RI Research Department, Research Division, FUJIFILM Toyama Chemical Co., Ltd., 453-1, Shimo-Okura, Matsuo-Machi, Sammu-City, Chiba, 289-1592, Japan.
Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Sci Rep. 2019 Oct 25;9(1):15284. doi: 10.1038/s41598-019-51754-0.
C-X-C chemokine receptor type 4 (CXCR4) constitutes a promising target for tumor diagnosis and therapy. Herein, we evaluate a new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CXCR4 antagonist derived from LY2510924, FRM001, and its metal complexes as CXCR4-targeting probes. FRM001 was synthesized by modifying the C-terminus of LY2510924 with maleimido-mono-amide-DOTA via a cysteine linker. FRM001 exhibited CXCR4-specific binding with an affinity similar to that of the parental LY2510924. The binding affinity of FRM001 remained unchanged after complexation with Ga, Lu, and Y. The internalization of Ga-FRM001 into the cells was hardly observed. In mice biodistribution studies, Ga-FRM001 exhibited high accumulation in the tumor and the liver with rapid elimination rates from the blood. The hepatic accumulation of Ga-FRM001 was preferentially and significantly reduced by co-injecting a CXCR4 antagonist, AMD3100. The C-terminal-modified LY2510924 would constitute a versatile scaffold to develop CXCR4-targeting probes or therapeutics for tumor imaging or therapy.
C-X-C 趋化因子受体 4（CXCR4）是肿瘤诊断和治疗的有前途的靶点。在此，我们评估了一种新型的 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）缀合的 CXCR4 拮抗剂，它源自 LY2510924、FRM001，并评估了其金属配合物作为 CXCR4 靶向探针。FRM001 是通过半胱氨酸接头用马来酰亚胺单酰胺-DOTA 修饰 LY2510924 的 C 末端合成的。FRM001 表现出与母体 LY2510924 相似的 CXCR4 特异性结合亲和力。FRM001 与 Ga、Lu 和 Y 配位后，结合亲和力保持不变。Ga-FRM001 几乎不会内化到细胞中。在小鼠体内分布研究中，Ga-FRM001 在肿瘤和肝脏中具有高积累，并且从血液中快速消除。通过共注射 CXCR4 拮抗剂 AMD3100，可优先且显著降低 Ga-FRM001 在肝脏中的积累。C 末端修饰的 LY2510924 将构成开发用于肿瘤成像或治疗的 CXCR4 靶向探针或治疗剂的多功能支架。
