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Issue 37, 2014
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68Ga based probe for Alzheimer's disease: synthesis and preclinical evaluation of homodimeric chalcone in β-amyloid imaging

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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

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Publication details

The article was received on 07 May 2014, accepted on 29 Jul 2014 and first published on 29 Jul 2014


Article type: Paper
DOI: 10.1039/C4OB00941J
Org. Biomol. Chem., 2014,12, 7328-7337

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    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

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