Amyloid β-binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu PET Imaging in Alzheimer’s Disease

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid aggregates, strong binding affinity towards Cu(II) and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate pendant arms offer up to three orders of magnitude higher binding affinity towards Cu(II) vs. the parent chelating fragment, and can generate fairly stable Cu complexes, including ⁶⁴Cu-radiolabeled compounds. Among the five compounds tested, the ⁶⁴Cu-YW-7 and ⁶⁴Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these compounds have promising partition coefficient (Log D) values of 0.91-1.26 and show moderate brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography (PET) imaging agents for AD diagnosis.