’), 121.3
(C3’’), 81.8 (C1), 75.8 (C2), 73.6 (C3),
69.7 (C4), 68.1 (C5), 61.9 (C6), 32.8
Figure 2. HPLC radiation traces for the histidine challenge experiment with 17 compared to the sample [99mTc-
(His)(CO)3].
(S-CH2-), 20.7 ppm (CH3-acetyl); ESI-
MS: m/z (%): 931.26 (100) [M+Na]+,
1839.53 (5) [2M+Na]+; elemental
analysis calcd (%) for C40H48N2O18S2: C 52.86, H 5.32, N 3.08; found: C
52.76, H 5.33, N 3.01.
independency of the complex formation reaction on the
nature of the sugar substituent can be exploited for the syn-
thesis of the corresponding technetium(I) complexes.
In a histidine challenge experiment, the glucose-substitut-
ed 99mTc complex 17, which is representative of all the com-
plexes, is stable in vitro for 4.5 h. This stability is rather low
compared to other sugar-containing complexes derived from
2,2’-dipicolylamine for instance.[17] In light of the intrinsic
fluorescence and the possibility of binding different carbo-
hydrates externally, future in vivo experiments are expected
to show a sugar-dependent biodistribution.
4,4’-Bis[(2,3,4,6-tetra-O-acetyl-b-d-galactopyranosyl)thiomethyl]-2,2’-bi-
pyridine (6): This compound was synthesised in an analogous manner to
5 from crude 1 (2.479 g, 7.25 mmol) and 2,3,4,6-tetra-O-acetyl-b-d-galac-
topyranosylthiol (5.81 g, 15.95 mmol) to yield 2.19 g (85%) of 6.
1H NMR (250 MHz, CDCl3): d=8.59 (d, 3J6’’,5’’ =4.9 Hz, 2H; H-6’’), 7.29
3
(d, 2H; H-5’’), 8.39 (s, 2H; H-3’’), 4.36 (d, J1,2 =9.9 Hz, 2H; H-1), 5.29 (t,
3J2,3 =10.0 Hz, 2H; H-2), 4.98 (dd, 3J3,4 =3.4 Hz, 2H; H-3), 5.41 (dd,
3J4,5 =0.9 Hz, 2H; H-4), 3.92 (dd, J5,6 =6.6 Hz, 2H; H-5), 4.13 (d, 4H; H-
3
6), 4.04, 3.85 (2d, 2JH,H =13.5 Hz, 4H; CH2), 2.15, 2.04, 2.03, 1.95 ppm
(4 s, 24H; CH3-acetyl); 13C NMR (CDCl3): d=170.3, 170.2, 169.9, 169.6
(CO-acetyl), 156.1 (C2’’), 149.4 (C6’’), 147.5 (C4’’), 124.1 (C5’’), 121.5
(C3’’), 82.5 (C1), 74.6 (C2), 71.7 (C3), 67.3 (C4), 67.0 (C5), 61.4 (C6),
32.8 (S-CH2-), 21.0, 20.7, 20.6, 20.5 ppm (CH3-acetyl); DEI-MS: m/z (%):
908 (15) [M]+; elemental analysis calcd (%) for C40H48N2O18S2: C 52.86,
H 5.32, N 3.08, S 7.06; found: C 52.80, H 5.27, N 3.05, S 6.88.
