Glycoconjugated Rhenium(I) and 99m-technetium(I) carbonyl complexes from pyridyltriazole ligands obtained by "click chemistry"

Article abstract of DOI:10.1002/ejic.201402881

A series of pyridyltriazole ligands containing sugar moieties have been prepared by copper(I)-mediated 1,3-dipolar cycloaddition ("click" reaction) of azides functionalized with D-glucose, D-galactose, D-mannose, D-xylose as well as D-maltose residues, an

Full text of DOI:10.1002/ejic.201402881

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DOI:10.1002/ejic.201402881
1
Glycoconjugated Rhenium(I) and 99m-Technetium(I)
Carbonyl Complexes from Pyridyltriazole Ligands
Obtained by “Click Chemistry”
Justyna A. Czaplewska,[a,b] Frank Theil,[a] Esra Altuntas,[a,b]
Tobias Niksch,[c] Martin Freesmeyer,[c] Bobby Happ,[a,b]
David Pretzel,[a,b] Hendrik Schäfer,[a] Makoto Obata,[d]
Shigenobu Yano,[e] Ulrich S. Schubert,[a,b] and
Michael Gottschaldt*[a,b]
6
Keywords: Click chemistry / Rhenium / Technetium / Glycoconjugates / Ligand design
A series of pyridyltriazole ligands containing sugar moieties
spectroscopy, mass spectrometry, and by elemental analysis.
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16
21
have been prepared by copper(I)-mediated 1,3-dipolar cyclo- Coordination of the metal ion occurred by both the pyridyl
addition (“click” reaction) of azides functionalized with
D
-
nitrogen atoms and one of the triazole nitrogen atoms. Upon
treatment with an excess of histidine, the ReI complexes were
stable for only 2.5 h. After a longer period (24 h) ligand ex-
change was detected by HPLC measurements. In contrast, a
complex labeled with 99mTc was found to be stable for up to
26
31
36
glucose, -galactose, -mannose, -xylose as well as -malt-
D
D
D
D
ose residues, and 2-ethynylpyridine as alkyne. The peracet-
ylated saccharide residues as well as their water-soluble de-
protected derivatives were treated with Re(CO)5Cl to obtain
the corresponding mononuclear rhenium(I) carbonyl com- 24 h against an excess of histidine. Cytotoxicity was screened
plexes [LRe(CO)3Cl]. For comparison, one ReI complex
bearing a tert-butylbenzyl residue instead of a sugar moiety
as well as two dinuclear rhenium complexes derived from
a branched ligand containing two pyridyltriazole units were
prepared. The structure and integrity of the ligands and com-
plexes was established by NMR, IR, UV/Vis and fluorescence
for all ReI complexes against HepG2 cells using a concentra-
tion of 100 μ . All sugar-functionalized complexes were
found to be nontoxic, except for the complex derived from
the pyridyl (tert-butylbenzyl)-triazole, which exhibited re-
markable toxicity.
M
detectable by techniques using γ-radiation sensitive cameras
for example scintigraphy or single-photon emission com-
puted tomography (SPECT), and the radioisotope has a
half-life of 6.01 h. The success of 186Re-hydroxyethyl-
idenediphosphonate (HEDP) as a radiopharmaceutical
(treatment of bone metastasis)[5,6] has focused particular
attention on the coordination chemistry of rhenium
ions.[7–10] The half-life of 186Re is 3.7 d, and it decays
through emission of β (1.07 MeV) and γ (137 keV) rays. In
contrast, the half-life for 188Re is 17 h and this rhenium
isotope also emits β (2.12 MeV) and γ (155 keV) rays.[3]
Given that β-decay causes cell damage[11,12] and γ-rays can
be easily detected and used for monitoring the distri-
bution,[6,13] dual decay of 186/188Re isotopes can be used for
imaging as well as for radiotherapy.
Carbohydrates play an important role in many biological
processes,[14–17] and there have been many attempts to take
advantage of the high specificity and selectivity of processes
involving saccharides. The most prominent example in
terms of radio imaging is 18F-2-fluoro-2-deoxyglucose (18F-
FDG), which is used as a tracer in positron emission
tomography (PET), taking advantage of the increased
Introduction
Technetium (99mTc) and rhenium (186/188Re) isotopes are
important radionuclides that possess diagnostic and thera-
peutic potential.[1–4] 99mTc complexes are popular
radiotracers in medicine due to their nuclear properties and
easy accessibility. 99mTc emits γ rays (140 keV) that are
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51
56
61
41
[a] Laboratory of Organic and Macromolecular Chemistry
(IOMC),
Friedrich Schiller University Jena,
Humboldtstr. 10, 07743 Jena, Germany
E-mail: michael.gottschaldt@uni-jena.de
www.schubert-group.com
[b] Jena Center for Soft Matter (JCSM),
Friedrich Schiller University Jena,
Philosophenweg 7, 07743 Jena, Germany
[c] Clinics for Nuclear Medicine, University Hospital Jena,
Bachstraße 18, 07743 Jena, Germany
[d] Interdisciplinary Graduate School of Medicine and
Engineering,
University of Yamanashi,
Takeda 4-4-37, Kofu 400-8510, Japan
[e] Graduate School of Material Science,
Nara Institute of Science and Technology (NAIST),
8916-5, Takayama-cho, Ikoma, Nara 630-0192, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201402881.
