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

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 (t_1/2 = 12.7 h, β⁺ = 17%, β^- = 39%, EC = 43%, E_max = 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.