1276 Inorganic Chemistry, Vol. 50, No. 4, 2011
Chang et al.
longitudinal and transverse relaxation time (i.e., T1 and T2)
of water protons.2 Primary clinical CAs, such as [Gd-
(DTPA)(H2O)]2- (Magnevist), [Gd(DTPA-BMA)(H2O)]
(Omniscan), and [Gd(DOTA)(H2O)]- (Dotarem), display
relaxivities of around 4-5 mM-1 s-1 in the range of magnetic
fields (0.5-1.5 T) used in clinical MRI at 37 ꢀC.3 However,
the Solomon-Bloembergen-Morgan (SBM) theory pre-
dicts an over 20-fold relaxivity enhancement for the Gd(III)
complex with single hydration state (q=1) at regular imag-
ing fields used for clinical imaging, upon the simultaneous
optimization of key parameters, such as the electronic relaxa-
tion rate (1/T1,2e), the water exchange rate (kex), and the
molecular rotational correlation time (τR).4,5 However, in
practice, the electronic relaxation rate (1/T1,2e) of the para-
magnetic center is still hard to alter.3
In the past few years many endeavors have been made to
develop hypersensitive CAs. In this front, CAs endowed with
much higher relaxivity,6 targeting specific organ and tissue,7
and behaving as smart CAs8 have been extensively explored.
Recently, special attention has been devoted to the optimiza-
tion of water exchange rate on Gd(III) complexes.9-11 The
inner-sphere water exchange rate has been shown to reach its
optimal value when steric compression is created around the
water binding site in the Gd(III) complex.12 Steric crowding
facilitates in squeezing out the bound water molecules in the
rate determining step and consequently accelerates the water
exchange. This phenomenon has been observed in both
acyclic13 and macrocyclic14 Gd(III) complexes. However,
for low molecular weight Gd(III) complexes, high water
exchange rate has only limited advantages since relaxivity is
mainly restricted by fast molecular motion.15 T1 relaxation is
optimum when the frequency of molecular motion is close to
the Larmor frequency. However, the small gadolinium com-
plexes are characterized by rotational correlation times rang-
ing between 50 and 100 ps, which corresponds to rotational
frequencies of 10-20 GHz in contrast to the optimal imaging
field strength for clinical imaging ranging from 0.5 to 1.5 T
which corresponds to Lamor frequencies of 20-65 MHz.16
Fortunately, it is well established from previous studies that
the metal complex fluctuates at frequency somewhat closer to
the proton Larmor frequency on slowing down rotational
diffusion and, consequently, relaxivity gain can be achieved.17
A systematic review identifies a number of strategies em-
ployed to design high molecular weight CAs. Small molec-
ular weight Gd(III) complexes can be covalently or non-
covalently bound to macromolecules, for instance, linear
polymers,18 dendrimers,19 viral capsids,20 proteins,21 polysa-
ccharides,22 DNA quadruplex scaffolds,23 self- assembled
peptide amphiphile nanofibers,24 and liposomes.25 However,
some of these approaches suffer from internal flexibility or
nonrigid attachment of ligand to macromolecule.26 Nonco-
valent interaction of small Gd(III) complexes to in vivo
proteins has drawn much attention due to diverse physiolo-
gical congenial reasons. This approach is often called recep-
tor-induced magnetization enhancement (RIME).27 The
commercial contrast agent MS-325 (Vasovist) is an example
of a rationally designed RIME CA for angiographic applica-
tion. It possesses a lipophilic diphenylcyclohexyl residue wh-
ich facilitates noncovalent interaction with human serum
albumin (HSA).28,29 The binding augments the blood plasma
circulation time and also slows down its tumbling rate,
leading to greater contrast enhancements of blood vessel
MR image.30 It is apparent from previous studies that
(16) Caravan, P.; Cloutier, N. J.; Greenfield, M. T.; McDermid, S. A.;
Dunham, S. U.; Bulte, J. W.; Amedio, J. C., Jr.; Looby, R. J.; Supkowski,
R. M.; Horrocks, W. D., Jr.; McMurry, T. J.; Lauffer, R. B. J. Am. Chem.
Soc. 2002, 124, 3152–3162.
