1-(<i>N</i>,<i>N</i>-Dialkylcarbamoyl)-1,1-difluoromethanesulfonyl ester as a stable and effective precursor for a neopentyl labeling group with astatine-211

Sasaki, Ichiro; Tada, Masatoshi; Liu, Ziyun; Tatsuta, Maho; Okura, Takeru; Aoki, Miho; Takahashi, Kazuhiro; Ishioka, Noriko S.; Watanabe, Shigeki; Tanaka, Hiroshi

doi:10.1039/d3ob00944k

Cited by 3 publications

(1 citation statement)

References 26 publications

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“…During the 211 At-labeling process with either sulfonate esters 6a or 6b, polar and aprotic organic solvents, such as acetonitrile, are preferred. 14 However, these solvent properties complicate the direct labeling of water-soluble carriers such as antibodies and peptides. This paper presents an efficient methodology for the synthesis of an activated ester with an 211 At-labeled neopentyl group and its application to the synthesis of an 211 At-labeled antibody with suppressed astatine release.…”

Section: Introductionmentioning

confidence: 99%

Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

Tada,

Kaizuka,

Kannaka

et al. 2024

Preprint

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In this study we developed a neopentyl 211At-labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211At-labeled cetuximab. The activated ester was synthesized via the nucleophilic 211At-astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. The triazole spacer significantly enhanced the reactivity of the neopentyl sulfonate towards nucleophilic substitution. Additionally, we developed a novel Resin-Assisted Purification and Deprotection (RAPD) protocol involving a solid-phase extraction of the protected 211At-labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211At-labeled activator from the resin. This method allows the synthesis of an 211At-labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211At-labeled activated ester, we efficiently synthesized 211At-labeled cetuximab in 27±1% radiochemical yield with 95% radiochemical purity. This activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 minutes. In comparative biodistribution studies between 211At-labeled cetuximab and the corresponding 125I-labeled cetuximab in normal mice, we observed equivalent radioactivity distribution after administration, and both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose. These findings indicate a suppressed dehalogenation of the 211At-labeled cetuximab, which emphasizes the effectiveness of the 211At-labeled activated ester.

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Section: Introductionmentioning

confidence: 99%

Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

Tada,

Kaizuka,

Kannaka

et al. 2024

Preprint

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Development of a Neopentyl ²¹¹At‐Labeled Activated Ester Providing In Vivo Stable ²¹¹At‐Labeled Antibodies for Targeted Alpha Therapy

Tada,

Kaizuka,

Kannaka

et al. 2024

ChemMedChem

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In this study we developed a neopentyl 211At‐labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211At‐labeled cetuximab. The activated ester was synthesized via the nucleophilic 211At‐astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. Additionally, we developed a novel Resin‐Assisted Purification and Deprotection (RAPD) protocol involving a solid‐phase extraction of the protected 211At‐labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211At‐labeled activator from the resin. This method allows the synthesis of an 211At‐labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211At‐labeled activated ester, we efficiently synthesized 211At‐labeled cetuximab in 27±1% radiochemical yield with 95% radiochemical purity. This 211At‐activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 min. In comparative biodistribution studies between 211At‐labeled cetuximab and the corresponding 125I‐labeled cetuximab in normal mice, both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose.

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Astatine-211 radiolabelling chemistry: from basics to advanced biological applications

Vanermen,

Ligeour,

Oliveira

et al. 2024

EJNMMI radiopharm. chem.

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1-(N,N-Dialkylcarbamoyl)-1,1-difluoromethanesulfonyl ester as a stable and effective precursor for a neopentyl labeling group with astatine-211

Abstract: Radiotheranostics uses radiopharmaceuticals to combine diagnostic imaging and therapeutic intervention. Radiopharmaceuticals use radiohalogens as radioisotopes due to their unique radioactive properties, but their chemical characteristics tend to vary. Due to...

Cited by 3 publications

References 26 publications

Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

Development of a Neopentyl ²¹¹At‐Labeled Activated Ester Providing In Vivo Stable ²¹¹At‐Labeled Antibodies for Targeted Alpha Therapy

Astatine-211 radiolabelling chemistry: from basics to advanced biological applications

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1-(N,N-Dialkylcarbamoyl)-1,1-difluoromethanesulfonyl ester as a stable and effective precursor for a neopentyl labeling group with astatine-211

Abstract: Radiotheranostics uses radiopharmaceuticals to combine diagnostic imaging and therapeutic intervention. Radiopharmaceuticals use radiohalogens as radioisotopes due to their unique radioactive properties, but their chemical characteristics tend to vary. Due to...

Cited by 3 publications

References 26 publications

Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

Resin-assisted synthesis of a neopentyl 211At-labeled activated ester possessing a triazole spacer and its application to the synthesis of in vivo stable 211At-labeled antibodies.

Development of a Neopentyl 211At‐Labeled Activated Ester Providing In Vivo Stable 211At‐Labeled Antibodies for Targeted Alpha Therapy

Astatine-211 radiolabelling chemistry: from basics to advanced biological applications

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Development of a Neopentyl ²¹¹At‐Labeled Activated Ester Providing In Vivo Stable ²¹¹At‐Labeled Antibodies for Targeted Alpha Therapy