Successful Design of a Multivalent Bifunctional Chelator for Diagnostic 64Cu PET Imaging in Alzheimer’s Disease

Herein, we report to the best of our knowledge the first ⁶⁴Cu PET imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta-amyloid (Aβ) aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of WT mice. The employed approach uses a bifunctional chelator with two Aβ-interacting fragments that dramatically improves the Aβ-binding affinity and lipophilicity for favorable BBB penetration, while the use of optimized-length spacers between the Cu-chelating group and the Aβ-interacting fragments further improves the in vivo Aβ-binding specificity and brain uptake of the corresponding ⁶⁴Cu PET imaging agent.