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glucose uptake and metabolization by cancerous cells. Com- carbohydrate-linked azides.[37,38] The cytotoxicity and sta-
bining the useful features of saccharides such as biocompat- bility of the resulting complexes were studied as prerequi- 106
ibility, hydrophilicity and targeting properties, with those sites for their ability to be applied as radiotracers.
of metal complexes (e.g., fluorescence, cytotoxicity, but also
66
71
76
81
86
91
96
101
radioactive decay) has led to the synthetic analysis of a vari-
ety of sugar metal complexes for various applications.[18–20]
Many research groups have undertaken investigations on
new 99mTc radiotracers and rhenium complexes bearing
sugar residues, mainly with the aim of identify more eco-
Results and Discussion
Synthesis and Characterization
Azide derivatives 1a–e of sugars including glucose,
nomically viable substitutes for 18F-FDG. Initially, Yang et xylose, galactose, and mannose, were synthesized from the 111
al. synthesized the 99mTc complex of ethylenedicystein-de- corresponding bromides by reaction with sodium azide in
oxyglucose (99mTc-ECDG) and studied its biodistribution N,N-dimethylformamide (DMF), according to a previously
in lung-tumor-bearing mice.[21] The authors observed published method.[39] The products were converted into the
higher tumor-to-brain and tumor-to-muscle tissue ratios for corresponding pyridyltriazole derivatives 2a–e by copper(I)-
the distribution of 99mTc-ECDG compared with 18F-FDG, catalyzed “Huisgen” cycloaddition reaction with 2-ethynyl- 116
but a lower tumor-to-blood ratio. Connection of either pyridine (Scheme 1) using CuSO4 and sodium ascorbate as
monoamino-monoamide dithiol (MAMA) or mercapto- catalytic system in a mixture of tetrahydrofuran (THF) and
acetylglycylglycylglycine (MAG3) to 2-deoxy-2-aminogluc- water. The yields of the reactions were between 80 and 88%
ose (DG), galactose (Gal) or glucose (Glc) with different (with exception of maltose with only 48% yield).
linking units and radiolabeling with 99mTc yielded radio-
Deacetylation of 2a–e using DOWEX OH– exchange 121
tracers with a sugar-dependent biodistribution in vivo, dis- resin was performed in EtOH/H2O (1:1). The reaction mix-
playing promising tumor-to-muscle ratios (99mTc-MAG3- ture was stirred overnight at 60 °C. After removing the resin
DG in MA891 breast-tumor-bearing mice;[22] 99mTc- by filtration through silica gel and evaporation of the sol-
MAG3-Glc in Ehrlich-tumor-bearing mice[23,24]) or en- vent mixture, white powders were obtained. These reactions
richment in the liver as potential imaging agent for hepatic led to compounds 3a–e containing deprotected sugar moie- 126
function (99mTc-MAG3-Gal in healthy Swiss mice[25]). ties. In an analogous procedure, ligands 2f and 3f contain-
Moreover, additional binding functionalities such as 1,3-di- ing two 2-pyridyltriazole groups and glucose as the sugar
amines,[26] 3-hydroxypyridone,[27] 2-hydroxybenzyl,[28] pyr- moiety were prepared.
idyltriazole,[29,30]
2,2Ј-dipycolylamine,[31]
bis(2-pyr-
One triazole ligand without a sugar moiety, namely 2-{1-
idylmethyl)amine (DPA),[32,33] bis(2-quinolylmethyl)amine [4-(tert-butyl)benzyl]-1H-1,2,3-triazol-4-yl}pyridine (4), was 131
(DQA),[32] N-(2-pyridylmethyl)glycine (NPG),[32] 2,2Ј-bi- synthesized as a reference for further analysis and tests.[40]
pyridine,[34] N-(2-picolyl-4-hydroxy-3amino)benzoic acid The synthesis of 4 was performed in a mixture of EtOH
(PHAB),[35] and tripodal amines,[36] functionalized with and water (7:3 ratio) in the presence of CuSO4 and sodium
sugar moieties (limited to specific monosaccharides), have ascorbate. This mixture was heated in a microwave at
been used as ligands and reported as promising chelators 125 °C for 45 min, crystallized from a mixture of CH2Cl2/ 136
for TcI and ReI cores.
n-pentane, and the product was collected as a white powder.
