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Cc 15 1677-1683.b401186d chapter . page1677

Novel coordinating motifs for lanthanide(III) ions based on
5-(2-pyridyl)tetrazole and 5-(2-pyridyl-1-oxide)tetrazole. Potential new
contrast agents†

Antonio Facchetti,*a Alessandro Abbotto,b Luca Beverina,b Silvia Bradamante,c Palma Mariani,d
Charlotte L. Stern,a Tobin J. Marks,a Alberto Vaccad and Giorgio A. Pagani*b
a Department of Chemistry, Northwestern University, 2145 Sheridan Road, 60208, Evanston, IL, USA
b Department of Materials Science, University of Milano-Bicocca, Via Cozzi 53, I-20125, Milano, Italy
c CNR-Institute of Molecular Science and Technologies, Via Golgi 19, I-20133, Milano, Italy
d Department of Chemistry, University of Florence, Via della Lastruccia 3, I 50019, Sesto Fiorentino, Italy

Received (in Cambridge, UK) 9th February 2004, Accepted 2nd June 2004
First published as an Advance Article on the web 30th June 2004
Water-soluble and neutral Ln(III) and Zn (II) complexes of
employing m-chloroperbenzoic acid in MeOH. This result is pyridine- and (pyridine-1-oxide)tetrazole have been synthesized
remarkable considering the large number of azine nitrogens present and the Gd derivatives have great potential as high-relaxivity
in 1 and 3. Indeed, other oxidizing agents such as H2O2 and
low-osmolarity MRI contrast agents.
CH3CO3H afford inseparable mixture of products. The protonation
constant of 1 (pKa = 4.11) and 2 (pKa = 3.55) were obtained via
The emergence of magnetic resonance imaging (MRI) techniques potentiometric titration. The pKa values are lower than in tetrazole for medical diagnosis has been accompanied by an intensive growth due to conjugation with the electron-poor pyridine ring. To fully of interest in the study of paramagnetic metal complexes as contrast explore the ligand capacities of both –NNC–C–N2– and O2– agents (CAs) designed to enhance tissue differentiation.1,2 The N+NC–C–N2– moieties present in this new class of ligands, anions majority of the approved CAs are Gd(III) chelates, the efficiency of 12 and 22 were reacted with both a transition metal ion [Zn(II), to
which is given by the proton relaxivity, r1, described as the proton allow chelate 1H NMR analysis] and a set of lanthanide [Gd(III), relaxation rate enhancement in the presence of the CA compared to Eu(III), and Dy(III)] ions, whereas ligands 32 and 42 were
a diamagnetic environment. Currently, all Gd(III)-based chelates investigated targeting both Zn(II) and Gd(III) ions.
approved for use in MRI are nine-coordinate complexes in which a The synthesis of neutral chelates 1–4 was planned depending on
ligand occupies eight binding sites at the metal center and the ninth their expected solubility properties. Poorly or relatively soluble coordination site is occupied by one water molecule. Most of the chelates were prepared by reacting LH with the stoichiometric investigated CAs are derivatives of a limited number of coordinat- amount of K2CO3 in H2O (Scheme 2A). The corresponding anion ing core structures, such as those of DTPA (diethelenetriamine- L2 was then reacted with concentrated aqueous solutions of the N,N,NA,NB,NB-pentaacetic acid) and DOTA (1,4,7,10-tetraazacy- corresponding metal salts (acetate or chloride) and the resulting clododecane-N,NA,NB,NÚ-tetraacetic acid) which have relaxivity complexes isolated by filtration. For highly soluble Gd chelates, the values of ~ 4–5 mM21s21.3 Incorporation/functionalization of ligand anion was prepared by reacting LH with BaCO3 (Scheme these ligand motifs into polymeric, dendrimeric, and protein 2B). A solution of Gd2(SO4)4 was then added to the barium salt, and structures increases the rotational correlation time and results in the insoluble BaSO4 filtered off. Evaporation of water afforded the dramatically improved r1 values.3,4 However, the maximum values chelate. All the chelates (Table S1, Supporting Information†) were are still about half of the possible theoretical limit ( ~ 100 purified by crystallization from either H2O or H2O–MeOH.
