Neutral Metal-Chelating Compounds with High 64Cu Affinity for PET Imaging Applications in Alzheimer’s Disease
2021
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.
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