Ligands 2a–f, 3a–f, and 4 were used to prepare the
To be able to study the influence of a variety of sac-
charide residues and to reduce the time-consuming prepara- rhenium complexes (Scheme 2) by reaction with Re(CO)5Cl
tion and purification of ligands, we chose to apply the in methanol.[29] The reaction mixture was stirred overnight
“Huisgen” cycloaddition reaction using readily available at 60 °C, concentrated, and cooled to low temperature 141
Scheme 1. Schematic representation of the synthesis of 2-pyridyltriazole ligands. Reagents and conditions: (a) 2-ethynylpyridine, CuSO4,
sodium ascorbate, THF/H2O (1:1), 60 °C, overnight, in the dark; (b) DOWEX OH–, EtOH/H2O (1:1), 60 °C, overnight.
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(4 °C). All complexes precipitated and were filtered off from Table 1. 13C NMR and IR data for selected rhenium complexes
5a,e and 6a,e.
Compound 13C NMR δ CO (ppm) IR νReCO [cm–1]
the solutions and obtained as yellow powders.
[c]
5a
5e
6a
6e
197.09, 195.70, 189.13[a] 2027 (νsym) 1926 (νasym) 1900 (νasym
)
[d]
197.07, 195.57, 189.10[a] 2022 (νsym) 1914 (νasym) 1887 (νasym
197.90, 197.11, 189.80[b] 2022 (νsym) 1933 (νasym) 1898 (νasym
)
)
[d]
[d]
198.14, 197.13, 194.01[b] 2022 (νsym) 1925 (νasym) 1891 (νasym
)
[a] Measured in CDCl3. [b] Measured in [D7]DMF + D2O. [c] Mea-
sured in KBr. [d] ATR-IR.
nals corresponding to the pyridyltriazole groups, which
were shifted to low field compared with those of the un-
complexed ligands. Furthermore, the 1H NMR spectra
showed double singlets between δ = 8 and 9 ppm, which
were assigned to the protons of the triazole rings in the 5- 161
position of 5a–f. Analogous peaks were observed for com-
plexes 6a–f. A typical ratio of 1:1 was observed by the 5-
1
proton of the triazole ring in the H NMR spectrum. The
13C NMR spectra contained a doubled set of signals, which
were caused by the obtained mixtures of diastereoisomers.
The UV/Vis spectra of the ligands (Figure 1) and com-
plexes 5a–f, 6a–f, and 7 (Figure 2) were measured in aceto-
166
Scheme 2. Synthesis of rhenium complexes 5a–f, 6a–f, and 7.
Reagents and conditions: (a) Re(CO)5Cl, MeOH, 60 °C, overnight.
The purity of the compounds was established by NMR,
UV/Vis, and IR spectroscopy, ESI-MS spectrometry as well
146 as elemental analysis. The mass spectra of 5a–f, 6a–f, and
7 showed signals of the complexes corresponding to [M –
Cl–]+ and [M + Na]+ ions. The IR spectra of 5a–f, 6a–f,
and 7 showed the appearance of new absorption bands cor-
responding to CO groups. Three absorption bands, which
151 appeared at 1900–2000 cm–1 (Table 1) are characteristic for
νCO stretching frequencies in rhenium carbonyl com-
plexes.[41,42]
The NMR spectra indicated that the products consist of
a mixture of diastereoisomers of complexes due to the chi-
156 rality of the sugar moiety. H NMR spectra displayed sig- azole ligand 3d bearing a mannose moiety in acetonitrile.
Figure 1. Absorption and emission spectra for selected 2-pyridyltri-
1
Figure 2. Absorption and emission spectra for a selected rhenium(I) complex 5a bearing a glucose moiety in acetonitrile.
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nitrile. The absorption bands at 330 nm can be assigned to
The preparation of 99mTc-labeled compound was per-
–
the metal-to-ligand charge transfer (MLCT) transitions. formed by addition of 99mTcO4 in 0.9% NaCl solution to
171 The strong absorptions at 200 nm were associated with the TYCO isolink kit and was followed by heating for
πǞπ* transitions of the ligands. Emission spectra have been 30 min at 100 °C. After cooling to room temperature, a mix- 211
measured for all ligands and rhenium complexes in aceto- ture of PBS and HCl was added for neutralization. The
nitrile (Figure 2). The complexes exhibited luminescence in resulting solution of [99mTc(H2O)3(CO)3]+ was added to 2-
the visible region, with λmax at 530 nm. In comparison to [4-(2-pyridyl)-1,2,3-triazol-1-yl]ethyl β-d-glucopyranoside
176 bipyridine-based rhenium complexes (λmax = 633 nm), (3a) and the mixture was heated to 100 °C for another
which were measured previously,[29] the absorption and 30 min. After cooling to room temperature, the radiochemi- 216
emission spectra of the pyridyltriazole-based rhenium com- cal purity of the product 8 (Figure 4) was analyzed by
plexes is blueshifted by 100 nm.
HPLC and found to be 94%.