Experimental Section
4,4’-Bis[(2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl)thiomethyl]-2,2’-bi-
pyridine (7): Diethylamine (1.84 g, 25 mmol) was added to a solution of
2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl thioacetate (10.2 g, 25 mmol)
in 50 mL of DMF at 08C. After stirring for 15 min an excess of sodium
carbonate and the two dibromobipyridyls (12.6 g, 12.6 mmol) in DMF
(30 mL) were added. The mixture was stirred for two days and worked
up analogous to 5 to give 3.2 g (56%) of 7 as a white foam. 1H NMR
General: All reagents and solvents were purchased from commercial
sources and were used as received. IR spectra were recorded with a
Perkin–Elmer 2000 spectrometer, NMR spectra with a JEOL JMTC-400/
54/SS or a Bruker AC-200 spectrometer and ESI mass spectra with a
JEOL JMS-T100 LC, Finnigan MAT SSQ 710 or a Finnigan MAT 95XL
TRAP spectrometer. Elemental analyses were performed with a Leco
CHNS 932 or Perkin Elmer PE2400 Series II CHNS/O Analyzer (Nara
Institute of Science and Technology). UV/Vis absorption spectra (accu-
racy: Æ2 nm) were recorded with an Analytikjena Specord S 600 spec-
trometer with standard software-based tools. Emission spectra (accuracy:
Æ5 nm) were recorded at 298 K with a Perkin–Elmer LS50B lumines-
3
(400 MHz, CDCl3): d=8.63 (d J6’’,5’’ =4.9 Hz, 2H; H-6’’), 7.30 (d, 2H; H-
5’’), 8.37 (s, 2H; H-3’’), 5.11 (d, 3J1,2 =1.2 Hz, 2H; H-1), 5.24–5.33 (m,
6H; H-2, H-3, H-4), 4.37 (m, J5,6 =5.4 Hz, J5,6’ =2.2 Hz, 2H; H-5), 4.31
(dd, 2J6,6’ =12.2 Hz, 3J5,6 =5.4 Hz, 2H; H-6), 4.03 (dd, 3J5,6’ =2.2 Hz, 2H;
H-6’), 3.87 and 3.79 (2d, 2JH,H =13.9 Hz, 4H; CH2), 2.14, 2.12, 2.05,
1.98 ppm (4 s, 24H; CH3-acetyl); 13C NMR (CDCl3): d=170.3, 169.5,
(CO-acetyl), 155.9 (C2’’), 149.3 (C6’’), 146.9 (C4’’), 123.9 (C5’’), 121.3
(C3’’), 81.4 (C1), 70.3 (C2); 69.5 (C3), 69.1 (C4), 66.0 (C5), 62.3 (C6),
33.8 (S-CH2-), 20.9 ppm (CH3-acetyl); ESI-MS: m/z (%): 931.23 (100)
[M+Na]+; elemental analysis calcd (%) for C40H48N2O18S2: C 52.86, H
5.32, N 3.08; found: C 52.61, H 5.40, N 2.94.
cence spectrophotometer equipped with
a red-sensitive Hamamatsu
R298 PMT detector and interfaced with an Elonex PC466 employing the
Perkin–Elmer FlWinLab custom-built software. Emission spectra are un-
corrected for the photomultiplier response. Quartz cells (path length:
10 mm) were used.
4,4’-Bis[(2,3,4,6-tetra-O-acetyl-b-d-glycopyranosyl)thiomethyl]-2,2’-bipyr-
idine
(5):
2,3,4,6-Tetra-O-acetyl-b-d-glucopyranosylthiol
(2.114 g,
General procedure for the synthesis of unprotected ligands 8–10: The
corresponding peracetylated ligand 5–7 (1.09 g, 1.2 mmol) was dissolved
in methanol (50 mL), sodium methoxide (200 mg) was added and the so-
5.801 mmol) and Na2CO3 (2 g) were added to a solution of a mixture of
the two dibromomethylenebipyridyls (902 mg, 2.637 mmol) in DMF and
this suspension was stirred at room temperature for two days. After re-
Chem. Eur. J. 2007, 13, 10273 – 10280
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10277

M. Gottschaldt et al.
lution was stirred for 12 h. The white precipitate formed was filtered off,
washed with methanol and dried to give the unprotected ligand as a
white powder in about 70% yield.
