Design of novel bifunctional chelators for diagnostic 64 Cu PET imaging in Alzheimer’s disease

Abstract Background Metal radiotracers exhibit beneficial properties that can improve in vivo positron emission tomography (PET) imaging over traditional radionuclides, such as longer half‐lives, facile last‐stage radiolabeling steps, and the potential for dual imaging‐therapy applications. Among such radionuclides, 64 Cu exhibits a longer half‐life (t 1/2 = 12.7 h) that allows for later PET imaging times and the ability to distribute 64 Cu imaging agents to facilities that do not have an on‐site cyclotron. Method The employed approach uses a bifunctional chelator with two Aβ‐interacting fragments that dramatically improves the Aβ‐binding affinity and lipophilicity for favorable blood‐brain barrier (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 64 Cu PET imaging agent. Result Herein, we report to the best of our knowledge the first 64 Cu PET imaging agent that shows appreciable in vivo brain uptake and exhibits high specific affinity for beta‐amyloid aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of WT mice. Conclusion 64 Cu PET imaging agents can be used for in vivo imaging of beta‐amyloid aggregates.