11228
J. Am. Chem. Soc. 2000, 122, 11228-11229
Scheme 1
A Tris-hydroxymethyl-Substituted Derivative of
Gd-TREN-Me-3,2-HOPO: An MRI Relaxation
Agent with Improved Efficiency
Sharad Hajela,† Mauro Botta,‡ Sabrina Giraudo,§ Jide Xu,†
Kenneth N. Raymond,*,† and Silvio Aime*,§
Department of Chemistry, UniVersity of California
Berkeley, California 94720
Dipartimento di Scienze e Tecnologie AVanzate
UniVersita` del Piemonte Orientale “Amedeo AVogadro”
Corso Borsalino 54, I-15100 Alessandria, Italy
Dipartimento di Chimica I.F.M., UniVersita` di Torino
Via P. Giuria 7, I-10125 Torino, Italy
ReceiVed December 9, 1999
mM-1 s-1), Gd(HP-DO3A) (4.2 mM-1 s-1), and Gd(DTPA-BMA)
(4.4 mM-1 s-1).7,8 The presence of two water molecules in the
GdIII inner coordination sphere for 2 does not fully account for
this increment. Indeed, it is well-known that for small poly-
aminocarboxylate-derived GdIII chelates, only about 2.5 to 3.0
mM-1 s-1of r1p is due to the contribution of each of the metal-
bound water molecules (r1is, the inner-sphere contribution);
additionally, approximately 2.0 to 2.5 mM-1 s-1 is attributable
to the outer-sphere water molecules diffusing next to the complex
(r1os, the outer-sphere contribution).9 For example, the nine-
coordinate GdIII complex of the heptadentate macrocyclic ligand
DO3A also features two inner-sphere waters (q) and has a r1p
ReVised Manuscript ReceiVed August 29, 2000
Gadolinium is used as a relaxation agent in magnetic resonance
imaging (MRI) because of its large paramagnetic moment, high
water exchange rate, and consequent high proton relaxivity.
However, the ion must be complexed to avoid toxicity. The
Gd(III) complex of TREN-Me-3,2-HOPO (1) {TREN-Me-3,2-
HOPO ) tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-
4-carboxamido)ethyl]amine} has been proposed as the basis for
a promising new class of relaxation agents for magnetic resonance
imaging (MRI) applications.1 The tris-bidentate chelation of the
ligand is unique among imaging agents and offers several
advantageous features: (1) high stability; (2) low expected
toxicity; and (3) high relaxivity, based on an initial measurement
at 37 °C.1 In particular, the high relaxivity of 1 has been attributed
to the high number of water molecules (two) in the inner sphere
of the eight-coordinate ground state of the complex with favorable
(rapid) water exchange kinetics expected via an associative
exchange mechanism through an easily accessible nine-coordinate
transition state. Unfortunately, attempts to more clearly delineate
the origins for this high relaxivity have been frustrated by the
low solubility of the complex (less than 0.1 mM at pH 7).
To selectively modify the properties of TREN-linked podand
ligands and their metal complexes, we have explored methodolo-
gies for synthesis of functionalized TREN derivatives.2 The
gadolinium complex of homochiral tris(2-hydroxymethyl)-TREN-
Me-3,2-HOPO, 2, was chosen as the initial target and its synthesis
is outlined in Scheme 1.3 As desired, the increased water solubility
of 2 (ca. 15 mM at 25 °C, pH 7) has allowed for a complete
characterization of the relaxivity behavior of these new types of
gadolinium compounds as a function of temperature and magnetic
value of 6.1 mM-1 s-1 10
. In the case of 2, the approximately 3.0
mM-1 s-1 enhancement observed for r1p most likely arises from
variations in two other key parameters for relaxivity: a slower
molecular reorientation rate (1/τR) and/or a shorter Gd-Owater
distance. Support for this hypothesis can be gained by the analysis
of the magnetic field dependence of r1p over a range of proton
Larmor frequencies from 0.1 to 50 MHz, the so-called nuclear
magnetic relaxation dispersion (NMRD) profile.11 Figure 1
compares the experimental NMRD profile of 2 (CN ) 8, q ) 2)
with those of Gd(DTPA)12 (CN ) 9, q ) 1) and Gd(DO3A)8
(CN ) 9, q ) 2). The experimental data were analyzed in terms
of the Solomon-Bloembergen-Morgan (SBM)13,14 and Freed15
equations for inner-sphere and outer-sphere contributions, re-
spectively (with best fitting curves as indicated in Figure 1). The
inner-sphere term depends on the number of metal-bound waters
(q), their mean residence lifetime (τM), the water proton-
gadolinium distance (r), τR, the electronic relaxation time at zero-
field (τS0), and the correlation time for the modulation of τS0 (τV).
