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Neutral Metal-Chelating Compounds with High 64Cu Affinity for PET Imaging Applications in Alzheimer’s Disease

submitted on 08.02.2021, 04:54 and posted on 09.02.2021, 10:21 by Liviu M. Mirica, Yiran Huang, Truc T. Huynh, Liang Sun, Chi-Herng Hu, Wang Yung-Ching, Buck E. Rogers

Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer’s disease (AD). The development of longer-lived radiolabeled compounds is essential for further expanding the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as 64Cu (t1/2 = 12.7 h, β+ = 17%, β- = 39%, EC = 43%, Emax = 0.656 MeV) are capable of accomplishing this. One limitation of 64Cu PET agents is that they could release free radioactive Cu ions from the metal complexes, which decreases the signal to noise ratio and accuracy of imaging. Herein, a series of 1,4,7-triazacyclononane (TACN) and 2,11-diaza[3.3]-(2,6)pyridinophane (N4)-based metal-chelating compounds with pyridine arms were designed and synthesized by incorporating Aβ-interacting fragments into metal-binding ligands, which allows for excellent Cu chelation without diminishing their Aβ-binding affinity. The crystal structures of the corresponding Cu complexes confirmed the pyridine N atoms are involved in binding to Cu. Radiolabeling and autoradiopraphy studies show that the compounds efficiently chelate 64Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections vs. WT controls.


NIH R01GM114588


Email Address of Submitting Author


University of Illinois at Urbana-Champaign


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

no conflict of interest

Version Notes

version 1.0