Development of Cu-64/67 labeled novel amino acid as a radiotheranostics agent targeting LAT1 overexpressed in malignant tumor

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: Suzuka University of Medical Science
• Principal Investigator: Fujisawa Yutaka 鈴鹿医療科学大学, 薬学部, 助手 (30511993)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ATSM含有新規アミノ酸 / LAT1 / 悪性腫瘍診断／治療薬開発

Outline of Final Research Achievements

L-type amino acid transporter 1 (LAT1), which is classified as system L amino acid transporter and is highly expressed in a wide variety of cancer cells, is attracted as a novel target in theranostics for the malignant tumors. In this study, we synthesized the novel amino acids Cu-ATSMaa containing the structure of Cu-ATSM in the side chain, and evaluated its physical properties and its influx/efflux profiles using human breast cancer MCF7 cells. Five Cu-ATSMaa possessed similar physical properties; logD at pH7.4, protein binding to mouse serum, and stability in mouse serum or in glutathione solution. However, small difference in side chain of Cu-ATSMaa produced an alteration in behaviors of influx in and efflux from MCF7 cells. It was revealed that a Cu-67 labeled ATSMaa had retained in the target tumor over a prolonged time in biodistribution studies using MCF7-implanted mice, and had hopeful properties as a radiotheranostics agent targeting LAT1.

Free Research Field

創薬錯体化学

Academic Significance and Societal Importance of the Research Achievements

本研究により、新規アミノ酸Cu-ATSMaaがLAT1の基質として細胞内に取り込まれることを明らかにした。側鎖サイズのわずかな違いが細胞内外へのCu-ATSMaaの移行に影響を与えること、また、LAT1基質となるCu-ATSMaaのCu-67標識体の投与により、モデルマウスにおいて腫瘍にCu-67を長時間保持できることを明らかとした。本研究で得た、構造と細胞内外への移行挙動の関係は、LAT1標的薬剤開発における基礎データとして活用できるものと考える。また、更なる構造発展は必要であるが、放射性銅Cu-64/67標識ATSMaaのLAT1標的診断／治療薬剤として有用性を示せたものと考える。