acetyl); 13C NMR (CDCl3): d=197.1, 189.4 (CO-carbonyl), 170.3, 170.2,
169.9, 169.8 (CO-acetyl), 155.7 (C2’’), 152.9 (C6’’), 151.0 (C4’’), 127.6,
127.5 (C5’’), 123.8 (C3’’), 82.6 (C1), 74.9 (C2), 71.4 (C3), 67.1 (C4), 66.7
(C5), 61.3 (C6), 29.6 (S-CH2-), 21.0, 20.7, 20.6, 20.5 ppm (CH3-acetyl); IR
(ATR): n˜ =2018, 1886 (C=O), 1740 cmÀ1 (C=O); UV/Vis (CH2Cl2): lmax
(e)=390 (3900), 298 nm (16800 mÀ1 cmÀ1); DEI-MS: m/z (%): 1213 (30)
[MÀH]+, 1185 (80) [MÀCO]+, 1178 (100) [MÀClÀ]+, 1157 (60)
4,4’-Bis[(b-d-glycopyranosyl)thiomethyl]-2,2’-bipyridine (8): 1H NMR
(400 MHz, [D6]DMSO): d=8.58 (d, 3J6’’,5’’ =5.1 Hz, 2H; H-6’’), 7.41 (d,
2H; H-5’’), 8.38 (s, 2H; H-3’’), 4.71–4.74 (m, 2H; OH), 4.96 (s, 2H; OH),
3
5.06 (s, 2H; OH), 5.17 (s, 2H; OH), 4.04 (d, J1,2 =9.8 Hz, 2H; H-1), 3.74
[MÀ2CO]+; elemental analysis calcd (%) for C43H48ClN2O21ReS2·C6H14
:
(dd, 3J5,6 =5.4 Hz, 2J6,6’ =11.7 Hz, 2H; H-6), 3.46 (dd, 3J5,6’ =6.8 Hz, 2H;
2
C 45.24, H 4.80, N 2.15, S 4.93; found: C 44.93, H 4.66, N 1.98, S 4.31.
H-6’), 3.05–3.15 (m, 8H; H-2, H-3, H4, H-5), 4.03, 3.90 ppm (2d, JH,H
=
13.1 Hz, 4H; CH2); 13C NMR ([D6]DMSO): d=155.0 (C2’’), 149.0 (C6’’),
148.7 (C4’’), 124.5 (C5’’), 120.9 (C3’’), 83.0 (C1), 81.1 (C2), 78.1 (C3), 73.1
(C4), 70.1 (C5), 61.3 (C6), 31.5 ppm (S-CH2-); ESI-HRMS: m/z calcd for
C24H32N2NaO10S2: 595.13961; found: 595.13994; elemental analysis calcd
(%) for C24H32N2O10S2·0.5H2O: C 49.56, H 5.72, N 4.82, S 11.03; found:
C 49.51, H 5.51, N 4.76, S 10.67.
Tricarbonyl-4,4’-bis[(2,3,4,6-tetra-O-acetyl-a-d-mannopyranosyl)thio-
methyl]-2,2’-bipyridinerhenium chloride (13): 1H NMR (400 MHz,
CDCl3): d=8.96, 8.97 (2d, 3J6’’,5’’ =5.6 Hz, 2H; H-6’’), 7.51, 7.49 (2d, 2H;
H-5’’), 8.31 (s, 2H; H-3’’), 5.01, 5.06 (2d, 3J1,2 =1.2 Hz, 2H; H-1), 5.26–
5.37 (m, 6H; H-2, H-3, H-4), 4.31 (m, 2H; H-5), 4.26, 4.25 (2 s, 4H; H-6,
H-6’), 3.84–3.95 (m, 4H; CH2), 2.12, 2.05, 2.04, 1.70 ppm (4 s, 24H; CH3-
acetyl); 13C NMR (CDCl3): d=197.0, 196.9, 189.3 (CO-carbonyl), 170.5,
169.9, 169.8, 169.5 (CO-acetyl), 155.9, 155.8 (C2’’), 153.1, 153.0 (C6’’),
150.4, 150.3 (C4’’), 127.5, 127.4 (C5’’), 123.9, 123.8 (C3’’), 81.0, 80.8 (C1),
69.9 (C2), 69.8, 69.7 (C3), 69.4 (C4), 66.0, 65.8 (C5), 62.1, 62.0 (C6), 32.9,
32.8 (S-CH2-), 20.9, 20.8, 20.7, 20.6 ppm (CH3-acetyl); IR (ATR): n˜ =
2019, 1887 (C=O), 1740 cmÀ1 (C=O); UV/Vis (CH2Cl2): lmax (e)=394
(4500), 299 nm (20900 mÀ1 cmÀ1); ESI-MS: m/z (%): 1237.12 (15)
[M+Na]+, 1179.20 (100) [MÀClÀ]+; elemental analysis calcd (%) for
C43H48ClN2O21ReS2·0.5C6H14: C 43.93, H 4.41, Cl 2.82, N 2.23, S 5.10;
found: C 43.76, H 4.54, Cl 2.93, N 2.14, S 4.75.