Single crystals of Gd(12)3, Gd(22)3, and Zn(22)2 were obtained
From this intense research effort, all heteroaromatic-based either by cooling of a saturated solution or slow evaporation of an ligands are practically absent. This is surprising considering the aqueous solution of the complex.§ The Gd(III) ion in Gd(12)3 and
rich chemistry, stability, and good coordinating properties of many Gd(22)3 (Fig. 1) is nona- and octacoordinate by three bidentate
heterocycles.5 We describe here a new family of ligands (LH =
1–4) based on the pyridine/pyridine-N-oxide–tetrazole skeleton.
Ligands 3 and 4 bearing hydrophilic chains were envisioned to
improve solubility in water. Thanks to the acidity of tetrazole (pKa
= 4.89 in H2O)5 all these systems form stable anions (L2) at physiological pH range, which act as efficient ligands to transition[Zn(II)] and lanthanide [Gd (III), Eu(III), Dy(III)] metal ions.
Scheme 1 Synthetic routes to ligands 1–4.
Compound 16 and new ligands 2–4 were prepared according to
Scheme 1.‡ The tetrazole ring in 1 and 3 was synthesized by
reaction of the corresponding cyanopyridine with HN3 (NaN3 +
NH4Cl) in DMF at 130 °C. Regioselective oxidation of the pyridine
nitrogen of 1 and 3 to afford 2 and 4, respectively was achieved
† Electronic supplementary information (ESI) available: chelate analytical data, crystal structure of Zn(22)2, potentiometric titrations, and relaxivity
plots. See Scheme 2 Synthetic routes to the neutral chelates.
C h e m . C o m m u n . , 2 0 0 4 , 1 7 7 0 – 1 7 7 1 T h i s j o u r n a l i s T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4 mL) was reacted at 130 °C for 2–4 h. After cooling, the inorganic salts were
discarded by filtration and the solvent removed under reduced pressure. The
residue was taken up with dilute HCl (0.1 M, 20 mL) and the formed solid
collected and recrystallized from H2O. 1 (78%): mp 213 °C; 1H NMR (300
MHz, DMSO-d6): d 8.79 (dd, J = 5.0, 1.7, H-6); 8.22 (d, J = 8.0, H-3); 8.08
(td, H-4); 7.63 (dd, J = 8.0, H-5). 3 (76%): mp > 240 °C; 1H NMR (300
MHz, DMSO-d6): d 9.18 (d, J = 2.0, H-2); 8.47 (dd, J = 8.3, 2.0, H-4); 8.44
(d, J = 8.0, –CONH–); 8.32 (d, J = 8.0, H-5); 4.70 (s, OH); 4.01 (dtt, J =
8.0, 5.8, 5.8, CH); 3.60–3.48 (m, CH2). Ligands 2 and 4. A mixture of parent
pyridyltetrazole (6.8 mmol) and m-chloroperbenzoic acid (11.6 mmol) in
MeOH (200 mL) was reacted overnight at room temperature without
Fig. 1 Crystal structure of Gd(12)3 and Gd(22)3.
