Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer (PCa) cells. In the last decade, PSMA-targeting positron emission tomography (PET) has gained increasing acceptance for PCa imaging. Among the different available PSMA ligands, theranostic agents that can be labelled with both diagnostic and therapeutic radioisotopes have raised particular interest. Androgen deprivation therapy (ADT) is known to upregulate PSMA expression. However, studies investigating this phenomenon in humans are limited. In the clinical context, while the use of PSMA PET has been established in detecting recurrence after radical treatment, the role of PSMA PET in primary staging was only recently affirmed.

The aim of this doctoral thesis was to investigate novel aspects of PSMA PET imaging, from the kinetics of a novel theranostic radiotracer, through the physiology of PSMA expression, to its use for primary staging in the clinical practice. The uptake kinetics of radiohybrid [18F]-rhPSMA-7.3 in PCa lesions and reference tissues were assessed in a prospective Phase I trial and demonstrated dominant irreversible components. The uptake in PCa lesions and lesion-to-reference ratios increased over time, with the optimal visual detection starting from 60 minutes postinjection. Two prospective studies demonstrated a heterogeneous increase in PSMA uptake after short-term ADT (PSMA flare) in treatment-näive PCa patient, most evidently seen in bone metastases. This phenomenon was negatively correlated with glucose metabolism, which suggests that lesions with low or absent flare might be more aggressive. Finally, [ 18F]-PSMA-1007 PET/computed tomography (CT) was prospectively compared to whole body magnetic resonance imaging (WBMRI) and CT in the primary nodal staging of patients with unfavourable intermediate or highrisk PCa. The study demonstrated improved sensitivity and accuracy while maintaining high specificity.