4,4’-Bis[(b-d-galactopyranosyl)thiomethyl]-2,2’-bipyridine (9): 1H NMR
3
(400 MHz, [D7]DMF): d=8.65 (d, J6’’,5’’ =4.9 Hz, 2H; H-6’’), 7.51 (d, 2H;
3
3
H-5’’), 8.53 (s, 2H; H-3’’), 4.27 (d, J1,2 =10.4 Hz, 2H; H-1), 3.64 (t, J2,3
=
9.3 Hz, 2H; H-2), 3.45 (dd, 3J3,4 =3.2 Hz, 2H; H-3), 3.91 (d, 2H; H-4),
3.56 (t, 3J5,6 =3J5,6’ =6.2 Hz, 2H; H-5), 3.83 (dd, 2J6,6’ =11.1 Hz, 2H; H-6’),
3.75 (dd, 2H; H-6), 4.15, 3.99 ppm (2d, 4H; S-CH2, 2JH,H =13.4 Hz);
13C NMR ([D7]DMF): d=155.9 (C2’’), 149.6 (C6’’), 149.4 (C4’’), 124.6
(C5’’), 121.3 (C3’’), 84.5 (C1), 80.0 (C2), 75.6 (C3), 69.4 (C4), 68.6 (C5),
61.6 (C6), 32.1 ppm (S-CH2-); ESI-HRMS: m/z calcd for
C24H32N2NaO10S2: 595.13961; found: 595.13955; elemental analysis calcd
(%) for C24H30.5N2Na1.5O10S2: C 47.64, H 5.00, N 4.63, S 10.60; found: C
47.98, H 5.32, N 4.64, S 10.55.
Tricarbonyl-4,4’-bis(b-d-glycopyranosylthiomethyl)-2,2’-bipyridinerheni-
3
um chloride (14): 1H NMR (400 MHz, CD3OD): d=8.87 (d, J6’’,5’’
=
4,4’-Bis[(a-d-mannopyranosyl)thiomethyl]-2,2’-bipyridine (10): 1H NMR
5.6 Hz, 2H; H-6’’), 7.64 (d, 2H; H-5’’), 8.69, 8.63 (2 s, 2H; H-3’’), 4.10 (m,
2H; H-1), 3.29–3.20 (m, 8H; H-2, H-3, H4, H-5), 3.61 (m, 2H; H-6’),
3.88–3.96 (m, 4H; H-6, CH2), 4.25, 4.23 ppm (2d, 2JH,H =13.9 Hz, 2H;
CH2); 13C NMR (CD3OD): d=198.1, 190.4 (CO), 157.0 (C2’’), 154.3
(C6’’), 153.7 (C4’’), 128.8 (C5’’), 125.5, 125.4 (C3’’), 84.4, 84.2 (C1), 82.0
(C2), 79.3 (C3), 74.5 (C4), 71.8 (C5), 63.2 (C6), 32.9 ppm (S-CH2-); IR
(ATR): n˜ =2020, 1878 cmÀ1 (C=O); UV/Vis (H2O): lmax (e)=345 (5300),
323 (14400), 311 nm (13400 mÀ1 cmÀ1); ESI-MS: m/z (%): 901.01 (10)
[M+Na]+, 843.05 (100) [MÀClÀ]+; elemental analysis calcd (%) for
C27H32ClN2O13ReS2·H2O: C 36.18, H 3.82, N 3.13; found: C 36.11, H 3.89,
N 2.93.