In Vitro Stability Test for Rhenium Complexes
181
A histidine challenge experiment was performed to check
the stability of the chosen complexes based on a slightly
modified method described previously.[34,43,44] The experi-
ment was performed in the presence of histidine (20 fold
excess) in PBS buffer at 37 °C. The HPLC traces (MeOH/
186 triethylamine phosphate) of samples taken from the reac-
tion mixture were measured after 0, 2.5, 4.5, and 24 h. The
results of the stability tests for rhenium complexes are
shown in Figure 3.
Figure 4. 99mTcI complex 8 of glucosylated ligand 3a.
Histidine Stability Test of 99mTc Complex 8
A histidine stability test was performed for the techne-
tium complex of the pyridyltriazole ligand containing a 221
glucose moiety. The experiment was done in an analogous
way to the stability test of the rhenium complex described
above. A solution of histidine in PBS was added to a solu-
tion of technetium complex of 2-[4-(2-pyridyl)-1,2,3-triazol-
1-yl]ethyl β-d-glucopyranoside (8). The resulting mixture 226
was incubated at 37 °C and samples for HPLC analysis
were taken after 1, 2, 3, 4, 6, and 24 h. The HPLC traces
for the stability test are shown in Figure 5. Surprisingly, the
signal corresponding to the 99mTc labeled complex did not
change over time (retention time: 16.5 min) and the com- 231
plex was stable up to 24 h, with no other radioactive species
Figure 3. Histidine challenge experiment results (HPLC, UV/Vis
detector) for the mannose-bearing rhenium complex 6d.
A decrease of the main peak and an increase in the size
191 of new peaks was observed over time. Two peaks of
rhenium complexes were observed in the HPLC profile
(retention time: 13 min) corresponding to the mixture of
the diastereoisomers. The in vitro stability test showed that
the rhenium complex was stable for approximately 2.5 h.
196 After that time a new peak appeared (retention time:
11.5 min) corresponding to binding of histidine to the
rhenium complex, with concomitant reduction in the size
of the histidine peak over time (retention time: 15.5 min).
Some peaks related to decomposition and other side prod-
201 ucts were also observed (retention time: 9 and 13 min).
Labeling with 99mTc
Technetium and rhenium isotopes (99mTc, 186/188Re) of
tricarbonyl cores have been studied intensively. The 99mTc
isotope is one of the most important radionuclides due to
206 its short half-life (6 h) and emissions of readily detectable
140 keV γ-rays.
Figure 5. Histidine challenge experiment results (HPLC radiodetec-
tor traces) for the 99mTc complex 8.
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being detected. This is in contrast to the observations for termination of sugar-dependent biodistribution and further
the Re complexes described above as well as to previously development of selective radiotracers.
published trials with sugar-containing 99mTc complexes
286
236 based on bipyridine (stable only 4.5 h).[34] To our knowl-
edge, this is the first histidine-stable 99mTc complex with a Experimental Section
bidentate pyridyltriazole ligand. There is only one pyridyl-
Materials and General Experimental Details: All reagents and sol-
triazole ligand described (without a sugar moiety) that was
vents were commercial products purchased from Aldrich, Sigma,
used for complexation of 99mTc, but no stability tests were
Fluka, Across Organics, or Alfa Aesar and were used without fur-
ther purification. The Isolink kits were a gift from Mallinckrodt.
241 performed in that study.[45] The described stable 99mTcI
291
296
301
complexes are derived from ligands that are at least triden-
tate and always require a third coordination side.
Chromatographic separation was performed with standardized sil-
ica gel 60 (Merck). The progress of reactions was monitored by
thin-layer chromatography (TLC) using glass plates precoated with
silica gel 60 (Merck). Azides 1a–f were prepared according reported
procedures.[46–50] For cytotoxicity tests, HepG2 cells, 96-well-plates
(Greiner Bio-One), Trypsin (Lonza), HBBS (Lonza), DMEM-F12
(Invitrogen) + 1% Penicillin/Streptomycin 100x (PAA) + 10% fetal
calf serum (Sigma–Aldrich), plate reader POLARstar Omega
(BMG Labtech), CellTiter-Blue Cell Viability Assay (Promega),
DMSO (AppliChem) were used.
Cytotoxicity Test
For all rhenium(I) complexes, cytotoxicity tests were per-
246 formed against HepG2 cells. Cells were cultivated in 37 °C
in DMEM-F12 and incubated for 24 to 96 h. Every 24 h,
96-well-plates were taken to perform a CellTiter-Blue Cell
Viability Assay. For detection, resazurin dye was used. The
resazurin itself is a non-fluorescent, dark-blue dye (absorp-
251 tion maximum at 650 nm) and it is reduced to resorufin in
viable cells (the color changes to pink, emission maximum
at 590 nm, absorption maximum at 573 nm). The ab-
sorbance was measured at 0, 1, 2, and 4 h. The cytotoxicity
tests for the complexes against HepG2 cells showed that
256 none of the sugar-bearing ligands or complexes was cyto-
toxic up to a concentration of 100 μm. In contrast, the
rhenium complex of the ligand which did not contain a
sugar moiety (7) showed significant toxicity.
