MRI or optical imaging modality has its own strengths
and weaknesses. Thus, different and complementary sys-
tems are combined to overcome inherent limitations asso-
ciated with any individual technique. In particular, the
dualmodality of optical/MRIimaging may findpreclinical
and clinical applications. In the intraoperative procedure,
diseased tissues can be localized by MRI, which is then
biopsied for histologic validation by an optical method.
Duan et al.11 reported a copper-induced bimodal contrast
agent. However, none of the cases with contrast agent
toxicity in vitro has been evaluated so far.
Scheme 1. Synthesis Scheme of Probe 1 and 1ꢁCu2þ Complex
In this study, we report the synthesis and optical/MR
properties of the bimodal contrast agent (1). Probe 1showed
selective optical changes in the copper ions (Cu2þ) level in
physiological relevant milieus over other competitive ca-
tions. Additionally, T1-weighted MR signal enhancement at
3 T, together with turning-off of the optical signal, depend-
ing on cellular copper ion level, suggested that the probe 1
could be a suitable candidate for the Cu2þ ion-induced
bimodal imaging of cells.
Compound 2 was synthesized by the literature proce-
dures.12 As indicated in Scheme 1, 2 was reacted with
tert-butyl 2,20-(2-aminoethylazanediyl)diacetate (10) to give
3 in 18% yield. Compound 3 with ethanolamine was
refluxed in acetonitrile to obtain 4, whose bromination with
PPh3 and CBr4 at room temperature gave 5 in 90% yield.
Then, tert-butyl 2,20,200,2000-(2,20-azanediylbis(ethane-2,1-
diyl)bis(azanetriyl))tetraacetate (14) was attached to 5.
The deprotection of the tert-butyl group by trifluoroacetic
acid (TFA) in dichloromethane afforded 7. The ligand 7
was complexed with GdCl3 in deionized water at pH 6.5 to
give the Gd3þ complex 1. The detailed synthetic procedure
and the corresponding spectroscopic data are available in
the Supporting Information (SI).
To prove the chelating ability of compound 1 toward
various metals ions, we investigated the fluorescence
changes of 1 in the presence of various metal ions, includ-
ing Cu2þ ions (Figure 1A). We observed that the fluores-
cence of probe 1 was selectively quenched by Cu2þ ions,
because of the paramagnetic nature of the Cu2þ ions. No
fluorescence changes were observed upon the addition of
metal ions, except for Zn2þ ions. When the Zn2þ ions were
added to the solution of 1, the fluorescence intensity was
moderately enhanced due to the Chelation Enhanced
Fluorescence (CHEF) effect.13 From the Cu2þ ion titra-
tion experiment, the binding constant of 1 for Cu2þ ions
was calculated to be 9.30 ꢀ 104 Mꢁ1 based on 1:1 stoichio-
metry in the HEPES buffer solution (Figure 1B).
Figure 1. Fluorescence spectra of probe 1 (5 μM, λex = 440 nm)
in the presence of various metal ions (Liþ, Zn2þ, Ba2þ, Mn2þ
,
Hg2þ, Kþ, Naþ, Ca2þ, Sr2þ, Mg2þ, Fe2þ, Fe3þ, and Cu2þ) (A),
and different concentrations of Cu2þ ions (0ꢁ2500 μM) (B) in
HEPES buffer (10 mM, pH 7.4).
Then, we investigated the selectivity of Cu2þ ions toward
1 in the presence of other interfering cations such as Liþ,
Zn2þ, Ba2þ, Mn2þ, Hg2þ, Kþ, Naþ, Ca2þ, Sr2þ, and Mg2þ
in the aqueous milieu. We also observed that the fluores-
cence change is unaltered with other metal ions, including
Zn2þ ions (see Figure S3 in SI). It indicates that compound
1 is highly selective toward Cu2þ ions, which is in good
(11) Zhang, X.; Jing, X.; Liu, T.; Han, G.; Li, H.; Duan, C. Inorg.
Chem. 2012, 51, 2325.
(12) Lu, C.; Xu, Z.; Cui, J.; Zhang, R.; Qian, X. J. Org. Chem. 2007,
72, 3554.
(13) (a) Lu, X.; Zhu, W.; Xie, Y.; Li, X.; Gao, Y.; Li, F.; Tian, H.
Chem.;Eur. J. 2010, 16, 8355. (b) Tian, Y.; Su, F.; Weber, W.;
Nandakumar, V.; Shumway, B. R.; Jin, Y.; Zhou, X.; Holl, M. R.;
Johnson, R. H.; Meldrum, D. R. Biomaterials 2010, 31, 7411. (c) Lee, H.;
Lee, H.-S.; Reibenspies, J. H.; Hancock, R. D. Inorg. Chem. 2012, 51,
10904.
(14) (a) Motreff, A.; da Costa, R. C.; Allouchi, H.; Duttine, M.;
ꢀ
Mathoniere, C.; Duboc, C.; Vincent, J.-M. J. Fluorine Chem. 2012, 134,
49. (b) Reger, D. L.; Debreczeni, A.; Smith, M. D. Inorg. Chem. 2012, 51,
1068.
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