Institute of Inorganic Chemistry, University of Zürich, Winterthurerstr. 190, 8057, Zürich, Switzerland.
Org Biomol Chem. 2011 Feb 21;9(4):1071-8. doi: 10.1039/c0ob00504e. Epub 2010 Dec 24.
The development of molecular imaging agents with multiple functions has become a major trend in radiopharmaceutical chemistry. We present herein the syntheses of trifunctional compounds, combining an acridine orange (AO) based intercalator with a GRP receptor specific bombesin like peptide (BBN). Metal-mediated conjugation of these two functions via the [2 + 1] approach to the third function, the M(CO)(3) (M = (99m)Tc, Re) moiety, yielded the final trifunctional molecules. The strongly fluorescent acridine orange, a nuclear targeting agent, has been derivatised with 4-imidazolecarboxylate as a bidentate ligand and bombesin with an isonitrile group as a monodentate ligand. For cell and nuclear uptake studies, [Re(L(1)-BBN)(L(2)-Ical)(CO)(3)] type complexes were synthesized and characterized. For radiopharmaceutical purposes, the (99m)Tc analogues have been prepared in a stepwise synthesis. Fluorescence microscopy studies on PC-3 cells, bearing the BBN receptor, showed high and rapid uptake into the cytoplasm. For the bifunctional molecule, lacking the BBN peptide, no internalization was observed.
多功能分子成像剂的开发已成为放射性药物化学的主要趋势。本文介绍了三联化合物的合成，将吖啶橙（AO）基嵌入剂与 GRP 受体特异性蛙皮素样肽（BBN）结合在一起。通过[2 + 1]方法将这两种功能与第三种功能（[M（CO）（3）] + （M = （99m）Tc，Re）部分）金属介导偶联，得到了最终的三联分子。强荧光吖啶橙是一种核靶向剂，已衍生为 4-咪唑羧酸酯作为双齿配体，并用异腈基团作为单齿配体衍生为蛙皮素。为了进行细胞和核摄取研究，合成并表征了[Re（L（1）-BBN）（L（2）-Ical）（CO）（3）]型配合物。为了放射性药物的目的，已逐步合成了（99m）Tc 类似物。在具有 BBN 受体的 PC-3 细胞上进行的荧光显微镜研究表明，细胞质中具有高摄取率和快速摄取。对于缺少 BBN 肽的双功能分子，未观察到内化。
