title: Metal complex mediated conjugation of peptides to nucleus targeting acridine orange: a modular concept for dual-modality imaging agents.
abstract: To target the nucleus of specific cells, trifunctional radiopharmaceuticals are required. We have synthesized acridine orange derivatives which comprise an imidazole-2-carbaldehyde function for coordination to the [Re(CO)₃](+) or [(99m)Tc(CO)₃](+) core. Upon coordination, this aldehyde is activated and rapidly forms imines with amines from biological molecules. This metal-mediated imine formation allows for the conjugation of a nuclear targeting portion with a specific cell receptor binding function directly on the metal. With this concept, we have conjugated the acridine orange part to a bombesin peptide directly on the (99m)Tc core and in one step. In addition, a linker containing an integrated disulfide has been coupled to bombesin. LC/MS study showed that the disulfide was reductively cleaved with a 60 min half-life time. This concept enables the combination of a nucleus targeting agent with a specific cell receptor molecule directly on the metal without the need of separate conjugation prior to labeling, thus, a modular approach. High uptake of the BBN conjugate into PC-3 cells was detected by fluorescence microscopy, whereas uptake into B16BL6 cells was negligible.
authors.affiliation: Institute of Inorganic Chemistry, University of Zürich, Winterthurerstrasse 190, Zürich, Switzerland.
authors.forename: Karel
authors.initials: K
authors.lastname: Zelenka
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
authors.forename: Roger
authors.initials: R
authors.lastname: Alberto
mesh_terms: D000165:Acridine Orange / Q000737:chemistry* / Q000378:metabolism*; D000447:Aldehydes / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D001839:Bombesin / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002853:Chromatography, Liquid; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D013058:Mass Spectrometry; D008670:Metals / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry; D017556:Technetium Compounds / Q000737:chemistry
chemical_list: D000447:Aldehydes; D000588:Amines; D007093:Imidazoles; D007097:Imines; D008670:Metals; D009942:Organometallic Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D017556:Technetium Compounds; C543202:triaquatricarbonyltechnetium(I); D012211:Rhenium; D000165:Acridine Orange; D001839:Bombesin