chemicallytechFine Chemical TechnologiesТонкие химические технологии2410-65932686-7575MIREA – Russian Technological University (RTU MIREA).10.32362/2410-6593-2022-17-2-107-130chemicallytech-1820Research ArticleCHEMISTRY AND TECHNOLOGY OF MEDICINAL COMPOUNDS AND BIOLOGICALLY ACTIVE SUBSTANCESХИМИЯ И ТЕХНОЛОГИЯ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ И БИОЛОГИЧЕСКИ АКТИВНЫХ СОЕДИНЕНИЙBifunctional gallium cation chelatorsБифункциональные хелаторы к катиону галлияhttps://orcid.org/0000-0003-4502-0745ПоливановаА. Г.PolivanovaA. G.

Поливанова Анна Геннадьевна, к.х.н., доцент кафедры химии и технологии биомедицинских препаратов

125047, Москва, Миусская площадь, д. 9

Anna G. Polivanova, Cand. Sci. (Chem.), Associate Professor, Department of Chemistry and Technology of Biomedical Preparations

9, Miusskaya pl., Moscow, 125047

zagchem@mail.ruhttps://orcid.org/0000-0002-0079-6710СоловьёваИ. Н.SolovievaI. N.

Соловьёва Инна Николаевна, к.х.н., доцент кафедры химии и технологии биомедицинских препаратов

125047, Москва, Миусская площадь, д. 9

Inna N. Solovieva, Cand. Sci. (Chem.), Associate Professor, Department of Chemistry and Technology of Biomedical Preparations

9, Miusskaya pl., Moscow, 125047

solandsol@yandex.ruhttps://orcid.org/0000-0003-4954-6779БотевД. О.BotevD. O.

Ботев Дмитрий Олегович, магистрант, кафедра химии и технологии биомедицинских препаратов

125047, Москва, Миусская площадь, д. 9

Dmitrii O. Botev, Master Student, Department of Chemistry and Technology of Biomedical Preparations

9, Miusskaya pl., Moscow, 125047

botev.dm@gmail.comhttps://orcid.org/0000-0002-5906-4020ЮрьевД. Ю.YurievD. Y.

Юрьев Данил Юрьевич, магистрант, ведущий инженер, кафедра химии и технологии биомедицинских препаратов

125047, Москва, Миусская площадь, д. 9

Danil Yu. Yuriev, Master Student, Leading Engineer, Department of Chemistry and Technology of Biomedical Preparations

9, Miusskaya pl., Moscow, 125047

DanilYuriev35@yandex.ruhttps://orcid.org/0000-0002-8297-8322МыльниковаА. Н.MylnikovaA. N.

Мыльникова Алёна Николаевна, ведущий инженер, ассистент, кафедра химии и технологии биомедицинских препаратов

125047, Москва, Миусская площадь, д. 9

Alyona N. Mylnikova, Leading Engineer, Assistant, Department of Chemistry and Technology of Biomedical Preparations

9, Miusskaya pl., Moscow, 125047

pobeg_is_raya@mail.ruhttps://orcid.org/0000-0002-2892-4884ОщепковМ. С.OshchepkovM. S.

Ощепков Максим Сергеевич, д.х.н., заведующий кафедрой химии и технологии биомедицинских препаратов

Scopus Author ID 50262866400; Researcher ID AAA-6443-2022

125047, Москва, Миусская площадь, д. 9

Maxim S. Oshchepkov, Dr. Sci. (Chem.), Head of the Department of Chemistry and Technology of Biomedical Preparations

Scopus Author ID 50262866400; Researcher ID AAA-6443-2022

9, Miusskaya pl., Moscow, 125047

maxim.os@mail.ruРоссийский химико-технологический университет им. Д.И. МенделееваРоссияD.I. Mendeleev Russian University of Chemical TechnologyRussian Federation202231052022172107130Copyright © Polivanova A.G., Solovieva I.N., Botev D.O., Yuriev D.Y., Mylnikova A.N., Oshchepkov M.S., 20222022Поливанова А.Г., Соловьёва И.Н., Ботев Д.О., Юрьев Д.Ю., Мыльникова А.Н., Ощепков М.С.Polivanova A.G., Solovieva I.N., Botev D.O., Yuriev D.Y., Mylnikova A.N., Oshchepkov M.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.finechem-mirea.ru/jour/article/view/1820Objectives

Objectives. The chemistry of 67Ga and 68Ga radionuclides plays a key role in nuclear medicine for applications in radiopharmaceuticals, in particular, in noninvasive in vivo molecular imaging techniques. The use of radiometals for labeling biomolecules typically requires the use of bifunctional chelators, which contain a functional group for covalent bonding with the targeting vector in addition to the polydentate fragment coordinating the metal. The aim of the present review article is to analyze the currently accumulated experimental material on the development and application of bifunctional chelators of gallium cations in medical research, as well as to identify the main requirements for the structure of the chelator and its complexes with 68Ga, which are used to create effective Gabased pharmaceutical preparations.

