Trifunctional 99mTc based radiopharmaceuticals: metal-mediated conjugation of a peptide with a nucleus targeting intercalator?

Organic & Biomolecular Chemistry Pub Date: 2010-12-24 DOI: 10.1039/C0OB00504E

Abstract

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 = 99mTc, 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(L1-BBN)(L2-Ical)(CO)3] type complexes were synthesized and characterized. For radiopharmaceutical purposes, the 99mTc 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.

Graphical abstract: Trifunctional 99mTc based radiopharmaceuticals: metal-mediated conjugation of a peptide with a nucleus targeting intercalator
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