(17) (a) Lauffer, R. B.; Brady, T. J. Magn. Reson. Imaging 1985, 3, 11–16.
(b) Lauffer, R. B.; Brady, T. J.; Brown, R. D., III; Baglin, C.; Koenig, S. H. Magn.
Reson. Med. 1986, 3, 541–548.
(18) (a) Lucas, R. L.; Benjamin, M.; Reineke, T. M. Bioconjugate Chem.
2008, 19, 24–27. (b) Zhang, G.; Zhang, R.; Wen, X.; Li, L.; Li, C. Biomacro-
molecules 2008, 9, 36–42. (c) Fu, Y.; Raatschen, H. J.; Nitecki, D. E.; Wendland,
M. F.; Novikov, V.; Fournier, L. S.; Cyran, C.; Rogut, V.; Shames, D. M.; Brasch,
R. C. Biomacromolecules 2007, 8, 1519–1529.
(19) Xu, H.; Regino, C. A.; Koyama, Y.; Hama, Y.; Gunn, A. J.;
Bernardo, M.; Kobayashi, H.; Choyke, P. L.; Brechbiel, M. W. Bioconjugate
Chem. 2007, 18, 1474–1482.
ꢀ
ꢀ
(3) Costa, J.; Toth, E.; Helm, L.; Merbach, A. E. Inorg. Chem. 2005, 44,
4747–4755.
(4) Solomon, I. Phys. Rev. 1955, 99, 559–565.
(5) Bloembergen, N.; Morgan, L. O. J. Chem. Phys. 1961, 34, 842–850.
ꢀ
€
(6) (a) Fatin-Rouge, N.; Toth, E.; Meuli, R.; Bunzli, J. C. G. J. Alloys
Compd. 2004, 374, 298–302. (b) Vander Elst, L.; Port, M.; Raynal, I.; Simonot,
C.; Muller, R. N. Eur. J. Inorg. Chem. 2003, 2495–2501. (c) Aime, S.; Cabella,
C.; Colombatto, S.; Crich, S. G.; Gianolio, E.; Maggioni, F. J. Magn. Reson.
Imaging 2002, 16, 394–406.
(20) Anderson, E. A.; Isaacman, S.; Peabody, D. S.; Wang, E. Y.; Canary,
J. W.; Kirshenbaum, K. Nano Lett. 2006, 6, 1160–1164.
(21) (a) Yang, J. J.; Yang, J.; Wei, L.; Zurkiya, O.; Yang, W.; Li, S.; Zou,
J.; Zhou, Y.; Maniccia, A. L.; Mao, H.; Zhao, F.; Malchow, R.; Zhao, S.;
Johnson, J.; Hu, X.; Krogstad, E.; Liu, Z. R. J. Am. Chem. Soc. 2008, 130,
9260–9267. (b) Karfeld, L. S.; Bull, S. R.; Davis, N. E.; Meade, T. J.; Barron, A. E.
Bioconjugate Chem. 2007, 18, 1697–1700.
(7) (a) Weinmann, H. J.; Ebert, W.; Misselwitz, B.; Schmitt-Willich, H.
ꢁ
Eur. J. Radiol. 2003, 46, 33–44. (b) Kubícek, V.; Rudovskꢀy, J.; Kotek, J.;
Hermann, P.; Vander Elst, L.; Muller, R. N.; Kolar, Z. I.; Wolterbeek, H. T.; Peters,
ꢁ
J. A.; Lukes, I. J. Am. Chem. Soc. 2005, 127, 16477–16485.
(8) (a) Chang, Y. T.; Cheng, C. M.; Su, Y. Z.; Lee, W. T.; Hsu, J. S.; Liu,
G. C.; Cheng, T. L.; Wang, Y. M. Bioconjugate Chem. 2007, 18, 1716–1727.
(b) Duimstra, J. A.; Femia, F. J.; Meade, T. J. J. Am. Chem. Soc. 2005, 12847–
12855.
