Burnett Christopher A, Xie Jianwu, Quijano Jade, Shen Zhimin, Hunter Finie, Bur Monica, Li King C P, Danthi S Narasimhan
Molecular Imaging Laboratory, Clinical Center, National Institutes of Allergies and Infectious Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Bioorg Med Chem. 2005 Jun 1;13(11):3763-71. doi: 10.1016/j.bmc.2005.03.024.
Integrin alpha(v)beta(3) is a widely-recognized target for the development of targeted molecular probes for imaging pathological conditions. alpha(v)beta(3) is a cell-surface receptor protein that is upregulated in various pathological conditions including osteoporosis, rheumatoid arthritis, macular degeneration, and cancer. The synthesis of an alpha(v)beta(3)-targeted optical probe 7 from compound 1, and its in vitro and in vivo characterization is described. A series of aliphatic carbamate derivatives of the potent non-peptide integrin antagonist 1 was synthesized and the binding affinity to alpha(v)beta(3) was determined in both enzyme linked immunosorbent assay (ELISA) and cell adhesion inhibition assays. The hydrophobic carbamate-linked appendages improved the binding affinity of the parent compound for alpha(v)beta(3) by 2-20 times. A Boc-protected neopentyl derivative in the series is shown to have the best binding affinity to alpha(v)beta(3) (IC(50)=0.72 nM) when compared to compound 1 as well as to c-RGDfV. Optical probe 7 utilizes the neopentyl linker and demonstrates increased binding affinity and significant tumor cell uptake in vitro as well as specific tumor accumulation and retention in vivo. These results illustrate the potential of employing integrin-targeted molecular probes based on 1 to image a multitude of diseases associated with alpha(v)beta(3) overexpression.
整合素α(v)β(3)是开发用于成像病理状况的靶向分子探针的一个广泛认可的靶点。α(v)β(3)是一种细胞表面受体蛋白，在包括骨质疏松症、类风湿性关节炎、黄斑变性和癌症在内的各种病理状况中上调。本文描述了从化合物1合成靶向α(v)β(3)的光学探针7及其体外和体内表征。合成了一系列强效非肽整合素拮抗剂1的脂肪族氨基甲酸酯衍生物，并在酶联免疫吸附测定（ELISA）和细胞黏附抑制测定中测定了它们对α(v)β(3)的结合亲和力。疏水的氨基甲酸酯连接的附属基团使母体化合物对α(v)β(3)的结合亲和力提高了2至20倍。与化合物1以及c-RGDfV相比，该系列中的一种Boc保护的新戊基衍生物对α(v)β(3)具有最佳的结合亲和力（IC(50)=0.72 nM）。光学探针7利用新戊基连接子，在体外显示出增加的结合亲和力和显著的肿瘤细胞摄取，以及在体内的特异性肿瘤积累和滞留。这些结果说明了基于1的整合素靶向分子探针用于成像与α(v)β(3)过表达相关的多种疾病的潜力。
