***The following content was written by the author of the paper with URA.***
Professor Kazuma Ogawa from Graduate School of Medical Sciences and Associate Professor Kenji Mishiro from Institute for Frontier Science Initiative, Kanazawa University, in collaboration with Saki Hirata, Associate Professor Takeshi Fuchigami and Assistant Professor Masayuki Munekane from Graduate School of Medical Sciences, Professor Seigo Kinuya from Department of Nuclear Medicine, Kanazawa University Hospital, Kanazawa University, Professor Kazuhiro Takahashi and Associate Professor Kohshin Washiyama from Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, and Professor Emeritus Yasushi Arano from Graduate School of Pharmaceutical Sciences, Chiba University, demonstrated strategic structural modifications that reduce the dissociation of Astatin-211 (211At) (*1) directly conjugated to an aromatic ring (*2) of a chemical compound.
Alpha particles are a type of radiation characterized by their very high cytotoxicity and short radiation range (*3). Delivering drugs containing alpha-emitting radionuclides (*4) specifically to cancer cells will achieve high therapeutic efficacy while minimizing side effects. Thus, application of alpha particle emitting radionuclide labeled drugs has been focused for cancer treatment, however 211 At is almost the only alpha-emitter produced in Japan. Despite such therapeutic advantages, in the body211 At tends to detach from drugs when it is conjugated to an aromatic ring of drugs, leading to unintended accumulation of 211 At in healthy organs and causing harmful side effects. In this study, the scientists synthesized a variety of astatinated aromatic compounds containing substituents (*5) with different physical properties introduced at sites on an aromatic ring adjacent to 211At conjugated position. Through evaluation of their stabilities and tissue accumulations using experimental systems in and outside animals, they found that such chemical structural modifications improve the stability of 211 At on the aromatic ring. Applying this strategy established in this study to 211 At conjugated drugs will make nuclear medicine-oriented cancer treatment more effective with fewer side effects.
The research results were published in the online edition of the Journal of Medicinal Chemistry, an international journal published by the American Chemical Society on January 6, 2025.
Figure： Graphic summary of this study
【Glossary】
*1: Astatine-211
One of radioactive nuclides emitting alpha-particle. Since astatine is one of halogen elements such as iodine and bromine, common labeling methods for halogens can be applied to synthesize astatine derivatives. High cytotoxicity of Astatine-211 is expected to have a strong cancer therapeutic effect when correctly targeted to cancers.
*2: Aromatic ring
Organic compounds that consist of a conjugated planar ring structure such as benzene. It is included in the structure of chemical substances used as ingredients in many things related to our daily life, including pharmaceuticals, cosmetics, and fragrances.
*3: Radiation range
The distance until the radiation loses its energy, or gives off its energy to other substances, and stops. α particles have a range of 20-100 µm in tissue and β- particles have a range of a few millimeters.
*4：Alpha particle emitting nuclides
Alpha particle is a helium nucleus composed of two protons and two neutrons. Alpha particle emitting nuclides emit α particle when transformed into different atoms.
*5: Substituent
An atom or atomic group that constitutes the substructure of an organic molecule. In a molecule in which a hydrogen atom of a parent compound is replaced by another atom or atomic group, the replaced atom or atomic group is called a substituent.
Click here to see the press release【Japanese only】
Journal：Journal of Medicinal Chemistry
Researcher Information: Kazuma Ogawa
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