⁶⁴Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer

Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five ⁶⁴Cu-labeled inhibitors of PSMA, [⁶⁴Cu]3-7, which are based on the lysine-glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [⁶⁴Cu]3-7 were prepared in high radiochemical yield (60-90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [⁶⁴Cu]3-7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA- PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [⁶⁴Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [⁶⁴Cu]CB-TE2A as compared with [⁶⁴Cu]NOTA, [ ⁶⁴Cu]PCTA, [⁶⁴Cu]Oxo-DO3A, and [⁶⁴Cu]DOTA chelates in vivo.