Instrumentation: 1H and 13C NMR spectra were recorded with
Bruker spectrometers (400, 300 and 250 MHz). UV/Vis absorption
spectra were recorded with a Specord 250 (Analytik Jena) and
emission spectra with a FP 6500 (JASCO) spectrometer (298 K,
10–6 and 10–5 m solutions in acetonitrile or methanol). IR spectra
were recorded with a Bruker Tensor 37 and a Nicolet AVATAR
370 DTGS spectrometer using the ATR technique or with a
Shimadzu FTIR 8700 as KBr disks. MALDI-TOF MS spectra
were obtained with a Voyager DE PRO Biospectrometry Workst-
ation (Applied Biosystems) time-of-flight mass spectrometer with 311
dithranol as matrix. Elemental analyses were measured with a Leco
CHN-932. Electrospray ionization mass spectrometry (ESI-MS)
performed with a JEOL JMS-T100LC and a Bruker MicroQTof.
For HPLC analysis during the histidine stability test, a JASCO
306
system equipped with detector MWL (MD-1510), pump (PU-980),
and column (Daicel Chiracel OD-H; Phenomenex Synergi 4u
Hydro-RP 80A; 250ϫ4.6 mm) was used. To assess the radiochemi-
cal purity, a HPLC-system was used with a Binary pump (HP
1100), radio detector (Knauer Radioflow Detector LB 509), refrac-
tive index detector (Agilent technologies 1260 Infinity), and col-
umn (HP ODS Hypersil; 5 μm, 100ϫ4.6 mm).
316
Conclusions
261
New carbohydrate-based 2-pyridyltriazole ligands have
been synthesized by using the copper(I)-catalyzed azide-alk-
yne 1,3-dipolar Huisgen cycloaddition, which allowed the
straightforward synthesis of the desired compounds (yields
Ͼ80%) under mild conditions. Synthesis of pyridyltriazole
321
General Procedure for the Preparation of Azides: Azide derivatives
1a–e were synthesized from suitable bromides by reaction with an
excess of sodium azide in DMF.[46–50]
266 ligands can be applied to different saccharides. The ob-
tained organic ligands were treated with [Re(CO)5Cl] and
the formed complexes were characterized by means of
NMR, IR, and UV/Vis absorption and by emission spec-
troscopy, elemental analysis as well as mass spectrometry
271 to verify their molecular structure. Radiolabeling of one of
the ligands with 99mTc resulted in the formation of the cor-
responding complex in high radiochemical purity. The in
vitro stability tests for selected rhenium complexes showed
that the complexes are stable for only about 2.5 h before
276 they undergo side reactions. In contrast, the 99mTc complex
containing solely the gluco-conjugated 2-pyridyltriazole
ligand is stable for over 24 h in the histidine stability test.
Additionally, the cytotoxicity of the rhenium(I) complexes
against HepG2 cells was tested and the results showed that
281 the obtained complexes bearing sugar residues are not toxic
up to a concentration of 100 μm. Considering the stability
of the 99mTc complex and the observed nontoxicity, the syn-
General Procedure for the Copper(I)-Catalyzed Azide-Alkyne 1,3-
Cycloaddition: To a solution of suitable azide 1a–f and 2-ethynyl-
pyridine in THF/H2O (1:1), copper(II) sulfate solution (5–10 mol-
%) in water and a sodium ascorbate solution (50–100 mol-%) in
water were added. The mixture was stirred at 60 °C for 2 d in the
dark. The products were extracted with ethyl acetate, washed with
25% ammonia solution or filtered through silica gel to remove cop-
per residue and collected as white powders.
