Jump to main content
Jump to site search

Issue 37, 2014

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

Author affiliations

Abstract

In an attempt to explore use of PET radioisotope, 68Ga, 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 68Ga 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 68Ga-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 68Ga-complex, 68Ga-DT(Ch)2, may offer a new perspective in generator produced PET imaging probes for Alzheimer's disease.

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

Supplementary files

Article information


Submitted
07 May 2014
Accepted
29 Jul 2014
First published
29 Jul 2014

Org. Biomol. Chem., 2014,12, 7328-7337
Article type
Paper

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

K. Chauhan, A. Datta, A. Adhikari, K. Chuttani, A. Kumar Singh and A. K. Mishra, Org. Biomol. Chem., 2014, 12, 7328 DOI: 10.1039/C4OB00941J

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.


Social activity

Search articles by author

Spotlight

Advertisements