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Abstract

The prostate-specific membrane antigen (PSMA) has proven to be a promising target for diagnostic and therapeutic purposes. Although this biological target is well-recognized for prostate cancer, the expression of PSMA is not only restricted to prostate cancer. It is also expressed in many tumor types derived from the endothelial cells of tumor blood vessels. This thesis explores the development of inhibitors for specific targeting of PSMA. These inhibitors are small molecules that contain the Glu-NH-CO-NH-Lys moiety as binding motif, which was already shown to bind to PSMA with high affinity. The novel synthesized compounds were designed using PSMA-617 as reference. PSMA-617, bearing the linker moieties 2-naphthyl-L-alanine and 4-(aminomethyl) cyclohexanecarboxylic acid still the standard structure with respect to pharmacokinetics and internalization efficiency. Improvement of the linker moieties connected to alternative chelating agents to form stable complexes with copper radio-isotopes, in particular the theranostic pair 64Cu and 67Cu was one aim of the project. 64Cu represents an alternative in case where short-term PET imaging is not possible and it also allows the dosimetry of therapeutic 67Cu as an alternative to 177Lu. In the second part of this thesis, PSMA ligands were developed for labelling with lead radio-isotopes; for this study, the radioisotope 203Pb was used as an imaging agent to obtain an approximation for the dosimetry with 212Pb, a radionuclide that represents an in vivo alpha generator. In the last part of the project, a series of PSMA ligands that comprise a benzyl group in the chelator moiety was developed to further optimize the clinically established radiopharmaceutical PSMA- 617. These compounds were evaluated in vitro in the PSMA expressing cell line, C4-2 and in vivo in tumor bearing mice. Among the compounds evaluated, CA003, CA012, CA028 and CA030 were the most promising ones, as demonstrated by their high PSMAspecific cellular uptake and low kidney uptake. The performance of the novel compounds was assessed in first patient studies resulting in clear visualization of the cancer and metastatic lesions with high contrast.

Keywords: prostate-specific membrane antigen (PSMA), prostate cancer, PSMAinhibitors, PET imaging, endo-radiotherapy.