Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting

Westerberg, David A.; Carney, Patrick L.; Rogers, Patrick E.; Kline, Steven J.; Johnson, David K.

doi:10.1021/jm00121a042

Cited by 60 publications

(57 citation statements)

References 6 publications

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“…The reductive-amination procedure has been described by Westerberg for the synthesis of a (4-nitrophenyl)methyl derivative [8]. We, thus, adapted this method for the preparation of 12 (Scheme 2, a).…”

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confidence: 99%

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Relaxivity and Transmetallation Stability of New Benzyl‐Substituted Derivatives of GadoliniumDTPA Complexes

Laurent

Botteman

Elst

et al. 2004

Helvetica Chimica Acta

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In our efforts of finding new specific contrast agents of higher relaxivity and selectivity, we have prepared the two new benzyl-functionalized DTPA (−diethylenetriamine pentaacetate×) gadolinium complexes (S)-3 and (R,S)-4, and compared their properties with those of the known regioisomers (S)-2 and (S)-1. The theoretical fitting of the reduced transverse relaxation rates of the 17 O-nucleus of H 2 O gave values for the water-residence time (t M ) of 86 ± 143 ns at 310 K, values that are not limiting the proton relaxivity at body temperature. 1 H-NMRD (nuclear magnetic-relaxation dispersion) Profiles showed that the relaxivity of 1 ± 4 (r 1 4.3 ± 5.1 s À1 mm À1 at 20 MHz and 310 K) is higher than for the GdÀDTPA parent compound 5. Transmetallation assessment demonstrated that all substituted compounds, except for (S)-2, are more stable than 5. The highest stability towards Zn 2 -induced transmetallation was achieved with complexes 3, 1, and 4 (in decreasing order). Apparently, the steric hindrance of the benzyl substituents in positions 5, 4, and 2, respectively, favorably reduces the accessibility of Zn ions. From a synthetic point of view, 4-substituted DTPA complexes of type 1 are more readily accessible than 5-substituted compounds of type 3. Therefore, the former seem to be superior for linking substituted DTPA complexes to macromolecules or specific vectors.

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confidence: 99%

“…The sample was purified by anion-exchange chromatography (Dowex AG 1X8-400, HCOONa; column: 20 Â 2.4 cm). tert-Butyl N-{2-[(2,5-Dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}carbamate (8). N-Boc-Gly (10 g, 57.1 mmol) and N-hydroxysuccinimide (7.66 g, 66.51 mmol) were mixed in THF (90 ml) under an inert atmosphere.…”

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confidence: 99%

Relaxivity and Transmetallation Stability of New Benzyl‐Substituted Derivatives of GadoliniumDTPA Complexes

Laurent

Botteman

Elst

et al. 2004

Helvetica Chimica Acta

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“…With few exceptions, monoclonal antibody (mAb)-chelator conjugates have been prepared with bifunctional reagents that are members of the aminocarboxylate chelator family, with derivatives of diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) being most popular (1)(2)(3)(4)(5). These conjugates form stable radiopharmaceuticals with 1"'In that have been used for radioimmunodiagnosis of human tumors (6)(7)(8), although there is some concern about their uptake by normal tissues and possible metal release in vivo.…”

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confidence: 99%

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

Paxton

Beatty

Hawthorne

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy ( ABSTRACTA novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radiolabeled antibodies. VFC contained "Co, which was held tightly between the faces of two covalently bridged carborane ligands by cluster bonding of the metal with appropriate ligand orbitals. Anti-carcinoembryonic antigen monoclonal antibody T84.66 was conjugated to 57Co-VFC with full retention of immunological activity. Biodistribution studies in nude mice bearing carcinoembryonic antigen-producing tumors showed excellent tumor localization of 57Co-VFC-T84.66. The accumulation of radionuclide in normal liver was low and independent of dose, which may reflect the stability of the radionuclide complex. These results presage the use of VFC systems for binding transition metals that are clinically useful for radioimmunodiagnosis and radioimmunotherapy.The use of monoclonal and engineered antibodies for the selective delivery of diagnostic and therapeutic radiometals to tumors requires suitable bifunctional reagents that efficiently form covalent bonds with antibody and stable radionuclide chelate complexes. With few exceptions, monoclonal antibody (mAb)-chelator conjugates have been prepared with bifunctional reagents that are members of the aminocarboxylate chelator family, with derivatives of diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) being most popular (1-5). These conjugates form stable radiopharmaceuticals with 1"'In that have been used for radioimmunodiagnosis of human tumors (6-8), although there is some concern about their uptake by normal tissues and possible metal release in vivo. Conjugates of this type, however, form less stable radiopharmaceuticals with 90Y and 67Cu (9, 10), which can be used for radioimmunotherapy. There is therefore considerable interest in the development of new bifunctional reagents that will form more stable chelate complexes with these and other clinically relevant radionuclides.Radionuclides such as 67Cu, 991Tc, 105Rh, and '86Re are transition metals. Thus, very efficient ir-bonding ligands would be expected to form complexes of great stability with these radionuclides. Hawthorne and coworkers (11, 12) first described commo-bisdicarbollide transition metal complexes in which the metal ion is held between two ir-bonding[C2B9H11]2-dicarbollide ligands. With d6 metal ions these complexes conform to both the 18-electron and cluster electron-counting rules and display extraordinary stability due to the cluster bonding of the transition metal with ligand orbitals of appropriate symmetry. Metal ions having other than six d electrons, such as d3Cr3+ and d8Cu3+, also form stable bis-dicarbollide clusters, although in the case of electron-rich (d7, d8, etc.) species, the dicarbollide ligands undergo a "slip" distortion (12). The ability to produce these complexes in high yield in aqueous media, their expected stability to physiological co...

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“…The H 5 DTPA derivative with 4-aminobenzyl group attached to the terminal acetate arm has also been prepared employing a reductive amination of (4-nitrophenyl)pyruvic acid with substituted diethylenetriamine followed by introduction of the other acetate arms, reduction of the nitro group to amino group and hydrolysis of the amide [34] (Scheme 3.23).…”

Section: Derivatives With Only Carboxylic/carbamide Pendant Armsmentioning

confidence: 99%

“…The -NCS group can be generated also from aliphatic primary amines in the side-chain [250]. Some examples of ligands containing the aromatic amino group on the polyamine backbone [1,2,414] as well as on the pendants [34,317,415,416] are shown in Scheme 3.79.…”

Section: Bifunctional Ligands and Their Conjugationsmentioning

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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Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting

Cited by 60 publications

References 6 publications

Relaxivity and Transmetallation Stability of New Benzyl‐Substituted Derivatives of GadoliniumDTPA Complexes

Relaxivity and Transmetallation Stability of New Benzyl‐Substituted Derivatives of GadoliniumDTPA Complexes

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

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

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