Paving the way for future PSMA inhibitors: insights from comparative preclinical evaluations of structure modifications

The stereochemical modifications in the linker region significantly influenced the in vitro and in vivo behaviour of the PSMA inhibitors. Despite similar cellular uptake, differences in plasma protein binding and pharmacokinetics were evident. Among the three novel compounds, P19 emerged as a particularly promising candidate for further investigation, also indicating that the diphenyl moiety might serve as a favourable linker building block in analogy to the naphthyl moiety. Our observations suggest potential not only for diagnostic imaging with ⁶⁸Ga, but also for therapeutic applications using ¹⁷⁷Lu, which offers a longer half-life suitable for delayed imaging and treatment intervals in prostate cancer management.