Nuclear medicine and biology · 2025
Evaluation of astatine-211-labeled benzoate derivatives for improved in vivo stability.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Murata Mutsuho, Kannaka Kento, Tatsuta Souta, Terasaka Yui, Nonaka Ryota, Suzuki Hiroyuki, Takahashi Kazuhiro, Uehara Tomoya
Аннотация
PURPOSE: Astatine-211 (211At) is one of the most promising α-particle-emitting radionuclides used for targeted-alpha therapy. Benzene derivatives are currently commonly used as 211At-labeling moieties for preparing 211At-labeled compounds. However, 211At-labeled compounds using benzene derivatives as the 211At-labeling moiety have known low stability against in vivo deastatination. We hypothesized that the deastatination of 211At-labeled benzene derivatives is enzyme-mediated, and that the inclusion of a bulky structure near the 211At-astatobenzene would stabilize it by inhibiting recognition by the enzymes.
METHODS: In this study, we synthesized oligopeptides with D-type amino acids, such as D-glutamic acid (e), D-alanine (a), and d-lysine (k), which have high metabolic stability against peptidases, and bound them with 211At-astatobenzoate. Then, we evaluated the stability of these 211At-labeled compounds against deastatination in vivo.
RESULTS: 211At-labeled mono- or di-D-glutamic acid ([211At]At-Bz-e or [211At]At-Bz-ee) and 211At-labeled tri-D-alanine ([211At]At-Bz-aaa) showed high to moderate accumulation of radioactivity in the stomach and thyroid, whereas 211At-labeled tri-D-glutamic acid ([211At]At-Bz-eee) and 211At-labeled tri-d-lysine ([211At]At-Bz-kkk) showed low radioactivity levels in the stomach and thyroid. Furthermore, 211At-labeled tri-L-glutamic acid ([211At]At-Bz-EEE) displayed a higher accumulation in the stomach than [211At]At-Bz-eee. These results suggested that the in vivo deastatination of 211At-astatobenzene derivatives is not attributable to the weakness of the AtC bond, but rather to metabolization to smaller molecules with less steric hindrance to the 211At-labeling moiety in vivo and subsequent enzyme-mediated deastatination.
CONCLUSIONS: Our findings indicated that if 211At-labeled compounds can place the steric hindrance of the tripeptide size in the vicinity of 211At-astatobenzene, in vivo stable 211At-labeled compounds can be produced, even when using the 211At-astatobenzen structure as a 211At-labeling moiety.
METHODS: In this study, we synthesized oligopeptides with D-type amino acids, such as D-glutamic acid (e), D-alanine (a), and d-lysine (k), which have high metabolic stability against peptidases, and bound them with 211At-astatobenzoate. Then, we evaluated the stability of these 211At-labeled compounds against deastatination in vivo.
RESULTS: 211At-labeled mono- or di-D-glutamic acid ([211At]At-Bz-e or [211At]At-Bz-ee) and 211At-labeled tri-D-alanine ([211At]At-Bz-aaa) showed high to moderate accumulation of radioactivity in the stomach and thyroid, whereas 211At-labeled tri-D-glutamic acid ([211At]At-Bz-eee) and 211At-labeled tri-d-lysine ([211At]At-Bz-kkk) showed low radioactivity levels in the stomach and thyroid. Furthermore, 211At-labeled tri-L-glutamic acid ([211At]At-Bz-EEE) displayed a higher accumulation in the stomach than [211At]At-Bz-eee. These results suggested that the in vivo deastatination of 211At-astatobenzene derivatives is not attributable to the weakness of the AtC bond, but rather to metabolization to smaller molecules with less steric hindrance to the 211At-labeling moiety in vivo and subsequent enzyme-mediated deastatination.
CONCLUSIONS: Our findings indicated that if 211At-labeled compounds can place the steric hindrance of the tripeptide size in the vicinity of 211At-astatobenzene, in vivo stable 211At-labeled compounds can be produced, even when using the 211At-astatobenzen structure as a 211At-labeling moiety.