Receptor-specific nuclear targeting requires trifunctional metal complexes. We have synthesized [M(L2-pept)(L1-acr)(CO)3] (pept = peptide: acr = acridine-based agent) in which the fac-[M(CO) 3]+ moicty (1st function, M = 99mTc. Re) couples an acridine-based nuclear-targeting agent (2nd function. L 1-acr) and the specific cell-receptor-binding peptide bombesin (3rd function, L2-pept). The metalmediated coupling is based on the mixed ligand [2+1] principle. The nuclear targeting agents have been derivatised with an isocyanide group for monodentate (L1) and bombesin (BBN) with a bidentate ligand (L2) for complexation to fac-[M(CO)3]+. For nuclear uptake studies, the model complexes [Re(L2)(L 1-acr)(CO)3] (L2 = pyridine-2-carhoxylic acid and pyridine2.4-dicarhoxylic acid) were synthesized and structurally characterized. We selected acridine derivatives as nucleartargeting agents, because they are very good nucleus-staining agents and exhibit strong fluorescence. Despite the bulky metal complexes attached to acridine. all [Re(L2)(L1-acr)(CO)3] showed high accumulation in the nuclei of PC3 and B16F1 cells, as evidenced by fluorescence microscopy. For radio-pharmaceutical purposes, the 99mTc analogues have been prepared and radioactivity distribution confirmed the fluorescence results. Coupling of BBN to L2 gave the receptor-selective complexes [M(L 2-BBN)(L1-acr)(CO)3]. Whereas no internalization was found with B16F1 cells, fluorescence microscopy on PC3 cells bearing the BBN receptor showed high and rapid uptake by receptor-mediated endocytosis into the cytoplasm, but not into the nucleus. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

Cell-specific and nuclear targeting with [M(CO)3]+ (M = 99mTc, Re)-based complexes conjugated to acridine orange and bombesin

Viola G.;
2007

Abstract

Receptor-specific nuclear targeting requires trifunctional metal complexes. We have synthesized [M(L2-pept)(L1-acr)(CO)3] (pept = peptide: acr = acridine-based agent) in which the fac-[M(CO) 3]+ moicty (1st function, M = 99mTc. Re) couples an acridine-based nuclear-targeting agent (2nd function. L 1-acr) and the specific cell-receptor-binding peptide bombesin (3rd function, L2-pept). The metalmediated coupling is based on the mixed ligand [2+1] principle. The nuclear targeting agents have been derivatised with an isocyanide group for monodentate (L1) and bombesin (BBN) with a bidentate ligand (L2) for complexation to fac-[M(CO)3]+. For nuclear uptake studies, the model complexes [Re(L2)(L 1-acr)(CO)3] (L2 = pyridine-2-carhoxylic acid and pyridine2.4-dicarhoxylic acid) were synthesized and structurally characterized. We selected acridine derivatives as nucleartargeting agents, because they are very good nucleus-staining agents and exhibit strong fluorescence. Despite the bulky metal complexes attached to acridine. all [Re(L2)(L1-acr)(CO)3] showed high accumulation in the nuclei of PC3 and B16F1 cells, as evidenced by fluorescence microscopy. For radio-pharmaceutical purposes, the 99mTc analogues have been prepared and radioactivity distribution confirmed the fluorescence results. Coupling of BBN to L2 gave the receptor-selective complexes [M(L 2-BBN)(L1-acr)(CO)3]. Whereas no internalization was found with B16F1 cells, fluorescence microscopy on PC3 cells bearing the BBN receptor showed high and rapid uptake by receptor-mediated endocytosis into the cytoplasm, but not into the nucleus. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/3339986
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