Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone derivatives for SPECT imaging of survivin in tumors

• Published in: Bioorganic & medicinal chemistry 2018-07, Vol.26 (12), p.3111-3116
• Main Authors: Ishikawa, Natsumi, Fuchigami, Takeshi, Mizoguchi, Tatsuya, Yoshida, Sakura, Haratake, Mamoru, Nakayama, Morio
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - diagnostic imaging; Breast Neoplasms - pathology; Cancer imaging; Cell Line, Tumor; Female; Humans; Indoles - chemistry; Indoles - metabolism; Inhibitor of Apoptosis Proteins - chemistry; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Iodine Radioisotopes - chemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Oxindoles; Protein Binding; Quartz Crystal Microbalance Techniques; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - metabolism; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Single photon emission computed tomography (SPECT); Survivin; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Transplantation, Heterologous
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.04.034

We report here radioiodinated 3-phenethyl-2-indolinone (PI) derivatives as survivin targeting in vivo imaging agents for tumor imaging. [Display omitted] Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (Kd = 68.3 nM) to recombinant human survivin, as determined by quartz crystal microbalance (QCM). In vitro studies demonstrated that the [125I]IPI-1 binding in survivin-positive MDA-MB-231 cells was significantly higher than that in survivin-negative MCF-10A cells. In addition, uptake of [125I]IPI-1 by MDA-MB-231 cells decreased in a dose-dependent manner in the presence of the high-affinity survivin ligand S12; this is indicative of specific binding of [125I]IPI-1 to cellular survivin protein in vitro. Biodistribution studies in MDA-MB-231 tumor-bearing mice demonstrated the moderate uptake of [125I]IPI-1 in the tumor tissue (1.37% ID/g) at 30 min that decreased to 0.32% ID/g at 180 min. Co-injection of S12 (2.5 mg/kg) slightly reduced tumor uptake and the tumor/muscle ratio of [125I]IPI-1. Although further structural modifications are necessary to improve pharmacokinetic properties, our results indicate that PI derivatives may be useful as tumor-imaging probes targeting survivin.