(22) Sirlin, C. B.; Vera, D. R.; Corbeil, J. A.; Caballero, M. B.; Buxton,
R. B.; Mattrey, R. F. Acad. Radiol. 2004, 11, 1361–1369.
(23) Cai, J.; Shapiro, E. M.; Hamilton, A. D. Bioconjugate Chem. 2009,
20, 205–208.
(24) Bull, S. R.; Guler, M. O.; Bras, R. E.; Meade, T. J.; Stupp, S. I. Nano
Lett. 2005, 5, 1–4.
(9) Wang, Y. M.; Lee, C. H.; Liu, G. C.; Sheu, R. S. Dalton Trans. 1998,
24, 4113–4118.
(25) (a) Laurent, S.; Vander Elst, L.; Thirifays, C.; Muller, R. N.
Langmuir 2008, 24, 4347–4351. (b) Laurent, Vander Elst, L.; Thirifays, C.;
Muller, R. N. Eur. Biophys. J. 2008, 37, 1007–1014.
(10) Mato-Iglesias, M.; Platas-Iglesias, C.; Djanashvili, K.; Peters, J. A.;
ꢀ
ꢀ
Toth, E.; Balogh, E.; Muller, R. N.; Vander Elst, L.; de Blas, A.; Rodrı
´
guez-
Blas, T. Chem. Commun. 2005, 4729–4731.
ꢁ
ꢁ
(26) (a) Hermann, P.; Kotek, J.; Kubı
´
cek, V.; Lukes, I. Dalton Trans.
ꢀ
(11) Balogh, E.; Mato-Iglesias, M.; Platas-Iglesias, C.; Toth, E.;
ꢀ
ꢀ
2008, 3027–3047. (b) Jaszberenyi, Z.; Moriggi, L.; Schmidt, P.; Weidensteiner,
Djanashvili, K.; Peters, J. A.; de Blas, A.; Rodrı
2006, 45, 8719–8728.
´
guez-Blas, T. Inorg. Chem.
ꢀ
ꢀ
C.; Kneuer, R.; Merbach, A. E.; Helm, L.; Toth, E. J. Biol. Inorg. Chem. 2007,
12, 406–420. (c) Rudovskꢀy, J.; Botta, M.; Hermann, P.; Hardcastle, K. I.; Lukes,
I.; Aime, S. Bioconjugate Chem. 2006, 17, 975–987.
(27) (a) Jenkins, B. G.; Armstrong, E.; Lauffer, R. B. Magn. Reson. Med.
1991, 17, 164–178. (b) Lauffer, R. B. Magn. Reson. Med. 1991, 22, 339–342.
(28) Lauffer, R. B.; Parmelee, D. J.; Dunham, S. U.; Ouellet, H. S.; Dolan,
R. P.; Witte, S.; McMurry, T. J.; Walovitch, R. C. Radiology 1998, 207, 529–
538.
(29) Parmelee, D. J.; Walovitch, R. C.; Ouellet, H. S.; Lauffer, R. B.
Invest. Radiol. 1997, 32, 741–747.
ꢁ
(12) Powell, D. H.; Ni Dhubhghaill, O. M.; Pubanz, D.; Helm, L.;
Lebedev, Y. S.; Schlaepfer, W.; Merbach, A. E. J. Am. Chem. Soc. 1996,
118, 9333–9346.
(13) Aime, S.; Barge, A.; Borel, A.; Botta, M.; Chemerisov, S.; Merbach,
A. E.; Muller, U.; Pubanz, D. Inorg. Chem. 1997, 36, 5104–5112.
(14) Ruloff, R.; Toth, E.; Scopelliti, R.; Tripier, R.; Handel, H.; Merbach,
€
ꢀ
ꢀ
A. E. Chem. Commun. 2002, 2630–2631.
ꢀ
(15) Burai, L.; Toth, E.; Sour, A.; Merbach, A. E. Inorg. Chem. 2005, 44,
3561–3568.