Neopentyl Glycol as a Scaffold to Provide Radiohalogenated Theranostic Pairs of High In Vivo Stability

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. W...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-11, Vol.64 (21), p.15846-15857
Main Authors: Suzuki, Hiroyuki, Kaizuka, Yuta, Tatsuta, Maho, Tanaka, Hiroshi, Washiya, Nana, Shirakami, Yoshifumi, Ooe, Kazuhiro, Toyoshima, Atsushi, Watabe, Tadashi, Teramoto, Takahiro, Sasaki, Ichiro, Watanabe, Shigeki, Ishioka, Noriko S, Hatazawa, Jun, Uehara, Tomoya, Arano, Yasushi
Format: Article
Language:English
Subjects:
Animals
Astatine - chemistry
Cytochrome P-450 Enzyme System - metabolism
Fluorine Radioisotopes - chemistry
Glycols - chemistry
Iodine Radioisotopes - chemistry
Male
Mice
Mice, Inbred ICR
Precision Medicine
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - pharmacokinetics
Radiopharmaceuticals - urine
Tissue Distribution
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01147