Fe(III)-templated Gd(III) self-assemblies - A new route toward macromolecular MRI contrast agents

Article abstract of DOI:10.1021/ja061323j

The self-assembly of supramolcular clusters of Gd(III) hydroxypyridinone complexes, templated by an Fe(III) terephthalamide center, is presented. The peripheral Gd(III) ions are each coordinated by two water molecules which exchange rapidly with the bulk

Full text of DOI:10.1021/ja061323j

Published on Web 07/04/2006
Fe(III)-Templated Gd(III) Self-AssembliessA New Route toward
Macromolecular MRI Contrast Agents1
Vale´rie C. Pierre,† Mauro Botta,‡ Silvio Aime,§ and Kenneth N. Raymond*,†
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460, Dipartimento di Scienze
dell’Ambiente e della Vita, UniVersita` del Piemonte Orientale “A. AVogadro”, Via Bellini 25/G, I-15100
Alessandria, Italy, and Dipartimento di Chimica I.F.M., UniVersita` di Torino, Via P. Giuria 7, I-10125 Torino, Italy
Received February 23, 2006; E-mail: raymond@socrates.berkeley.edu
The Solomon-Bloembergen-Morgan theory predicts that the
longitudinal relaxivity of a small Gd(III) complex, r1p, increases
upon slowing down its rotational correlation time. This is usually
achieved by grafting the complex onto a macromolecule. Previous
efforts in designing such macromolecules have concentrated on the
synthesis of dendrimeric analogues and covalent or reversible
protein conjugates.2 These studies demonstrated the necessity not
only of attaining fast water exchange but also of creating rigid
systems in attaining high relaxivity agents.3
Surprisingly, there has been little study of supramolecular self-
assemblies. These complexes, however, present several advantages,
as their syntheses require fewer steps and they can be highly rigid.
Although several mixed f block/d block self-assemblies have already
been described,4 the macromolecular MRI contrast agents studied
have been only Gd(III) chelates grafted onto tris-bidentate Fe(III)
Figure 1. Selectivity of 1-methyl-2,3-dihydroxypyridinone (HOPO) and
2,3-dihydroxyterephthalamide (TAM) for Fe(III) over Gd(III).7,8
complexes.5 However, these do not constitute true supramolecular
self-assemblies6 in that, in each case, the Gd(III) complexes were
already completely synthesized prior to building the macromolecule.
Herein we describe our approach to Gd(III)-containing supramo-
lecular self-assemblies using Fe(III) as a template. Bis-bidentate
ligands were designed comprising two different binding sites, one
more selective for Gd(III) and the other for Fe(III). It has previously
been shown (Figure 1) that Gd(III) is selective for 1-methyl-2,3-
dihydroxypyridinone (HOPO) over 2,3-dihydroxyterephthalamide
(TAM) (pGdTREN-trisHOPO ) 19.2, pGdTREN-trisTAM < 13),7 whereas
Fe(III) is selective for TAM over HOPO (pFeTREN-trisHOPO ) 26.8,
pFeTREN-trisTAM ) 34.2).8,9 It was therefore predicted that three bis-
bidentate ligands, each comprising both one HOPO and one TAM
moiety, would coordinate both one Gd(III) and one Fe(III).
In the complexes studied (Figure 2), each ligand contains one
TAM moiety (for Fe(III) coordination) linked to either one or two
Figure 2. Heteronuclear Fe(III)-templated Gd(III) self-assemblies based
on a three-carbon linker.
HOPO moieties (for Gd(III) coordination) through a three-carbon
linker. This linker has been shown to favor the formation of triple-
stranded helicates.10 In Fe,Gd-L1, the three strands are joined by a
TREN backbone, while in the other two complexes Fe,Gd-3L2 and
Fe,2Gd-3L3, they are left free to self-assemble (or not). All
complexes are 3- charged. In Fe,Gd-3L2, a small PEG chain was
grafted for increased water solubility.
The mixed complexes were synthesized in six, four, and three
steps, respectively, starting from previously described building
blocks. Formation of the mixed self-assemblies, with the correct
ratio of Gd(III) and Fe(III), was confirmed by high-resolution
electrospray mass spectrometry. The spectrum of Fe,2Gd-3LC
(Figure 3), for instance, clearly shows only one product, containing
