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

Abstract

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 ¹⁸F-labeled PSMA ligands to today's standard radiopharmaceutical ⁶⁸Ga-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 [¹⁸F]F-DCFPyL-PET, TBR with the liver as the reference organ (TBR_liver) was comparable to [⁶⁸Ga]Ga-PSMA-11-PET, while [¹⁸F]F-PSMA-1007-PET and [¹⁸F]F-JK-PSMA-7-PET showed significantly lower values. Using the parotid gland as the reference (TBR_parotidgland), [¹⁸F]F-DCFPyL-PET exhibited significantly higher values, whereas [¹⁸F]F-PSMA-1007-PET and [¹⁸F]F-JK-PSMA-7-PET were comparable. For the spleen (TBR_spleen), [¹⁸F]F-JK-PSMA-7-PET was comparable, but [¹⁸F]F-DCFPyL-PET and [¹⁸F]F-PSMA-1007-PET showed significantly higher and lower values, respectively. An additional Bland-Altman analyses revealed low bias for [¹⁸F]F-DCFPyL-PET in TBR_parotidgland, whereas significant differences in TBR_liver and TBR_spleen 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 [⁶⁸Ga]Ga-PSMA-11-PET. Thus, the use of alternative [¹⁸F]-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.

Fig. 1

Box-plots showcasing tumor-to-background ratios in PET employing [⁶⁸Ga]Ga-PSMA-11 as well as in PET using one of the alternative ¹⁸F-labeled radiopharmaceutical [¹⁸F]F-DCFPyL, [¹⁸F]F-PSMA-1007 and [¹⁸F]F-JK-PSMA-7 for the most clinically relevant background regions in theranostics (liver, parotid gland and spleen). This diagram is drawn with a logarithmic (log₁₀) scale on the y-axis. Minimum, first quartile, median, third quartile and maximum as well as outliers are depicted. SUV standardized uptake values corrected for body weight, PET positron emission tomography, (*) significant difference in Wilcoxon test, (#) without significant difference in Wilcoxon test

Fig. 2

Bland-Altman plots (A – I) comparing tumor-to-background ratios in PET employing [⁶⁸Ga]Ga-PSMA-11 as well as in PET using one of the alternative ¹⁸F-labeled radiopharmaceutical [¹⁸F]F-DCFPyL (A, D, G), [¹⁸F]F-PSMA-1007 (B, E, H) and [¹⁸F]F-JK-PSMA-7 (C, F, I) for the most clinically relevant background regions in theranostics (liver A – C, parotid gland D – F and spleen G – I). Bland-Altman plots in general depict the difference between two measurements as a function of the average of these measurements for each sample. In this context, bias is an indicator of the extent of the deviation in tumor-to-background ratios between the two radiopharmaceuticals. SUV standardized uptake values corrected for body weight; PET positron emission tomography

Fig. 3

Maximum-intensity projection images from PSMA-PET scans of three patients (Case A, Case B, Case C) from our study are shown. Each patient received two PSMA-PET scans within a short interval: one scan employing the standard PET radiopharmaceutical [⁶⁸Ga]Ga-PSMA-11 (top row) and a second scan using one of the analyzed ¹⁸F-labeled PSMA tracers (bottom row). Case A represents the [¹⁸F]F-PSMA-1007 cohort. Here a local recurrence of prostate cancer can be seen in both scans (blue arrows). Moreover, both scans reveal a small PSMA-positive lymphnode in the mediastinum, which is better shown in the ¹⁸F-PET showcasing the superior lesion detectability for small tumors. The green arrow marks a typical unspecific bone uptake in PET using [¹⁸F]F-PSMA-1007. Case B represents the [¹⁸F]F-JK-PSMA-7 cohort. Here a local recurrence of prostate cancer can be seen in both scans (blue arrow). Case C represents the [¹⁸F]F-DCFPyL cohort. This patient suffers from a local recurrence of prostate cancer as well as an extensive lymphonodal metastasis in the retroperitoneum (blue arrows) shown on both scans. Nevertheless, some of the retroperitoneal metastasis can be seen better in the ¹⁸F-PET showcasing the superior lesion detectability for small tumors. PSMA prostate specific membrane antigen; PET positron emission tomography