Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors

Since
prostate-specific membrane antigen (PSMA) is up-regulated
in nearly all stages of prostate cancer (PCa), PSMA can be considered
as a viable diagnostic biomarker and treatment target in PCa. This
project is focused on the development and evaluation of a series of
compounds directed against PSMA. The modifications to the linker are
designed to improve the binding potential and pharmacokinetics for
theranostic application. In addition, the results help to further
elucidate the structure–activity relationships (SAR) of the
resulting PSMA inhibitors. Both in vitro and in vivo experiments of 18 synthesized PSMA inhibitor variants
showed that systematic chemical modification of the linker has a significant
impact on the tumor-targeting and pharmacokinetic properties. This
approach can lead to an improved management of patients suffering
from recurrent prostate cancer by the use of one radiolabeling precursor,
which can be radiolabeled either with 68Ga for diagnosis
or with 177Lu or 225Ac for therapy.