Structural and Dynamic Parameters Obtained from 17O NMR, EPR, and NMRD Studies of Monomeric and Dimeric Gd3+ Complexes of Interest in Magnetic Resonance Imaging:  An Integrated and Theoretically Self-Consistent Approach1

Powell, D. Hugh; Dhubhghaill, O. M. N.; Pubanz, Dirk; Helm, Lothar; Lebedev, Ya. S.; Schlaepfer, Willi; Merbach, André E.

doi:10.1021/ja961743g

Cited by 631 publications

(1,083 citation statements)

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“…The s M values are similar for the three complexes and larger than that for the parent compound Gd-DTPA. Such increase of the residence time of the coordinated water molecule has already been reported for numerous Gd-DTPA bisamide derivatives, such as for example gadolinium(III) diethylenetriaminepentaacetate-bis(methylamide) Gd-DTPABMA (Powell et al 1996;Botteman et al 2002). Moreover, the insertion of both hydrophobic chains of the gadolinium(III) complex in the liposome structure could also prevent the exchange of the water molecule.…”

Section: Resultsmentioning

confidence: 57%

“…The paramagnetic liposomes containing the Gd-DTPA-BPT showed the highest relaxivity, most likely because the optimal length match between the hydrophobic chains of the DPPC and the DTPA-BPT ligand allowed very efficient packing of the paramagnetic complex into the liposome. Powell et al (1996) c Model 1 includes the classical inner sphere and outer sphere theories with a single s R value whereas model 2 uses the Lipari-Szabo theory with two s R values, a ''global'' s R fixed to 10 À4 s (see text) and a fitted ''local'' s R shown in the table Fig. 5 Proton NMR spectrum of Pr-DTPA-BPO in the CD 3 OH/ CD 3 Cl (1:1) mixture at 278 K…”

Section: Resultsmentioning

confidence: 99%

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Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging

et al. 2005

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Three amphiphilic DTPA bisamide derivatives containing long-chain phenylalanine esters (with 14, 16 and 18 carbon atoms in the alkyl chain) were synthesized and their corresponding gadolinium(III) complexes were prepared. The attempts to form paramagnetic micelles carrying the gadolinium(III) complexes yielded unstable or polydisperse micelles implying that the presence of the bulky aromatic side groups in the amphiphilic Gd-DTPA bisamide complexes results in an inefficient packing of the paramagnetic complex into micelles. All complexes were efficiently incorporated into liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), yielding stable and monodisperse paramagnetic liposomes. All liposomes had a comparable size, typically between 120 and 160 nm. As a result of the reduced mobility of the gadolinium(III) complexes, solutions of these supramolecular structures show a higher relaxivity than solutions of Gd-DTPA. However, the relaxivity gain is lower compared to compounds consisting of purely aliphatic chains of the same length, most likely due to the less efficient packing or increased local mobility of the gadolinium(III) complex. In the case of the Gd-DTPA bisamide complex with 18 carbon atoms, the immobilization inside the liposomal structure is less effective, probably because the aliphatic chains of the complex are longer than the alkyl chains of the DPPC host, resulting in a relatively high local mobility. The paramagnetic liposomes containing the Gd-DTPA bisamide complexes with 14 carbon atoms showed the highest relaxivity because the optimal length match between the hydrophobic chains of the DPPC and the ligand allowed very efficient packing of the paramagnetic complex into the liposome.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging

et al. 2005

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“…However, the increase in relaxivity seen here is relatively small (~60%) compared with other systems studied previously (1,20,22). This may result from a combination of two factors; 1) the GdDO3A end of the conjugate may experience considerable motional freedom when bound to the anti-FLAG antibody due to the flexibility of the -Ser-Gly-Ser-Gly-linker sequence that was added to limit disruption of the peptide binding affinity and 2) the GdDO3A-peptide linkage introduces one amide bond into the Gd 3+ coordination sphere and this is known to slow water exchange [31]. Hence, it is possible that the relaxivity of this system is limited by water exchange (k ex −1 >T 1M ) when bound at the antibody surface.…”

Section: T 1 Measurements Of the Gddo3a-flag Conjugatementioning

confidence: 99%

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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Simple low MW chelates of Gd 3+ such as those currently used in clinical MR imaging are considered too insensitive for most molecular imaging applications. Here, we evaluated the detection limit of a molecularly targeted, low MW Gd 3+ -based, T 1 agent in a model where the receptor concentration was precisely known. The data demonstrate that receptors clustered together to form a microdomain of high local concentration can be imaged successfully even when the bulk concentration of the receptor is quite low. A GdDO3A-peptide identified by phage display to target the anti-FLAG antibody was synthesized, purified and characterized. T 1 weighted MR images were compared with the agent bound to antibody in bulk solution and with the agent bound to the antibody localized on agarose beads. Fluorescence competition binding assays show that the agent has a high binding affinity (K D = 150 nM) for the antibody while the fully bound relaxivity of the GdDO3A-peptide:anti-FLAG antibody in solution was a relatively modest 17 mM −1 s −1 . The agent:antibody complex was MR silent at concentrations below ~9 µM but was detectable down to 4 µM bulk concentrations when presented to antibody clustered together on the surface of agarose beads. These results provided an estimate of the detection limits for other T 1 -based agents with higher fully bound relaxivities or multimeric structures bound to clustered receptor molecules. The results demonstrate that the sensitivity of molecularly-targeted contrast agents depends on the local microdomain concentration of the target protein and the molecular relaxivity of the bound complex. A model is presented which predicts that for a molecularly targeted agent consisting of a single Gd 3+ complex with bound relaxivity of 100 mM −1 s −1 or, more reasonably, four tethered Gd 3+ complexes each having a bound relaxivity of 25 mM −1 s −1 , the detection limit of a protein microdomain is ~690 nM at 9.4T. These experimental and extrapolated detection limits are both well below current literature estimates and suggests that detection of low MW molecularly targeted T 1 agents is not an unrealistic goal.

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“…The ligand L 8À is also a prime candidate as a terminal ligand for constructing larger-size, Fe II and [Gd(DOTA)] À are commercial contrast agents. [7] [Fe{Gd(tpy-DTTA)} 2 ] and [Fe{Gd(phen)(HDO3A)} 3 ] 2+ [4] are self-assembled structures. Gadomer 17, [10] [G5{Gd(DO3A)} 52 ], [11] and [G10{Gd(DOTA)} 1850 ] [8] are dendrimers.…”

Section: Angewandte Chemiementioning

confidence: 99%

High Relaxivity Confined to a Small Molecular Space: A Metallostar‐Based, Potential MRI Contrast Agent

et al. 2005

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Structural and Dynamic Parameters Obtained from ¹⁷O NMR, EPR, and NMRD Studies of Monomeric and Dimeric Gd³⁺ Complexes of Interest in Magnetic Resonance Imaging: An Integrated and Theoretically Self-Consistent Approach¹

Cited by 631 publications

References 41 publications

Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging

Paramagnetic liposomes containing amphiphilic bisamide derivatives of Gd-DTPA with aromatic side chain groups as possible contrast agents for magnetic resonance imaging

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

High Relaxivity Confined to a Small Molecular Space: A Metallostar‐Based, Potential MRI Contrast Agent

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