Figure 3. Electrospray mass spectrum of Fe,2Gd-3LC. The calculated (blue)
and experimental (black) isotopic distributions of the molecular ion are
shown in the expanded region.
one Fe(III) and two Gd(III).
The nuclear magnetic resonance dispersion (NMRD) profiles of
the heteronuclear self-assemblies are shown in Figure 4. Since not
all complexes bear the same number of Gd(III) ions, the relaxivities
† University of California, Berkeley.
‡ Universita` del Piemonte Orientale “A. Avogadro”.
§ Universita` di Torino.
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10.1021/ja061323j CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
times of the supramolecules are also comparable to that of the parent
mononuclear complex. A comparison of the cylindrical architecture
of the self-assemblies with the spherical dendrimers or metallostars
indicates that the rodlike architectures of the former are still well
suited to the attainment of highly rigid, high relaxivity MRI contrast
agents. Furthermore, unlike the metallostars, whose relaxivities were
measured only under acidic conditions,5d the HOPO/TAM as-
semblies maintain the high relaxivity at physiological pH and when
dissolved in human serum.5
In summary, the templated self-assembly of Gd(III) hydroxy-
pyridinone and Fe(III) terephthalamide components of a supramo-
lecular structure presents a new class of MRI contrast agents. These
compounds utilize the rapid assembly of rigid macromolecules in
few synthetic steps. Relaxivity studies indicate that the high-
molecular-weight clusters effectively slow the molecular tumbling.
This and the fast water exchange produce high relaxivity at the
high magnetic fields relevant to future medical applications.
Figure 4. 1/T1 NMRD profile at 298 K and pH 7.4 of Fe,Gd-LA (1), Fe,-
Gd-3LB (O), and Fe,2Gd-3LC (9). Longitudinal relaxivities are given per
Gd(III) ion.
Table 1. Refinement Parameters of the 1/T1 NMRD Profiles of
Fe,Gd-LA, Fe,Gd-3LB, and Fe,2Gd-3LC
Acknowledgment. This research (UCB) was supported by NIH
grant HL69832, NATO Travel Grant PST.CLG.980380, and an
unrestricted research gift from Schering AG.
Fe,Gd-LA
Fe,Gd-3LB
Fe,2Gd-3LC
r1p at 20 MHz (mM-1 s-1
q
)
11.0
2
11.5
2
18.7
2
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for the syntheses of the complexes
Fe,Gd-LA, Fe,Gd-3LB, and Fe,2Gd-3LC; pH dependence of the selectiv-
ity of Fe(III) for TAM over HOPO ligands; inner- and outer-sphere
contributions to the NMRD profiles of the assemblies; and MM3 energy
minimization of the assemblies. This information is available free of
charge via the Internet at http://pubs.acs.org.
τ
R (ns)
150
5.4
25.9
10
3.06
4.0
2.24
172
6.5
22.5
10
3.06
4.0
2.24
312
4.9
31.7
10
3.06
4.0
2.24
∆2 (s-2 × 1019)
τv (ps)
τ
M (ns)a
r (Å)
a (Å)a
D (cm2 s-1 × 105)a
a Fixed.
References
given are per millimolar concentration of Gd(III) for direct
comparison. The complexes have high relaxivities, with a maximum
centered around 60-100 MHz. The relaxivity of the trinuclear
assembly, Fe,2Gd-3LC, is r1p ) 21 mM-1 s-1 per Gd(III) (or 42
mM-1 s-1 per molecule) at 90 MHz, an unprecedented high value,
especially given the relatively small molecular weight of the
assembly. Unlike macromolecules based on commercial contrast
agents, the relaxivity of the supramolecules increases significantly
at the high Larmor frequencies that are relevant for medical
applications. Such a peak at high field was previously observed
for medium molecular weight systems, such as the block dendrimer
Gd-TREN-bisHOPO-TAM-Asp-Asp2-12OH11 and hydrophilic den-
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structure.12 The high relaxivity in the 2 T field range is characteristic
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long rotational correlation time arising from a rigid structure. The
profiles thus strongly suggest that τM is still optimal for the
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of each assembly still coordinates two water molecules, which
continue rapid exchange with bulk solvent. The electronic relaxation
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