Towards the Rational Design of Magnetic Resonance Imaging Contrast Agents: Isolation of the Two Coordination Isomers of Lanthanide DOTA‐Type Complexes

Woods, Mark; Kovács, Zoltán; Zhang, Shanrong; Sherry, A. Dean

doi:10.1002/anie.200352234

Cited by 108 publications

(151 citation statements)

References 26 publications

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“…Of particular interest has been the nature of the two coordination isomers that exist naturally in a solution of LnDOTA. [1][2][3] Since the rate of water exchange is a critical parameter in contrast agent design 2 and one of the two coordination isomers of LnDOTA complexes exhibits substantially faster water exchange than the other, [4][5][6] understanding the physical characteristics of these two coordination isomers has been an important goal. Because they are in dynamic exchange in solution, the nature of each coordination isomer historically had to be deduced from measurements performed on mixtures of the two.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Chiroptical Properties of the Two Coordination Isomers of YbDOTA-Type Complexes

et al. 2005

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Studies of the structural, physical, and chemical properties of the lanthanide(III) complexes of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and related ligands are often complicated by the presence of two coordination isomers in solution. Since these coordination isomers are in exchange and cannot be separated, many techniques offer information only on the weighted average of the two isomers. Lanthanide ion complexes formed with the ligands S(RRRR)NO 2 BnDOTMA and S(SSSS)NO 2 BnDOTMA preferentially adopt only one of the two common coordination isomers in solution, so the ytterbium complexes of these ligands offer a unique opportunity to study the nearinfrared circular dichroism (NIR-CD) characteristics of each coordination geometry in isolation. The spectra acquired support many of the conclusions and assumptions of previous studies and demonstrate that this spectroscopy is particularly sensitive to the distortion of the coordination polyhedron. This will have particularly relevant consequences when studying achiral YbDOTA-like systems forming labile adducts with (chiral) hosts and receptors.

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Section: Introductionmentioning

confidence: 99%

“…5 Yb3 was isolated as a byproduct from the synthesis of Yb1. The corresponding S(SRRR) complex was also isolated from the synthesis of Yb2 but in low yield, and insufficient amounts of this complex were obtained to allow study of this complex.…”

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Structural and Chiroptical Properties of the Two Coordination Isomers of YbDOTA-Type Complexes

et al. 2005

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“…Since water exchange kinetics are critical to the performance of PARACEST agents, it is important to understand the influence that bifunctional architecture might have upon this process. In particular the relative distribution of the square antiprismatic (SAP) and twisted square antiprismatic (TSAP) coordination isomers must be considered as these two conformations are reported to exhibit distinctly different bound water lifetimes (16)(17)(18)(19)(20) with slower exchange kinetics of the SAP being most desirable (21). To begin surveying the influence of bifunctional ligand architecture on PARACEST performance we selected Eu-DOTA-4AmCE (Scheme 1) to serve as the base platform since this parent structure is known to generate highly efficient PARACEST agents (4).…”

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Spectral properties of a bifunctional PARACEST europium chelate: an intermediate for targeted imaging applications

Adair

Woods

Zhao

et al. 2007

Contrast Media & Molecular

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This report describes a preliminary study to investigate the effect of structural variations in a bifunctional ligand being developed for targeted PARACEST applications. Utilizing Eu-DOTA-4AmCE as the functional PARACEST core, a nitro-aromatic functionality was incorporated to provide the point for conjugation. This intermediate possesses a coordinated water proton signal at 57 ppm which upon saturation produces a 22% decrease in bulk water signal intensity using 10 mM agent. Curve fitting analysis of the CEST spectrum to an exchange model based upon modified Bloch equations gave an estimate of 687 +/- 100 micros for the bound water lifetime (tau(m)). Although substantially longer than the 382 micros observed for the parent chelate structure, this water exchange rate remains in the necessary window to produce a significant CEST effect. These findings demonstrate the need to recognize the influence of bifunctional linkers on water exchange rates in lanthanide complexes of this type and the potential for using this functionality as a means of fine-tuning PARACEST performance.