The outer-sphere contribution depends on τS0, τV, the distance of
closest approach between the paramagnetic center and the
field strength using H and 17O NMR methods (vide infra).
1
The efficacy of paramagnetic complexes as contrast enhance-
ment agents is given by their relaxivity, r1p (mM-1 s-1), which
represents the net increase in the water proton nuclear magnetic
relaxation rate per millimolar concentration of the paramagnetic
(4) Aime, S.; Botta, M.; Fasano, M.; Terreno, E. Chem. Soc. ReV. 1998,
27, 19.
(5) Peters, J. A.; Huskens, J.; Raber, D. J. Prog. NMR Spectrosc. 1996,
28, 283.
compound.4-6 At 20 MHz and 25 °C, r1p of 2 is 9.0 mM-1 s-1
,
(6) Powell, D. H.; Ni Dhubhghill, O. M.; Pubanz, D.; Helm, L.; Lebedev,
Y. S.; Schlaepfer, W.; Merbach, A. E. J. Am. Chem. Soc. 1996, 118, 9333.
(7) DTPA ) diethylenetriaminepentaacetic acid, DOTA ) 1,4,7,10-
a value remarkably higher than those of the currently used mono-
aquo contrast agents, Gd(DTPA) (4.7 mM-1 s-1), Gd(DOTA) (4.7
tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid, HP-DO3A
) 2-hy-
droxypropyl-1,4,7,10-tetraazacyclododecane-N,N′,N′′-triaacetic acid, DTPA-
BMA ) diethylenetriamine-N,N′,N′′-triacetic acid-N,N′′-bismethylamide, DO3A
) 1,4,7,10-tetraazacyclododecane-N,N′,N′′-triaacetic acid.
(8) Aime, S.; Botta, M.; Terreno, E. Unpublished results.
(9) Aime, S.; Botta, M.; Ermondi, G.; Terreno, E.; Anelli, P. L.; Fedeli,
F.; Uggeri, F. Inorg. Chem. 1996, 35, 2726 and references therein.
(10) Aime, S.; Botta, M.; Geninatti Crich, S.; Giovenzana, G.; Pagliarin,
R.; Sisti, M.; Terreno, E. Magn. Reson. Chem. 1998, 36, S200.
(11) Koenig, S. H.; Brown, R. D., III Prog. NMR Spectrosc. 1990, 22,
487.
† University of California.
‡ Universita` del Piemonte Orientale “Amedeo Avogadro”.
§ Universita` di Torino.
(1) Xu, J.; Franklin, S. J.; Whisenhunt, D. W.; Raymond, K. N. J. Am.
Chem. Soc. 1995, 117, 7245.
(2) The syntheses of these modified TREN derivatives will be described
in detail separately: Hajela, S. P.; Johnson, A. R.; Xu, J.; Sunderland, C. J.;
Cohen, S. M.; Caulder, D. L.; Raymond, K. N. Synthesis of Homochiral Tris-
(2-Alkyl-2-Aminoethyl)Amine Derivatives from Chiral (alpha)-Amino Alde-
hydes and Their Application in the Synthesis of Water Soluble Chelators.
Submitted for publication.
(12) Uggeri, F.; Aime, S.; Anelli, P. L.; Botta, M.; Brocchetta, M.; de Hae¨n,
C.; Ermondi, G.; Grandi, M.; Paoli, P. Inorg. Chem. 1995, 34, 633.
(13) Bloembergen, N.; Morgan, L. O. J. Chem. Phys. 1961, 34, 842.
(14) Banci, L.; Bertini, I.; Luchinat, C. Nuclear and Electron Relaxation;
VCH: Weinheim, 1991.
(3) For details of the synthesis and characterization of compound 2 and its
Gd(III) complex see Supporting Information.
(15) Hwang, L. P.; Freed, J. H. J. Chem. Phys. 1975, 63, 4017.
10.1021/ja994315u CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/28/2000