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Neopentyl Glycol as a Scaffold to Provide Radiohalogenated Theranostic Pairs of High In Vivo Stability
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-28 , DOI: 10.1021/acs.jmedchem.1c01147 Hiroyuki Suzuki 1 , Yuta Kaizuka 1 , Maho Tatsuta 2 , Hiroshi Tanaka 2 , Nana Washiya 1 , Yoshifumi Shirakami 3 , Kazuhiro Ooe 4 , Atsushi Toyoshima 3 , Tadashi Watabe 4 , Takahiro Teramoto 3 , Ichiro Sasaki 5 , Shigeki Watanabe 5 , Noriko S Ishioka 5 , Jun Hatazawa 6 , Tomoya Uehara 1 , Yasushi Arano 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-28 , DOI: 10.1021/acs.jmedchem.1c01147 Hiroyuki Suzuki 1 , Yuta Kaizuka 1 , Maho Tatsuta 2 , Hiroshi Tanaka 2 , Nana Washiya 1 , Yoshifumi Shirakami 3 , Kazuhiro Ooe 4 , Atsushi Toyoshima 3 , Tadashi Watabe 4 , Takahiro Teramoto 3 , Ichiro Sasaki 5 , Shigeki Watanabe 5 , Noriko S Ishioka 5 , Jun Hatazawa 6 , Tomoya Uehara 1 , Yasushi Arano 1
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The high in vivo stability of 2,2-dihydroxymethyl-3-[18F]fluoropropyl-2-nitroimidazole ([18F]DiFA) prompted us to evaluate neopentyl as a scaffold to prepare a radiotheranostic system with radioiodine and astatine. Three DiFA analogues with one, two, or without a hydroxyl group were synthesized. While all 125I-labeled compounds remained stable against nucleophilic substitution, only a 125I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against in vivo deiodination. 211At-labeled neopentyl glycol also remained stable against both nucleophilic substitution and CYP-mediated metabolism. 211At-labeled neopentyl glycol showed the biodistribution profiles similar to those of its radioiodinated counterpart in contrast to the 125I/211At-labeled benzoate pair. The urine analyses confirmed that 211At-labeled neopentyl glycol was excreted in the urine as a glucuronide conjugate with the absence of free [211At]At–. These findings indicate that neopentyl glycol would constitute a promising scaffold to prepare a radiotheranostic system with radioiodine and 211At.
中文翻译：
新戊二醇作为支架，可提供高体内稳定性的放射性卤化治疗诊断对
2,2-二羟甲基-3-[ 18 F]氟丙基-2-硝基咪唑（[ 18 F]DiFA）的高体内稳定性促使我们评估新戊基作为支架以制备具有放射性碘和砹的放射治疗系统。合成了三种具有一个、两个或没有羟基的 DiFA 类似物。虽然所有125 I 标记的化合物对亲核取代保持稳定，但只有125 I 标记的新戊二醇对细胞色素 P450 (CYP) 介导的代谢保持稳定，并显示出对体内脱碘的高稳定性。211 At 标记的新戊二醇对亲核取代和 CYP 介导的代谢也保持稳定。与125 I/ 211 At 标记的苯甲酸酯对相比， 211 At 标记的新戊二醇显示出与其放射性碘化对应物相似的生物分布曲线。尿液分析证实，211 At 标记的新戊二醇作为葡萄糖苷酸结合物从尿液中排出，不含游离的 [ 211 At]At –。这些发现表明，新戊二醇将构成一个有前途的支架，用于制备含有放射性碘和211 At 的放射治疗系统。
更新日期：2021-11-11
中文翻译：
新戊二醇作为支架，可提供高体内稳定性的放射性卤化治疗诊断对
2,2-二羟甲基-3-[ 18 F]氟丙基-2-硝基咪唑（[ 18 F]DiFA）的高体内稳定性促使我们评估新戊基作为支架以制备具有放射性碘和砹的放射治疗系统。合成了三种具有一个、两个或没有羟基的 DiFA 类似物。虽然所有125 I 标记的化合物对亲核取代保持稳定，但只有125 I 标记的新戊二醇对细胞色素 P450 (CYP) 介导的代谢保持稳定，并显示出对体内脱碘的高稳定性。211 At 标记的新戊二醇对亲核取代和 CYP 介导的代谢也保持稳定。与125 I/ 211 At 标记的苯甲酸酯对相比， 211 At 标记的新戊二醇显示出与其放射性碘化对应物相似的生物分布曲线。尿液分析证实，211 At 标记的新戊二醇作为葡萄糖苷酸结合物从尿液中排出，不含游离的 [ 211 At]At –。这些发现表明，新戊二醇将构成一个有前途的支架，用于制备含有放射性碘和211 At 的放射治疗系统。
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