Efficient Multigram Synthesis of the Bifunctional Chelating Agent (<i>S</i>)-1-<i>p-</i>Isothiocyanatobenzyl-diethylenetetraminepentaacetic Acid

Corson, Donald T; Meares, Claude F.

doi:10.1021/bc990125x

Cited by 36 publications

(34 citation statements)

References 16 publications

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“…The EPTPA-bz-NCS ligand was prepared from (dl)-p-nitrophenylalanine in a multistep synthesis with an overall yield of 39 %. In the last step, EPTPA-bz-NH 2 [41,44,45] was reacted with CSCl 2 by using a standard two-phase methodology to give EPTPA-bz-NCS. The isothiocyanates are known to react very slowly with water, but are very reactive to amine groups.…”

Section: Resultsmentioning

confidence: 99%

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Laus¹,

Sour²,

Ruloff³

et al. 2005

Chemistry A European J

115

118

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The EPTPA5) chelate, which ensures fast water exchange in GdIII complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H5EPTPA = ethylenepropylenetriamine-N,N,N',N'',N''-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)111, G7-(GdEPTPA)253 and G9-(GdEPTPA)1157 decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r1 = 20.5, 28.3 and 27.9 mM(-1) s(-1), respectively, at 37 degrees C, 30 MHz). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes. This originates from the pH-dependent rotational dynamics of the dendrimer skeleton, which was evidenced by a combined variable-temperature and multiple-field 17O NMR and 1H relaxivity study performed at pH 6.0 and 9.9 on G5-(GdEPTPA)111. The longitudinal 17O and 1H relaxation rates of the dendrimeric complex are strongly pH-dependent, whereas they are not for the [Gd(EPTPA)(H2O)]2- monomer chelate. The longitudinal 17O and 1H relaxation rates have been analysed by the Lipari-Szabo spectral density functions and correlation times have been calculated for the global motion of the entire macromolecule (tau(gO)) and the local motion of the GdIII chelates on the surface (tau(lO)), correlated by means of an order parameter S2. The dendrimer complex G5-(GdEPTPA)111 has a considerably higher tau(gO) under acidic than under basic conditions (tau(298)gO = 4040 ps and 2950 ps, respectively), while local motions are less influenced by pH (tau(298)lO = 150 and 125 ps). The order parameter, characterizing the rigidity of the macromolecule, is also higher at pH 6.0 than at pH 9.9 (S2 = 0.43 vs 0.36, respectively). The pH dependence of the global correlation time can be related to the protonation of the tertiary amine groups in the PAMAM skeleton, which leads to an expanded and more rigid dendrimeric structure at lower pH. The increase of tau(gO) with decreasing pH is responsible for the pH dependent proton relaxivities. The water exchange rate on G5-(GdEPTPA)111(k(298)ex = 150 x 10(6) s(-1)) shows no significant pH dependency and is similar to the one measured for the monomer [Gd(EPTPA)(H2O)]2-. The proton relaxivity of G5-(GdEPTPA)111 is mainly limited by the important flexibility of the dendrimer structure, and to a small extent, by a faster than optimal water exchange rate.

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Section: Resultsmentioning

confidence: 99%

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Laus¹,

Sour²,

Ruloff³

et al. 2005

Chemistry A European J

115

118

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“…To prevent polymer formation, a large excess of ethylenediamine was usually used and reactions took place at room temperature. This route was used for preparation of, for example, 4-nitrobenzyl [1,2], 4-aminobutyl [3], benzyl [1,4], octyl [5], and 2-naphthylmethyl [5] derivatives (Scheme 3.2).…”

Section: Synthesis Of Linear Polyamine Backbonementioning

confidence: 99%

“…Among bifunctional C-substituted H 5 DTPA derivatives, those bearing 4-aminobenzyl or 4-(isothiocyanato)benzyl groups [2] on C 2 -carbon atom are the most important and are available commercially. Unfortunately, in several papers, their structures were drawn obviously incorrectly, using phenyl instead of benzyl group or with benzylic group attached to α-carbon of pendant arm; it can be misleading, especially as the derivative with 4-amino/-NCS benzyl group attached to the α-carbon of a pendant arm was also synthesized and sometimes was really used.…”

Section: Derivatives With Only Carboxylic/carbamide Pendant Armsmentioning

confidence: 99%

Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes

Kotek¹,

Kubíček²,

Hermann³

et al. 2013

The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging

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“…Conjugation of an amino-functionalized Gd III ±DTPA complex to the SCKs was subsequently undertaken for incorporation of the Gd III into the nanostructure. The Gd III -complexed DTPA analogue was produced by the reaction of a DTPA-isothiocyanate [27] with ethylene diamine, and coordination of GdCl 3 with the amino-functionalized DTPA. A carbodiimidemediated coupling reaction was employed for covalent attachment of the small-molecule chelate to the nanostructure.…”

Section: Full Papermentioning

confidence: 99%

Synthesis of Gadolinium-Labeled Shell-Crosslinked Nanoparticles for Magnetic Resonance Imaging Applications

et al. 2005

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Shell‐crosslinked knedel‐like nanoparticles (SCKs; “knedel” is a Polish term for dumplings) were derivatized with gadolinium chelates and studied as robust magnetic‐resonance‐imaging‐active structures with hydrodynamic diameters of 40 ± 3 nm. SCKs possessing an amphiphilic core–shell morphology were produced from the aqueous assembly of diblock copolymers of poly‐(acrylic acid) (PAA) and poly(methyl acrylate) (PMA), PAA52–b–PMA128, and subsequent covalent crosslinking by amidation upon reaction with 2,2′‐(ethylenedioxy)bis(ethylamine) throughout the shell layer. The properties of these materials, including non‐toxicity towards mammalian cells, non‐immunogenicity within mice, and capability for polyvalent targeting, make them ideal candidates for utilization within biological systems. The synthesis of SCKs derivatized with GdIII and designed for potential use as a unique nanometer‐scale contrast agent for MRI applications is described herein. Utilization of an amino‐functionalized diethylenetriaminepentaacetic acid–Gd analogue allowed for direct covalent conjugation throughout the hydrophilic shell layer of the SCKs and served to increase the rotational correlation lifetime of the Gd. In addition, the highly hydrated nature of the shell layer in which the Gd was located allowed for rapid water exchange; thus, the resulting material demonstrated large ionic relaxivities (39 s–1 mM–1) in an applied magnetic field of 0.47 T at 40 °C and, as a result of the large loading capacity of the material, also demonstrated high molecular relaxivities (20 000 s–1 mM–1).

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Efficient Multigram Synthesis of the Bifunctional Chelating Agent (S)-1-p-Isothiocyanatobenzyl-diethylenetetraminepentaacetic Acid

Abstract: We have developed and optimized the synthesis of the title compound, eliminating all HPLC purifications prior to the final product. The yield (and scale) of the synthesis was increased from 19% (200 mg) to 75% (26 g).

Cited by 36 publications

References 16 publications

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes

Synthesis of Gadolinium-Labeled Shell-Crosslinked Nanoparticles for Magnetic Resonance Imaging Applications

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