(400 MHz, D2O): d=8.32 (d, 3J6’’,5’’ =5.2 Hz, 2H; H-6’’), 7.24 (d, 2H; H-
3
5’’), 7.71 (s, 2H; H-3’’), 5.11 (d, 3J1,2 =1.2 Hz, 2H; H-1), 3.92 (dd, J2,3
=
3.2 Hz, 2H; H-2), 3.81 (m, 2H; H-5), 3.74–3.58 ppm (m, 12H; H-3, H-4,
H-6, H-6’, S-CH2); 13C NMR (D2O): d=154.7 (C2’’), 149.5 (C6’’), 149.1
(C4’’), 124.7(C5’’), 122.0 (C3’’), 84.5 (C1), 73.3 (C2), 71.6 (C-3), 71.5 (C4),
E
67.1 (C5), 60.6 (C6), 33.4 ppm (S-CH2-); ESI-HRMS: m/z calcd for
C24H32N2NaO10S2: 595.13961; found: 595.14023; elemental analysis calcd
(%) for C24H30N2Na2O10S2: C 46.75, H 4.90, N 4.54, S 10.40; found: C
46.67, H 5.26, N 4.40, S 10.15.
General procedure for the synthesis of Re complexes 11–16: The corre-
sponding ligand 5–10 (0.2 mmol) and [Re(CO)5Cl] (0.2 mmol) in metha-
nol (30 mL) were heated under reflux for 10 h. The solvent was then
evaporated from the resulting yellow solution and the raw product puri-
fied by column chromatography (silica gel 60; ethyl acetate/hexane 2:1;
Rf =0.4 for 11–13; ethyl acetate/methanol 1:1; Rf =0.5 for 14–16) to yield
80% of the complex.
Tricarbonyl-4,4’-bis(b-d-galactopyranosylthiomethyl)-2,2’-bipyridinerheni-
3
um chloride (15): 1H NMR (250 MHz, CD3OD): d=8.90 (d, J6’’,5’’
=
5.7 Hz, 2H; H-6’’), 7.70 (d, 2H; H-5’’), 8.73, 8.69 (2 s, 2H; H-3’’), 4.14,
4.13 (2d, 3J1,2 =9.5 Hz, 2H; H-1), 3.63 (t, 3J2,3 =9.5 Hz, 2H; H-2), 3.39
(dd, 3J3,4 =3.2 Hz, 2H; H-3), 3.84 (d, 2H; H-4), 3.50 (dd, 3J5,6 =3.7 Hz,
3J5,6’ =7.3 Hz, 2H; H-5), 3.79–3.64 (m, 4H; H-6’, H-6), 4.28, 3.97 ppm (2d,
2JH,H =13.9 Hz, 4H; S-CH2); 13C NMR (CD3OD): d=198.5 and 190.7
(CO), 157.21/157.16 (C2’’), 154.76 (C6’’), 153.83 (C4’’), 129.06/129.01
(C5’’), 125.85/125.76 (C3’’), 84.95 (C1), 81.05 (C2), 76.11 (C3), 71.51 (C4),
70.71 (C5), 63.16 (C6), 32.82 ppm (S-CH2-); IR (ATR): n˜ =2018,
1876 cmÀ1 (C=O); UV/Vis (H2O): lmax (e)=349 (4600), 323 (11600),
310 nm (11300 mÀ1 cmÀ1); FAB-MS: m/z (%): 878 (30) [M]+, 843 (50)
[MÀClÀ]+; elemental analysis calcd (%) for C27H32ClN2O13ReS2·2H2O: C
35.47, H 3.06, N 3.19; found: C 35.18, H 3.41, N 3.07.
Tricarbonyl-4,4’-bis[(2,3,4,6-tetra-O-acetyl-b-d-glycopyranosyl)thiometh-
yl]-2,2’-bipyridinerhenium chloride (11): Crystallisation from methanol
gave yellow needles suitable for a single-crystal X-ray structure analysis.
