Do you know your PSMA-tracer? Variability in the biodistribution of different PSMA ligands and its potential impact on defining PSMA-positivity prior to PSMA-targeted therapy.

Background: In clinical practice, several radiopharmaceuticals are used for PSMA-PET imaging, each with distinct biodistribution patterns. This may impact treatment decisions and outcomes, as eligibility for PSMA-directed radioligand therapy is usually assessed by comparing tumoral uptake to normal liver uptake as a reference. In this study, we aimed to compare tracer uptake intraindividually in various reference regions including liver, parotid gland and spleen as well as the respective tumor-to-background ratios (TBR) of different F-labeled PSMA ligands to today's standard radiopharmaceutical Ga-PSMA-11 in a series of patients with biochemical recurrence of prostate cancer who underwent a dual PSMA-PET examination as part of an individualized diagnostic approach.

Results: Differences in background activity among different PSMA-PET tracers lead to variations in tumor-to-background ratios (TBR). In [F]F-DCFPyL-PET, TBR with the liver as the reference organ (TBR) was comparable to [Ga]Ga-PSMA-11-PET, while [F]F-PSMA-1007-PET and [F]F-JK-PSMA-7-PET showed significantly lower values. Using the parotid gland as the reference (TBR), [F]F-DCFPyL-PET exhibited significantly higher values, whereas [F]F-PSMA-1007-PET and [F]F-JK-PSMA-7-PET were comparable. For the spleen (TBR), [F]F-JK-PSMA-7-PET was comparable, but [F]F-DCFPyL-PET and [F]F-PSMA-1007-PET showed significantly higher and lower values, respectively. An additional Bland-Altman analyses revealed low bias for [F]F-DCFPyL-PET in TBR, whereas significant differences in TBR and TBR for the other tracers resulted in higher bias.

Conclusion: Different PSMA-PET tracers exhibit distinct biodistribution patterns, leading to variations in tumor-to-background ratios (TBR) in reference organs such as the liver, parotid gland, and spleen. Patient selection for PSMA-directed radioligand therapy is currently based on a semiquantitative approach using the liver as a reference region in [Ga]Ga-PSMA-11-PET. Thus, the use of alternative [F]-labeled tracers may result in under- or overestimation of a patient's suitability for therapy. This highlights the importance of a comprehensive understanding of the differences in tracer-specific uptake behavior for accurate decisions regarding PSMA-expression levels. However, as the patient cohort in this study is at earlier disease stages, the generalizability of these findings to later-stage patients remains unclear and requires further investigation.