title: (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.affiliation: Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Road, Delhi-54, India. anupama@inmas.drdo.in anuabha@hotmail.com akmishra63@gmail.com.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Chauhan
authors.forename: Anupama
authors.initials: A
authors.lastname: Datta
authors.forename: Anupriya
authors.initials: A
authors.lastname: Adhikari
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.forename: Ajai
authors.initials: A
authors.lastname: Kumar Singh
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011817:Rabbits; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D005710:Gallium Radioisotopes; D008024:Ligands; D002599:Chalcone