68Ga based probe for Alzheimer's disease: synthesis and preclinical evaluation of homodimeric chalcone in β-amyloid imaging

In an attempt to explore use of PET radioisotope, Ga-68, in the diagnosis of Alzheimer's disease, a metal-based homodimeric ligand exhibiting high affinity towards A beta aggregates was designed by conjugating two chalcone units with the chelating system, diethylenetriaminepentaacetic acid. Bischalcone derivative, 5,8-bis(carboxymethyl)-13-(4-((E)-3-(4-(dimethylamino)phenyl) acryloyl)phenoxy)-2-(2-(2-(4-(( E)-3-(4-(dimethylamino)phenyl)acryloyl)phenoxy)ethylamino)-2-oxoethyl)-10-oxo-2,5,8,11-tetra-azatridecane-1-carboxylic acid, DT(Ch)(2) was synthesized in 95% yield with high purity. It was radiolabelled with Ga-68 under mild conditions with 85.4% efficiency and 9.5-10 MBq nmol(-1) specific activity. An in vitro binding assay on A beta 42 aggregates displayed high binding affinity of Ga-68-DT(Ch)(2) and inhibition constant of 4.18 +/- 0.62 nM. The fluorescent properties of the ligand with peaks of absorption/emission at 410/540 nm exhibited a blue shift with 5.5-fold increase in emission intensity on binding with A beta aggregates. Blood kinetics of the complex performed on normal rabbit exhibited fast clearance (t(1/2)(F) = 24 +/- 0.08 min; t(1/2)(S) = 2 h 40 +/- 0.04 min). Ex vivo biodistribution analysis demonstrated blood-brain barrier penetration with brain uptake of 1.24 +/- 0.31% ID g(-1) at 2 min p.i. and rapid washout with negligible activity (0.36% ID g(-1)) left at 30 min p.i. These preliminary studies reveal that the bivalent approach of synthesis had minimal effect on binding affinity, signifying that the developed Ga-68-complex, Ga-68-DT(Ch)(2), may offer a new perspective in generator produced PET imaging probes for Alzheimer's disease.