stirring. 2 (66%) was isolated by filtration and recrystallized from H2O. mp
> 240 °C; 1H NMR (300 MHz, DMSO-d6): d 8.56 (d, J = 6.4, H-6); 8.41 (dd, J = 7.8, 2.1, H-3); 7.66 (td, H-4); 7.63 (dd, J = 7.7, H-5). 4 (80%) was
ligands and three/two H2O molecules, respectively. The different isolated by evaporating the solvent and, after washing the solid with CH2Cl2 coordination number probably reflects the dissimilar steric require- (300 mL), recrystallized from EtOH/H2O. mp > 240 °C; 1H NMR (300 ments3 of a five- versus a six-membered chelation motif for 1 and
MHz, DMSO-d6): d 8.97 (s, H-2); 9.49 (d, J = 8.5, H-4); 8.53 (d, J = 8.5, 2, respectively. Interestingly, three/five additional H2O molecules
– CONH–); 7.92 (d, J = 8.5, H-5); 4.70 (s, OH); 4.01 (m, CH); 3.60–3.40 are present in the second coordination sphere, suggesting large relaxivity values. The geometry of Zn(22)
§ Crystal Structure. All measurements were made on a Bruker SMART octahedral with two equatorial ligands and two H CCD diffractometer with graphite monochromated MoKa (0.71073 Å) radiation. The data were collected at a temperature of 153(2) K and thestructures were solved by direct methods and expanded using Fourier Ligands 1–4 and the corresponding Gd(III) chelates are highly
techniques using SHELXTL. All non-hydrogen atoms were refined soluble in H2O. Chelate solubility increases going from the anisotropically. Hydrogen atoms were included in idealized positions and unsubstituted 1 (2.1 g L21) and 2 (4.7 g L21)) to the hydroxyalkyl-
not refined. Intensities were corrected for absorption. Gd(12)3. Monoclinic,
substituted 3 (25.6 g L21) and 4 (21.2 g L21) systems. An
P2(1)/n, Z = 4. Cell dimensions: a = 9.0273(9) Å; b = 17.714(3) Å; c = additional requirement for practical application of Gd(III) com- 16.7480(19) Å; a = 90°; b = 99.819(9)°; g = 90.00°. V = 2639.0(6) Å3, plexes is thermodynamic stability, to avoid toxicity of the metal.
rcalcd = 1.794 g cm23, total/independent reflections = 24502/6489, R(int) Potentiometric data obtained by titration of a Gd:LH (LH = 1 and
= 0.0415, R = 0.0280. Zn(22)2. CCDC 232483.Monoclinic, C2/c, Z = 8.
2, Figs. S3 and S4†) mixture in the pH range of 2–5 (T = 298 K,
Cell dimensions: a = 31.01(2) Å; b = 8.561(4) Å; c = 7.546(3) Å; a = I = 0.1 M) can be fitted assuming the stepwise addition of up to 90°; b = 100.65(5)°; g = 90°. V = 1968.8(18) Å3, rcalcd = 1.875 g cm23,total/independent reflections = 8819/2401, R(int) = 0.0564, R = 0.0469.
three L2 to the Gd ion,7 leading to a cumulative stability constant (logb) values of 6.7(2) and 8.66(7) for Gd(12)
3. CCDC 232481. Monoclinic, P2(1)/n, Z = 4. Cell dimensions: a = 3 and Gd(22)3,
7.847(3) Å; b = 39.783(7) Å; c = 9.092(3) Å; a = 90°; b = 96.50(3)°; g respectively. As expected, these values are lower than those of = 90.00°. V = 2820.0(2) Å3, rcalcd = 1.780 g cm23, total/independent approved CAs based on macrocycle octadentate ligands ( > reflections = 18878/5168, R(int) = 0.0393, R = 0.0762. CCDC 232482.
See for crystallographic data 1 is the key property of a potential contrast agent. Measurements were performed at pH = 5.7–7.2 and r1values (mM21 s21) were obtained from the slope of a plot of 1/T 1 (a) The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, eds. A. Merbach and E. Toth, John Wiley and Sons, New York, 3] (concentration range 0.2–1 mM, Fig. S5†) and were 2001; (b) S. Aime, M. Botta, M. Fasano and E. Terreno, Acc. Chem. Res., found to be: Gd(12)3 (9.98); Gd(22)3 (9.25); Gd(32)3 (10.79);
1999, 32, 941; (c) P. Caravan, J. J. Ellison, T. J. McMurry and R. B.
