TY - JOUR
T1 - Neutral Ligands as Potential 64Cu Chelators for Positron Emission Tomography Imaging Applications in Alzheimer's Disease
AU - Huang, Yiran
AU - Huynh, Truc T.
AU - Sun, Liang
AU - Hu, Chi Herng
AU - Wang, Yung Ching
AU - Rogers, Buck E.
AU - Mirica, Liviu M.
N1 - Funding Information:
L.M.M. acknowledges research funding from the NIH (Grant R01GM114588). The authors thank the small animal imaging facility at Washington University School of Medicine for excellent technical assistance, Cedric Mpoy for valuable assistance with animal studies, the Isotope Production Group at Washington University for production of Cu, Dr. Toby Woods for help with solving the crystal structures, and Karna Terpstra for obtaining the high-resolution ESI-MS data for the Cu complexes. 64
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/3/21
Y1 - 2022/3/21
N2 - 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 expansion of 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%, electron capture EC = 43%, and Emax= 0.656 MeV) can accomplish this task. One limitation of 64Cu PET agents for neuroimaging applications is their limited lipophilicity due to the presence of several anionic groups needed to ensure strong Cu chelation. Herein, we evaluate a series of neutral chelators containing the 1,4,7-triazacyclononane or 2,11-diaza[3.3](2,6)pyridinophane macrocycles that have pyridyl-containing arms incorporating Aβ-peptide-interacting fragments. The crystal structures of the corresponding Cu complexes confirm that the pyridyl N atoms are involved in binding to Cu. Radiolabeling and autoradiography 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 versus wild-type controls.
AB - 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 expansion of 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%, electron capture EC = 43%, and Emax= 0.656 MeV) can accomplish this task. One limitation of 64Cu PET agents for neuroimaging applications is their limited lipophilicity due to the presence of several anionic groups needed to ensure strong Cu chelation. Herein, we evaluate a series of neutral chelators containing the 1,4,7-triazacyclononane or 2,11-diaza[3.3](2,6)pyridinophane macrocycles that have pyridyl-containing arms incorporating Aβ-peptide-interacting fragments. The crystal structures of the corresponding Cu complexes confirm that the pyridyl N atoms are involved in binding to Cu. Radiolabeling and autoradiography 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 versus wild-type controls.
UR - http://www.scopus.com/inward/record.url?scp=85126276948&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.2c00621
DO - 10.1021/acs.inorgchem.2c00621
M3 - Article
C2 - 35245023
AN - SCOPUS:85126276948
SN - 0020-1669
VL - 61
SP - 4778
EP - 4787
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 11
ER -