Blood-Brain Barrier Penetrating Luminescent Conjugates Based on Cyclometalated Platinum(II) Complexes.

Herein we report on the synthesis, structural characterization and photophysical properties of cyclometalated Pt(II) complexes [Pt(N^C)(PPh(CHCOOH))Cl] (where N^C ligands are 2-phenylpyridine, (2-benzofuran-3-yl)pyridine, and (2-benzo[]tiophen-3-yl)pyridine) and their conjugates with the histidine-containing RRRRRRRRRRHVLPKVQA peptide. This peptide contains the RHVLPKVQA sequence, which is responsible for antiamyloid activity, and the Arg9 RRRRRRRRR domain, which shows improved translocation through cell membranes. The chemistry underpinning the conjugation is regioselective complexation between Pt(II) complexes and histidine residue in the peptide. The prepared conjugates have been characterized using high-resolution mass spectrometry and NMR spectroscopy. It was shown that the conjugates are easily soluble in aqueous media and display emission band profiles essentially similar to those of the starting complexes but considerably higher luminescence quantum yield and much longer phosphorescence lifetime. MTT assay on HeLa cell culture revealed no cytotoxicity up to 10 μM after 24 h of incubation. Ex vivo and in vivo neuroimaging experiments on both wild and amyloid peptide expressing strains of revealed that the conjugates penetrate the blood-brain barrier and are evenly distributed throughout the brain independently of the strain used.