PSMA

Background

In the past years, the Division Radiopharmaceutical Chemistry was mainly focused on the development of novel radiotracers targeting the prostate-specific membrane antigen (PSMA). As a type II transmembrane protein with glutamate-preferring enzymatic function PSMA represents an ideal target for small molecule inhibitors which typically show fast clearance and low background activity. Furthermore, upon substrate binding PSMA is internalized via clathrin-coated pits and subsequent endocytosis resulting in an effective transportation of the bound molecule into the cells. Since internalization leads to enhanced tumor uptake and retention, targeting PSMA results in high image quality. Finally, PSMA is a cell surface protein that shows a significant overexpression on prostatic cells and especially in advanced stage prostate carcinomas with low expression in normal human tissue. PSMA thus can be considered as an outstanding biological target in nuclear medicine. These promising characteristics encouraged us to develop novel urea-based inhibitors for PET imaging with Ga-68.

Past and ongoing projects and significant accomplishments

Translation of Glu-NH-CO-NH-Lys-(Ahx)-Ga-68-HBED-CC (Ga-68-PSMA-HBED-CC) into the clinical situation.
© dkfz.de

The design of functionally active molecules which are able to internalize is complex, especially, when a chelator has to be introduced to incorporate radiometals. The “active binding site” of PSMA is composed of two structural motifs, one representing a lipophilic pocket and the other interacting with the small binding motif of urea-based inhibitors. Molecules lacking one of these interactions showed other modes of action resulting in reduced binding and internalization. Our investigations showed that aromatic interactions in the linker region between chelator and binding motif are crucial to ensure a fast and efficient internalization which typically results in high contrast PET imaging. With regard to the molecular weight and the pharmacokinetic properties, the rather lipophilic Ga-68--chelator HBED-CC was used to simultaneously introduce an aromatic motif in the linker region. This novel molecule turned out to interact advantageously with the lipophilic part of the binding pocket enabling effective preclinical Ga-68-PET imaging. The functional impact of the chelator HBED-CC could be demonstrated by direct comparison to the corresponding DOTA-conjugate which was not internalized efficiently. These promising preclinical results encouraged us to translate this novel PET imaging agent into the individual clinical scenario.

First clinical experiments realized in the Department of Nuclear Medicine at the University Hospital Heidelberg as well as in the clinical cooperation unit (CCU) Nuclear Medicine of the dkfz confirmed our preclinical findings. Ga-68-PSMA-HBED-CC is now a very successful clinical PET tracer showing better targeting properties than the current clinical standard method Choline-PET/CT.

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