Reduction of Salivary Gland Uptake in Endoradiotherapy of Prostate Cancer: First Preclinical Data of a Cleavable Derivative of PSMA-617

1027 Objectives: The endoradiotherapy of metastasized, hormone-refractory prostate cancer using PSMA-617 represents an efficient therapy. However, the concomitant irradiation of salivary glands remains the main dose-limiting side effect and significantly reduces patient’s quality of life. Thus, strategies minimizing the salivary gland uptake of PSMA-617 are urgently needed. Methods: After chemical modification of PSMA-617, the PSMA-binding properties of the novel compound were analyzed by competitive binding and internalization experiments in human PSMA expressing LNCaP cells. The cleavability was shown by investigating in vitro the 177Lu-labeled fraction over time. Biodistribution and µPET studies were performed in LNCaP tumor-bearing mice (BALB/c nu/nu) to determine first data on tumor uptake and pharmacokinetic properties. Results: The cleavable derivative of PSMA-617 retained high binding affinity, specific cell uptake and was effectively internalized into the PSMA expressing cell line LNCaP. The values obtained were comparable to PSMA-617 binding data. The cleavability of the linker was proven in vitro. In first in vivo studies the tumor uptake and pharmacokinetic profile of the novel modified compound were comparable to PSMA-617 at 1 h p.i. Conclusions: The chemical modification of PSMA-617 resulted in negligible impact and the excellent cell binding properties, tumor uptake and the pharmacokinetic characteristics of PSMA-617 could be preserved. As the cleavability of the novel compound was shown in the presented in vitro proof-of-concept, further studies need to investigate the related in vivo properties. The first preclinical data on a cleavable derivative of PSMA-617 emphasize the potential of this strategy to minimize dose-limiting side effects for an improved therapy of prostate cancer.