326
331
2-[4-(2-Pyridyl)-1,2,3-triazol-1-yl]ethyl 2,3,4,6-Tetra-O-acetyl-β-D-
glucopyranoside (2a):[51] 2-Ethynylpyridine (0.5 g, 4.86 mmol) was
added to a solution of 1a (1.87 g, 4.48 mmol), then sodium ascorb-
ate (297 mg, 1.5 mmol) and CuSO4·5H2O (22 mg, 0.1 mmol) were
added.[29] Yield: 1.8 g (80%). 1H NMR (300 MHz, CDCl3): δ =
336
341
3
8.57–8.55 (m, 1 H, 6-pyH), 8.17 (s, 1 H, 5-triazoleH), 8.13 (d, J =
3
4
7.8 Hz, 1 H, 3-pyH), 7.79–7.73 (dt, J = 7.8, J = 2.4 Hz, 1 H, 4-
pyH), 7.24–7.19 (ddd, 3J = 7.5, 3J = 3.8, J = 1.1 Hz, 1 H, 5-pyH),
4
5.19–4.98 (m, 3 H, 3-H, 4-H, 2-H), 4.68 (m, 1 H, CH2N), 4.61–
3
thesized derivatives are potential candidates for in vivo de- 4.51 (m, 1 H, CH2-N), 4.49 (d, J = 7.5 Hz, 1 H, 1-H), 4.33–4.21
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(m, 2 H, O-CH2, 6-H), 4.15–4.09 (m, 1 H, 6-H), 4.00–3.93 (m, 1 δ = 9.00 (d, J = 5.7 Hz, 2 H, 6-pyH), 8.42, 8.38 (2s, 2 H, 5-tri-
H, O-CH2), 3.71–3.65 (m, 1 H, 5-H), 2.07, 2.00, 1.98, 1.89 (4s, 12 azoleH), 8.04–8.01 (m, 4 H, 3-pyH, 4-pyH), 7.47–7.44 (m, 2 H, 5-
H, CH3) ppm. 13C NMR (CDCl3): δ = 170.58, 170.12, 169.44, pyH), 5.26–5.19 (m, 2 H, 3-H), 5.11–5.00 (m, 4 H, 4-H, 2-H), 4.84–
406
346
351
3
3
169.35 (CO), 150.17 (2-pyC), 149.40 (6-pyC), 148.37 (4-triazoleC),
136.78 (4-pyC), 123.27 (5-triazoleC), 122.80 (5-pyC), 120.08 (3-
4.65 (m, 4 H, CH2), 4.56 (d, J = 7.8 Hz, 1 H, 1-H), 4.51 (d, J =
7.8 Hz, 1 H, 1-H), 4.32–4.15 (m, 6 H, CH2, 6-H), 4.87–3.92 (m, 5-,
pyC), 100.53 (C-1), 72.55 (C-3), 71.98 (C-5), 70.85 (C-2), 68.18 (C- 2 H, H), 3.80–3.72 (m, 2 H, 6-H), 2.09–1.65 (8s, 24 H, CH3) ppm.
4), 67.73 (O-CH2), 61.68 (C-6), 50.14 (CH2-N), 20.68, 20.53, 20.36
13C NMR (CDCl3): δ = 197.09, 195.70, 189.13 (CO), 170.58–169.44 411
(CH3) ppm. ESI-TOF MS: m/z calcd. for C23H28N4O10Na [M + (CO,OAc), 153.20 (6-pyC), 149.37, 149.28, 148.77, 148.68 (2-pyC,
Na]+ 543.17; found 543.1; m/z calcd for C23H29N4O10 [M + H]+ 4-triazoleC), 139.28, 139.22 (4-pyC), 125.83 (5-triazoleC), 125.50,
521.19; found 521.1. C23H28N4O10 (520.50): calcd. C 53.07, H 5.42,
125.37 (5-pyC), 122.22 (3-pyC), 100.48, 100.11 (C-1), 72.19, 72.09
N 10.76; found C 53.11, H 5.36, N 10.42. IR (ATR): ν = 1736 (C-3), 71.23, 71.11 (C-5), 68.21, 68.13 (C-2), 66.77 (C-4), 66.23
˜
(νCO) cm–1. UV/Vis (CH3CN): λ (εϫ10–3/m–1 cm–1) = 281 (4.76), (CH2), 61.64, 61.57 (C-6), 52.05, 51.84 (CH2), 20.97–20.51 416
356 244 (8.91), 207 (16.72) nm. FL (CH3CN, λex = 281 nm): λ =
(CH3,OAc) ppm. ESI-TOF MS: m/z calcd. for C26H28O13N4Re
[M – Cl]+ 790.73; found 790.9; m/z calcd. for C26H28O13N4ClReNa
[M + Na]+ 849.08; found 848.9. C26H28ClN4O13Re (826.18): calcd.
C 37.80, H 3.42, N 6.78; found C 37.54, H 3.16, N 6.61. IR (ATR):
314 nm.
Ligands 2b–f were prepared as described for 2a. For more details
see the Supporting Information.
ν
˜
=
1736 (νC=O), 1879 (broad), 2022 (νMCO) cm–1. UV/Vis
421
426
(CH3CN): λ (εϫ10–3/m–1 cm–1) = 332 (3.72), 275 (10.26), 222
(22.52) nm. FL (CH3CN, λex = 332 nm): λ = 533 nm.
General Procedure for the Preparation of Deprotected Ligands: The
361
366
protected triazole ligands 2a–f were dissolved in an ethanol/water
solution, then DOWEX 550 OH– anion exchange resin was added.
The reaction mixture was stirred at 60 °C overnight. When TLC
(ethyl acetate) indicated that no starting material remained, the re-
action mixture was filtered and evaporated to afford the depro-
tected triazole ligands 3a–f as white powders. In the case of 3e,
compound 2e was dissolved in methanol and sodium methoxide
was added until pH 9. After 1 h, TLC (ethyl acetate) indicated that
no starting material remained and DOWEX H+ was added grad-
ually to reach pH 7.
Complexes 5b–f were prepared as described for 5a. For more details
see the Supporting Information.
2-[4-(2-Pyridyl)-1,2,3-triazol-1-yl]ethyl β-D-Glucopyranoside Rhe-
nium Complex (6a):[29] Rhenium pentacarbonyl chloride (69 mg,
0.19 mmol) was added to a solution of 3a (0.06 g, 0.17 mmol).