1H NMR (400 MHz, CDCl3): d=8.94 (d, 3J6’’,5’’ =5.6 Hz, 2H; H-6’’), 7.51
(d, 2H; H-5’’), 8.27 (s, 2H; H-3’’), 4.51, 4.49 (2d, 3J1,2 =9.8 Hz, 2H; H-1),
5.25 (t, 3J2,3 =9.3 Hz, 2H; H-2), 5.16 (t, 3J3,4 =9.8 Hz, 2H; H-3), 5.11 (t,
3J4,5 =9.8 Hz, 2H; H-4), 3.77 (ddd, 3J5,6 =4.4 Hz, 3J5,6’ =2.2 Hz, 2H; H-5),
4.16 (dd, 2J6,6’ =12.5 Hz, 2H; H-6’), 4.23–4.29 (m, 2H; H-6), 4.09, 3.97
(2d, 2JH,H =13.2 Hz, 4H; S-CH2), 2.10, 2.07, 2.04, 2.03 ppm (4 s, 24H;
CH3-acetyl); 13C NMR (CDCl3): d=196.7, 189.1 (CO-carbonyl), 170.2,
169.7, 169.4, 169.2 (CO-acetyl), 155.5 (C2’’), 152.7 (C6’’), 150.6, 150.5
(C4’’), 127.4 (C5’’), 123.7 (C3’’), 82.0, 81.9 (C1), 76.2 (C2), 73.3 (C3), 69.2
(C4), 68.0 (C5), 61.8 (C6), 31.9 (S-CH2-), 20.7, 20.9 ppm (CH3-acetyl); IR
(ATR): n˜ =2019, 1886, 1865 (C=O), 1742 cmÀ1 (C=O); UV/Vis (CH2Cl2):
lmax (e)=389 (4300), 298 nm (19900 mÀ1 cmÀ1); ESI-MS: m/z (%):
1179.12 (100) [MÀClÀ]+; elemental analysis calcd (%) for
C43H48ClN2O21ReS2·H2O: C 41.90, H 4.09, N 2.27; found: C 41.66, H 4.00,
N 2.26.
Tricarbonyl-4,4’-bis(a-d-mannopyranosylthiomethyl)-2,2’-bipyridinerheni-
3
um chloride (16): 1H NMR (400 MHz, CD3OD): d=8.88 (d, J6’’,5’’
=
3
5.6 Hz, 2H; H-6’’), 7.67 (dd, 2H; H-5’’), 8.57 (s, 2H; H-3’’), 5.08 (d, J1,2
=
2.0 Hz, 2H; H-1), 3.84–3.57 (m, 6H; H-2, H-3, H-4, H-5, H-6, H-6’), 4.02,
2
3.94 ppm (2d, JH,H =13.9 Hz, 4H; S-CH2); 13C NMR (CD3OD): d=198.1,
190.3 (CO), 156.8 (C2’’), 154.1 (C6’’), 153.7 (C4’’), 128.8 (C5’’), 125.4
(C3’’), 85.0 (C1), 75.3 (C2), 73.1 (C-3), 73.0 (C4), 68.6 (C5), 62.5 (C6),
33.9 ppm (S-CH2-); IR (ATR): n˜ =2009, 1865 cmÀ1 (C=O); UV/Vis
(H2O): lmax (e)=358 (4200), 321 (12100), 283 nm (15400 mÀ1 cmÀ1); ESI-
MS: m/z (%): 901.07 (30) [M+Na]+, 843.12 (100) [MÀClÀ]+; elemental
analysis calcd (%) for C27H32ClN2O13ReS2·5H2O: C 33.49, H 4.37, N
2.89; found: C 33.49, H 3.86, N 2.61.