Results

Results. The review analyzed macrocyclic bifunctional chelators forming stable in vivo complexes with 68Ga and acyclic chelators, whose main advantage is faster complexation kinetics due to the short half-life of 68Ga. The advantages and disadvantages of both types of ligands were evaluated. In addition, a critical analysis of the binding constants and the conditions for the formation of complexes was presented. Examples of the influence of the geometry, lipophilicity, and total charge of the metal complex on the biodistribution of target radiopharmaceuticals were also given.

Conclusions

Conclusions. Despite the progress made in the considered areas of bifunctional chelators, the problem of correlating the chemical structure of a metal-based radiopharmaceutical with its behavior in vivo remains important. Comparative studies of drugs having an identical targeting vector but containing different bifunctional chelating agents could help further elucidate the effectof metal chelate moiety on pharmacokinetics. In order to create effective bifunctional chelating agents, it is necessary to take into account such factors as the stability and inertness of the chelator and its complexes under physiological conditions, lipophilicity, complexation kinetics, chelation selectivity, combinatoriality of the basic structure, along with economic aspects, e.g., the availability of raw materials and the complexity of the synthesis scheme.

Цели

Цели. Химия радионуклидов 67Ga и 68Ga играет одну из ключевых ролей в ядерной медици­не для применения в радиофармпрепаратах, в частности, в неинвазивных методах мо­лекулярной визуализации in vivo. Использование радиометаллов для мечения биомолекул обычно требует использования бифункциональных хелаторов, которые, кроме полиден­татного фрагмента, координирующего металл, содержат функциональную группу для ковалентного связывания с вектором-мишенью. Цели данного обзора – проанализировать накопленный к настоящему времени экспериментальный материал, касающийся разра­ботки и применения в медицинских исследованиях бифункциональных хелаторов к кати­ону галлия, а также выявить и проанализировать основные требования, предъявляемые к структуре хелатора и его комплексов с 68Ga, необходимые для создания эффективных фармакологических препаратов на его основе.

Результаты

Результаты. Рассмотрены макроциклические бифункциональные хелаторы, образую­щие стабильные in vivo комплексы с 68Ga, а также ациклические хелаторы, преимуще­ство которых заключается в более быстрой кинетике комплексообразования, что явля­ется ключевым фактором, учитывающим короткий период полураспада 68Ga. Проведена оценка достоинств и недостатков обоих типов лигандов. Кроме того, осуществлен кри­тический анализ констант связывания и условий образования комплексов. Рассмотрены примеры влияния природы металлического комплекса (геометрия, липофильность, об­щий заряд) на биораспределение целевых радиофармацевтических препаратов.

Выводы

Выводы. Несмотря на достигнутые успехи в рассмотренных направлениях создания би­фунциональных хелаторов, по-прежнему важной остается проблема корреляции хими­ческой структуры радиофармпрепаратов на основе металлов с их поведением in vivo. В этом отношении сравнительные исследования препаратов, имеющих идентичный вектор нацеливания, но включающих разные бифункциональные хелатируюшие агенты, могут помочь в дальнейшем выявлении влияния металл-хелатного фрагмента на фар­макокинетику. В целом можно отметить, что для создания эффективного бифункци­онального хелатирующего агента нужно принимать во внимание целую совокупность факторов, включающую стабильность и инертность хелатора и его комплексов в физиологических условиях, липофильность, кинетику комплексообразования, селективность хеланирования, комбинаторность базовой структуры, а также экономические аспекты: доступность сырья, сложность схемы синтеза.

бифункциональный хелаторлигандгаллийрадиофармпрепаратbifunctional chelatorligandgalliumradiopharmaceuticalПредставленная работа поддержана Министерством науки и высшего образования Российской Федерации в рамках государственного задания (проект FSSM-2020-0004) «Разработка основ получения и изучение взаимодействия с организмом новых мультифункциональных наноразмерных макромолекулярных систем адресной доставки лекарственных веществ, диагностических и радиофармпрепаратов для борьбы с основными социально значимыми заболеваниями, в том числе методами тераностики».The presented work was supported by the Ministry of Science and Higher Education of the Russian Federation within the framework of the state task (project FSSM-2020-0004) «Development of the basics for obtaining and studying the interaction with the body of new multifunctional nanosized macromolecular systems for the targeted delivery of drugs, diagnostics and radiopharmaceuticals to combat the main socially significant diseases, including theranostics».ReferencesBartholomä M. 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The authors declare that there are no conflicts of interest present.