1
Yield: 96 mg (86%). H NMR (300 MHz, [D7]DMF + D2O): δ =
9.38 (2s, 2 H, 5triazoleH), 9.07 (d, 3J = 5.49 Hz, 4 H, 6-pyH), 8.33–
7.76 (m, 4 H, 3-pyH, 4-pyH), 7.75–7.71 (m, 2 H, 5-pyH), 4.98–4.92 431
3
371 2-[4-(2-Pyridyl)-1,2,3-triazol-1-yl]ethyl β-D-Glucopyranoside (3a):
(m, 4 H, CH2), 4.49 (dd, J = 7.6 Hz, 2 H, 1-H), 4.37–4.33 (m, 2
DOWEX 550 OH– anion exchange resin (10 g) was added to a solu-
tion of 2a (1 g, 1.92 mmol).[26] Yield: 0.32 g (60%). 1H NMR
(400 MHz, D2O): δ = 8.46–8.44 (m, 1 H, 6-pyH), 8.37 (s, 1 H, 5-
triazoleH), 7.89–7.82 (m, 2 H, 3-pyH, 4-pyH), 7.38–7.36 (t, 3J =
H, CH2), 4.21–4.17 (m, 2 H, CH2), 3.91–3.66 (m, 2 H, 6-Ha), 3.65–
3.41 (m, 2 H, 6-Hb), 3.40–3.18 (m, 4 H, 5-H,4-H, 3-H,2-H) ppm.
13C NMR ([D7]DMF + D2O): δ = 197.90, 197.11, 189.80 (CO),
153.19 (6-pyC), 149.37,148.56, 148.54 (2-pyC, 4-triazoleC), 126.89,
126.82 (5-triazoleC), 126.52 (5-pyC), 122.73 (3-pyC), 103.51,
103.35 (C-1), 77.29 (C-4), 77.00 (C-5), 73.81 (C-2), 70.56 (C-3),
67.31, 67.09 (CH2), 61.65 (C-6), 52.31, 52.24 (CH2) ppm. ESI-TOF
MS: m/z calcd. for C18H20O9N4Re [M – Cl]+ 622.07; found 622.9;
436
3
376 6.6 Hz, 1 H, 5-pyH), 4.69 (m, 2 H, CH2-N), 4.45 (d, J = 7.92 Hz,
1-H), 4.35–4.30 (m, 1 H, O-CH2), 4.18–4.13 (m, 1 H, O-CH2), 3.87–
2
3
3.83 (m, 1 H, 4-H), 3.67–3.63 (dd, J = 12.8, J = 6.8 Hz, 1 H, 6-
3
H), 3.48–3.32 (m, 3 H, 6-H, 5-H, 3-H), 3.28–3.24 (t, J = 9.2 Hz,
1 H, 2-H) ppm. 13C NMR (D2O): δ = 148.93 (6-pyC), 148.09,
146.77 (2-pyC, 4-triazoleC), 138.59 (4-pyC), 124.39 (5-triazoleC),
123.98 (5-pyC), 120.93 (3-pyC), 102.53 (C-1), 75.98 (C-5), 75.71
(C-3), 73.03 (C-2), 69.65 (C-4), 68.06 (O-CH2), 60.79 (C-6), 50.59
(CH2-N) ppm. ESI-TOF MS: m/z calcd. for C15H20N4O6Na [M +
Na]+ 375.13; found 375.2; m/z calcd. for C15H21N4O6 [M + H]+
353.15; found 353.2. C15H20N4O6 (352.35): calcd. C 51.13, H 5.72,
m/z calcd. for C18H20O9N4ClReNa [M + Na]+ 681.04; found 680.9. 441
C18H20ClN4O9Re·0.5H2O (667.0): calcd. C 32.41, H 3.17, N 8.40,
381
386
Cl 5.31; found C 32.41, H 2.97, N, 8.22, Cl 5.58. IR (ATR): ν =
˜
1898, 1933, 2022 (νMCO), 3434 (νOH) cm–1. UV/Vis (CH3CN): λ
(εϫ10–3/m–1 cm–1) = 330 (3.57), 271 (12.62), 222 (20.13) nm. FL
(CH3CN, λex = 330 nm): λ = 533 nm.
446
451
Complexes 6b–f were prepared as described for 6a. For more details
see the Supporting Information.
N 15.90; found C 51.31, H 5.75, N 15.82. IR (ATR): ν = 3279
˜
(νOH) cm–1. UV/Vis (CH3CN): λ (εϫ10–3/m–1 cm–1) = 281 (4.54),
243 (8.22), 204 (10.78) nm. FL (CH3CN, λex = 281 nm): λ =
322 nm.
tert-Butylbenzyl-4-(2-pyridyl)-1,2,3-triazole Rhenium Complex (7):
Rhenium pentacarbonyl chloride (124 mg, 0.34 mmol) was added
to a solution of 4 (0.10 g, 0.34 mmol). Yield: 129 mg (65%). 1H
NMR (300 MHz, [D7]DMF): δ = 9.59 (s, 1 H, 5triazoleH), 9.27 (d,
391
396
Ligands 3b–f were prepared as described for 3a. For more details
see the Supporting Information.