General procedure for the synthesis of 99mTc complexes 17–19: the Iso-
link kit from TYCO, which contains sodium boranocarbonate (4.5 mg),
sodium tetraboronate decahydrate (2.85 mg), sodium tartrate dihydrate
(8.5 mg) and sodium carbonate (7.15 mg), was used for the labelling reac-
Tricarbonyl-4,4’-bis[(2,3,4,6-tetra-O-acetyl-b-d-galactopyranosyl)thio-
methyl]-2,2’-bipyridinerhenium chloride (12): 1H NMR (250 MHz,
3
CDCl3): d=8.88 (d, J6’’,5’’ =5.7 Hz, 2H; H-6’’), 7.46 (d, 2H; H-5’’), 8.19 (s,
2H; H-3’’), 4.44 (d, 3J1,2 =9.8 Hz, 2H; H-1), 5.25 (dd, 3J2,3 =9.9 Hz, 2H;
H-2), 5.02 (dd, 3J3,4 =3.4 Hz, 2H; H-3), 5.39 (d, 2H; H-4), 4.08–3.89 (m,
10H; H-5, H-6, H-6’, 2CH2), 2.11, 2.04, 1.97, 1.93 ppm (4 s, 24H; CH3-
10278
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 10273 – 10280

Sugar-Substituted Bipyridine Complexes of Re and 99mTc
FULL PAPER
À
tions. After the addition of 99mTcO4 in 0.9% saline solution the mixture
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was heated at 1008C for 30 min, then cooled to room temperature and
neutralised to pH 7 with a mixture of phosphate buffer (0.6m, 0.4 mL)
and HCl (1.0m, 0.6 mL). A 250-mL aliquot of this [99 mTc(H2O)3(CO)3]+
A
solution was added to compounds 8–10 (1.0 mg, 1.75 mmol) and the mix-
ture heated in a glass vial at 1008C for 30 min. After cooling to room
temperature the products were analysed for their radiochemical purity
(>95%) by HPLC under the following conditions: HPLC pump: Jasco
PU-1580; quaternary gradient unit: Jasco LG-1580-04; radio detector:
biostep IsoScan LC g; RI detector: Jasco RI 1530; column: RP-18, Li-
ChroCART 250-4, LiChrospher 100, RP-18e (5 mm); solvent A: triethyl-
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A
pH 2.25; solvent B: methanol; flow rate: 1.2 mLminÀ1; gradient: from 0–
3 min 100% A, 3–17 min to 100% B, from 17–22 min 100% B.
Histidine stability test of 99mTc complex 17: A solution of histidine
(0.1 mm, 500 mL PBS, pH 7.4) was added to a solution of complex 17
(500 mL; final ligand concentration: 0.05 mm) and the mixture was incu-
bated at 378C. Samples were taken at 1, 2.5, 4.5 and 24 h for HPLC anal-
ysis.
X-ray crystallography: The intensity data for compound 11 were collect-
ed on a Nonius KappaCCD diffractometer, using graphite-monochromat-
ed MoKa radiation. Data were corrected for Lorentz and polarisation ef-
fects, but not for absorption.[31] The structures were solved by direct
methods (SHELXS[32]) and refined by full-matrix least-squares tech-
2
niques against Fo (SHELXL-97[33]). The hydrogen atoms of the struc-
tures were included at calculated positions with fixed thermal parameters.
All non-disordered, non-hydrogen atoms were refined anisotropically.[33]
XP (SIEMENS Analytical X-ray Instruments, Inc.) was used for structure
representations.
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189–194.
Crystal data for 11:[34] C43H48ClN2O21ReS2, Mr =1214.60 gmolÀ1, yellow
prism, 0.04”0.04”0.04 mm3, monoclinic, space group P21, a=13.566(3),
3
b=7.1534(14), c=25.791(5) Š, b=96.34(3)8, V=2487.5(9) Š
, T=
À908C, Z=2, 1calcd =1.622 gcmÀ3
,
m
N
,
F(000)=1224,
N
17408 reflections h
A
G
N
2.318ꢀVꢀ27.538, completeness to Vmax =99.3%, 10877 independent re-
flections, Rint =0.0421, 8658 reflections with Fo >4s(Fo), 620 parameters,
one restraint, Robs =0.0494, wR2obs =0.0974, Rall =0.0744, wR2all =0.1061,
GOOF=1.033, Flack parameter=0.014(7), largest difference peak and
À3
hole: 1.103/À0.783 eŠ
.
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