New leads for fragment-based design of rhenium/technetium radiopharmaceutical agents.

Multiple possibilities for the coordination of fac-[Re(CO)3(H2O)3](+) to a protein have been determined and include binding to Asp, Glu, Arg and His amino-acid residues as well as to the C-terminal carboxylate in the vicinity of Leu and Pro. The large number of rhenium metal complex binding sites that have been identified on specific residues thereby allow increased target identification for the design of future radiopharmaceuticals. The core experimental concept involved the use of state-of-art tuneable synchrotron radiation at the Diamond Light Source to optimize the rhenium anomalous dispersion signal to a large value (f'' of 12.1 electrons) at its LI absorption edge with a selected X-ray wavelength of 0.9763 Å. At the Cu Kα X-ray wavelength (1.5418 Å) the f'' for rhenium is 5.9 electrons. The expected peak-height increase owing to the optimization of the Re f'' was therefore 2.1. This X-ray wavelength tuning methodology thereby showed the lower occupancy rhenium binding sites as well as the occupancies of the higher occupancy rhenium binding sites.