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

Abstract

In an attempt to explore use of PET radioisotope, (68)Ga, in the diagnosis of Alzheimer's disease, a metal-based homodimeric ligand exhibiting high affinity towards Aβ 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-tetraazatridecane-1-carboxylic acid, DT(Ch)2 was synthesized in 95% yield with high purity. It was radiolabelled with (68)Ga under mild conditions with 85.4% efficiency and 9.5-10 MBq nmol(-1) specific activity. An in vitro binding assay on Aβ42 aggregates displayed high binding affinity of (68)Ga-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 Aβ aggregates. Blood kinetics of the complex performed on normal rabbit exhibited fast clearance (t1/2(F) = 24 ± 0.08 min; t1/2(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 (68)Ga-complex, (68)Ga-DT(Ch)2, may offer a new perspective in generator produced PET imaging probes for Alzheimer's disease.

• Authors: Kanchan Chauhan, Anupama Datta, Anupriya Adhikari, Krishna Chuttani, Ajai Kumar Singh, Anil K Mishra
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 12 Issue 37 Pg. 7328-37 (Oct 07 2014) ISSN: 1477-0539 [Electronic] England
• PMID: 25115649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Chelating Agents
• Gallium Radioisotopes
• Ligands
• Chalcone

Topics

• Alzheimer Disease (diagnosis)
• Amyloid beta-Peptides (analysis)
• Animals
• Chalcone (chemical synthesis, chemistry)
• Chelating Agents (chemical synthesis, chemistry)
• Gallium Radioisotopes (chemistry)
• Humans
• Kinetics
• Ligands
• Molecular Structure
• Positron-Emission Tomography
• Rabbits
• Thermodynamics