Concentration-Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides Aβ and Amylin**

Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents. The attachment of a metal complex to amyloid recognition units typically leads to a decrease in peptide affinity. We show here that by separating a macrocyclic GdL chelate and a PiB targeting unit with a long hydrophobic C10 linker, it is possible to attain nanomolar affinities for both A beta(1-40) (K-d=4.4 nm) and amylin (K-d=4.5 nm), implicated, respectively in Alzheimer's disease and diabetes. The Scatchard analysis of surface plasmon resonance data obtained for a series of amphiphilic, PiB derivative GdL complexes indicate that their A beta(1-40) or amylin binding affinity varies with their concentration, thus micellar aggregation state. The GdL chelates also affect peptide aggregation kinetics, as probed by thioflavin-T fluorescence assays. A 2D NMR study allowed identifying that the hydrophilic region of A beta(1-40) is involved in the interaction between the monomer peptide and the Gd3+ complex. Finally, ex vivo biodistribution experiments were conducted in healthy mice by using In-111 labeled analogues. Their pancreatic uptake, similar to 3 %ID g(-1), is promising to envisage amylin imaging in diabetic animals.

Automated summary

Metal chelates targeted to amyloid peptides show promising nanomolar affinities for both A beta(1-40) and amylin when separated with a hydrophobic linker. The binding affinity of GdL complexes to A beta(1-40) or amylin varies with concentration and micellar aggregation state, affecting peptide aggregation kinetics. Ex vivo biodistribution experiments using In-111 labeled analogues in healthy mice suggest potential for amylin imaging in diabetic animals.