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“…Radio-ligands are preferred because they can transform normally nonspecific radioisotopes into targeted agents to specifically bind to certain types of tissue which causes the radioisotope to accumulate in desired areas of the body, thereby increasing the amount of signal seen in the image in that area. FDA-approved radioisotopes include the following: 11 C, 14 C, 13 N, 15 O, 18 F, 67 Ga, 82 Rb, 89 Zr, 89 Sr, 90 Y, 99 Mo, 99 Tc, 111 In, 123 I, 125 I, 131 I, 133 Xe, 153 Sm, 201 Tl, and 223 Ra. Both labelled radiotracers and radioisotopes are injected into a patient and the natural decay process of the isotopes occurs inside the body while detectors monitor the radiation given off from the decay process in order to create images.…”

Section: Tomography (Spect) (1961)mentioning

confidence: 99%

“…When both substitutions are utilized together, both the arm rotations and ring inversions are halted, creating isomers which can be separated from one another using HPLC. [125][126][127][128] It was expected that only two isomers would be present when both ring and arm substitutions were utilized, since substitution on the ring allows for only the Λ(δδδδ) and Δ(δδδδ)…”

Section: Ligand Design and Chelate Structurementioning

confidence: 99%

Controlling Water Exchange Kinetics and Improving ParaCEST Imaging

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Generating MR image contrast from exogenous contrast media though chemical exchange saturation transfer (CEST) offers several exciting new possibilities, such as multicolored imaging, the interleaving of pre-and post-contrast images, and the potential to perform ratiometric metabolic imaging. The major limitation of the deployment of CEST imaging is the comparatively high detection limits of exogenous agents and particularly at the low B1 power levels required to meet SAR requirements. The large chemical shifts afforded by paramagnetic (paraCEST) agents permit more rapid exchange kinetics and therefore potentially more effective contrast agents. Despite comparatively large chemical shifts, many Ln 3+ DOTA-tetraamide (DOTAM) chelates traditionally investigated as CEST agents are predicted to have exchange kinetics that are considerably faster than optimal at very low B1 powers. This work explores two methodologies for slowing water exchange kinetics in Ln 3+ DOTAM chelates and improving CEST imaging: structural manipulation and encapsulation. In the first method, rigid Ln 3+ NB-DOTAM chelates with hydrophobic amide substituents was thoroughly studied using NMR spectroscopy techniques in order to assess their ability to produce CEST contrast at low B1 power levels. NMR techniques utilized included 1 H NMR, variable temperature, COSY, and CEST experiments. The phenyl amide substituent in the pseudo-axial position afforded chelates with considerably slow water proton exchange rates and appreciably more CEST contrast than isomeric chelates with the amide substituent in the pseudo-equatorial position. The second method involved characterizing a vesicle system to be used for encapsulating a Ln 3+ DOTAM chelate. The vesicles prepared were analyzed using the following NMR ii techniques: 1 H NMR, T1, shift reagent, and CEST experiments. The vesicle system chosen for study did not afford slow water exchange kinetics to enhance CEST contrast. A second vesicle system was attempted but the vesicle synthesis was difficult, parameters studied were not optimized, and the second system did not exhibit slow water exchange with the limited amount of experiments run and data collected.iii

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Towards the Rational Design of Magnetic Resonance Imaging Contrast Agents: Isolation of the Two Coordination Isomers of Lanthanide DOTA‐Type Complexes

Cited by 108 publications

References 26 publications

Structural and Chiroptical Properties of the Two Coordination Isomers of YbDOTA-Type Complexes

Structural and Chiroptical Properties of the Two Coordination Isomers of YbDOTA-Type Complexes

Spectral properties of a bifunctional PARACEST europium chelate: an intermediate for targeted imaging applications

Controlling Water Exchange Kinetics and Improving ParaCEST Imaging

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