3
3J = 5.4 Hz, 1 H, 6-pyH), 8.58 (d, J = 7.75 Hz, 1 H, 3-pyH), 8.49
2-{1-[4-(tert-Butyl)benzyl]-1H-1,2,3-triazol-4-yl}pyridine (4): The
ligand was prepared according to a previously described pro-
cedure.[40] For more details see the Supporting Information.
(td, 4J = 1.38, 3J = 7.65 Hz, 1 H, 4-pyH), 7.92–7.86 (m, 1 H, 5-
py), 7.71 (m, 4 H, benzylH), 6.14 (s, 2 H, CH2), 1.47 (s, 9 H,
CH3) ppm. 13C NMR ([D7]DMF): δ = 198.06, 197.21, 189.82 (CO), 456
153.24 (6-pyC), 151.96 (benzylCq), 149.36, 149.10 (2-pyC, 4-tri-
azoleC), 140.64 (4-pyC), 131.57 (benzylCq), 128.51 (benzylC),
126.51 (5-pyC), 126.08 (benzylC), 125.98 (5triazoleC), 122.88 (3-
pyC), 54.99 (CH2), 30.79 (CH3) ppm. ESI-TOF MS: m/z calcd. for
C21H20O3N4Re [M – Cl]+ 563.11; found 563.0; m/z calcd. for 461
General Procedure for Preparation of Rhenium(I) Complexes: To a
solution of the ligands 2a–f or 3a–f in methanol, rhenium penta-
carbonyl chloride was added. The mixture was stirred overnight at
60 °C. After cooling to room temperature, the solution was concen-
trated and left for precipitation. Yellow powders were collected.
401 2-[4-(2-Pyridyl)-1,2,3-triazol-1-yl]ethyl 2,3,4,6-Tetra-O-acetyl-β-
D
-
C21H20O3N4ClReNa [M
+
Na]+ 621.07; found 620.9.
glucopyranoside Rhenium Complex (5a):[29] Rhenium pentacarbonyl
C21H20ClN4O3Re (598.07): calcd. C 42.17, H 3.37, N 9.37; found
chloride (42 mg, 0.12) was added to a solution of 2a (0.06 g, C 42.35, H 3.62, N 9.72. IR (ATR): ν = 1895 (ν
broad), 2022
˜
MCO
0.12 mmol).[29] Yield: 60 mg (63%). H NMR (300 MHz, CDCl3):
(νMCO) cm–1. UV/Vis (CH3CN): λ (εϫ10–3/m–1 cm–1) = 335 (3.89),
1
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466 275 (13.97), 221 (36.71) nm. FL (CH3CN, λex = 335 nm): λ =
ditionally, the authors thank Mallinckrodt for providing Isolink
kits for radiolabeling.
533 nm.
526
In Vitro Stability Test for Rhenium Complex: A solution of histidine
(20 molar excess) in a mixture of PBS (phosphate buffered saline)
and water (1:9) was added to a solution of the complex in PBS.
The experiment was performed at 37 °C for 24 h and the progress
of the experiment was monitored by HPLC (MeOH/TEAP). The
samples were taken from the reaction mixture after 0, 1, 2.5, 4.5,
and 24 h. Rt = 9 (unidentified product), 11.5 {[Re(CO)3-His]},
13 (Re complex), 15.5 (histidine) min.
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99mTc(H2O)3(CO)3]+ solution (300 MBq, ca. 0.4 mL) was added
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Received: September 17, 2014
Published Online: ᭿
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Glycoconjugated Tc Radiotracers
J. A. Czaplewska, F. Theil, E. Altuntas,
T. Niksch, M. Freesmeyer, B. Happ,
D. Pretzel, H. Schäfer, M. Obata,
S. Yano, U. S. Schubert,
661
M. Gottschaldt* ................................ 1–9
Glycoconjugated Rhenium(I) and 99m-
Technetium(I) Carbonyl Complexes from
Pyridyltriazole Ligands Obtained by “Click
Chemistry”
666
671
A series of pyridyltriazole ligands contain-
ing sugar moieties and their corresponding
Re(I) complexes were synthesized and
characterized. Stability tests against histid-
ine showed that the complexes are stable
up to 2.5 h; the 99mTc-labeled complex was
stable up to 24 h. All sugar-based ReI com-
plexes were nontoxic against HepG2 cells;
in contrast, the ReI complex without a
carbohydrate moiety was toxic.
Keywords: Click chemistry / Rhenium /
Technetium / Glycoconjugates / Ligand
design
Eur. J. Inorg. Chem. 0000, 0–0
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