Gd(42)3 (17.72). These very high values cannot be explained solely
Lauffer, Chem. Rev., 1999, 99, 2293; (d) S. H. Koenig and R. D. Brown
on the basis of a large number of water molecules probably III, Prog. NMR Spectrosc., 1990, 22, 487; (e) B. L. Engelstad and G. L.
coordinating the metal ion in aqueous solution. Rather, very fast Wolf, in Magnetic Resonance Imaging, eds. D. D. Stark and W. G.
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2 (a) L. Luttuada and G. Lux, Tetrahedron Lett., 2003, 44, 3893; (b) L.
2O might be involved, as suggested for complexes of heptadentate Vander Elst, M. Port, I. Raynal, C. Simonot and R. N. Muller, Eur. J. In summary, we described here new bidentate ligand motifs Inorg. Chem., 2003, 2495; (c) K. Kimpe, T. N. Parac-Vogt, S. Laurent, C.
based solely on heteroaromatic units and leading to water-soluble Pierart, L. Vander Elst, R. N. Muller and K. Binnemans, Eur. J. Inorg.
, 2003, 3021; (d) R. D. Bolskar, A. F. Benedetto, L. O. Husebo, R.
neutral chelates. The Gd(III) complexes exhibit a large number of E. Price, E. F. Jackson, S. Wallace, L. J. Wilson and J. M. Alford, J. Am. coordinated H2O molecules and Gd(42)3 exhibits the highest r1
Chem. Soc., 2003, 125, 5471; (e) M. K. Thompson, M. Botta, G. Nicolle,
values reported to date for a low molecular weight molecule.
L. Helm, S. Aime, A. E. Merbach and K. N. Raymond, J. Am. Chem. Soc., Thanks to the facile functionalization of the pyridine ring, 2003, 125, 14274; (f) A. Borel, L. Helm and A. E. Merbach, Chem. Eur.
incorporation of these chelating motifs into a single tripodal J., 2001, 7, 600.
hexadentate structure should greatly improve stability (necessary 3 Contrast Agents I/Magnetic Resonance Imaging., Ed. W. Krause, Topics for application) and retain the intrinsic high relaxivity. Starting in Current Chemistry, Springer, Berlin, 2002, Vol 221.
4 (a) R. N. Muller, B. Raduchel, H. R. Maecke and A. E. Merbach, Eur. J. incorporation into slower rotational motion substrates such as Inorg. Chem., 1999, 1949; (b) É. Tóth, F. Connac, L. Helm, K. Adzamli
and A. E. Merbach, J. Biol. Inorg. Chem., 1998, 3, 606; (c) S. Aime, M.
proteins, dendrimers, and polysaccharides,1,2 as demonstrated Botta, S. G. Crich, G. Giovenzana, M. Sisti and E. Terreno, J. Biol. Inorg. successfully for functionalized DTPA-protein bound (r1 ~ 50 Chem., 1997, 2, 470; (d) É. Tóth, D. Pubanz, S. Vauthey, L. Helm and A.
mM21s21)4a and DOTA-dendrimer (r1 ~ 15–19 mM21s21) E. Merbach, Chem. Eur. J., 1996, 2, 1607; (e) V. S. Vexler, O. Clement,
systems.4d Efforts in this direction are in progress.
H. Schmitt-Willich and R. C. Brasch, J. Magn. Res. Imaging, 1994, 4,
This work was supported by grants MURST II (0103-97) and 5 A. R. Katritzky in, Handbook of Heterocyclic Chemistry, Pergamon 6 J. M. Mc Manus and R. M. Herbst, J. Org. Chem., 1959, 24, 1462.
Notes and references
7 Potentiometric data were analysed using HYPERQUAD program . P.
Gans, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739.
Synthetic details. Ligands 1 and 3. A mixture of parent cyanopyridine
8 Y. Bretonniere, M. Mazzanti, J. Pecaut, F. A. Dunand and A. E. Merbach, (5.3 mmol), NaN3 (8.0 mmol), NH4Cl (8.0 mmol) in anhydrous DMF (27 C h e m . C o m m u n . , 2 0 0 4 , 1 7 7 0 – 1 7 7 1


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