A Conversation with John Sunderland, Johannes Czernin, and Thomas Hope.

477 Background: Prostate specific-membrane antigen (PSMA) targeted radionuclide therapy (TRT) has emerged as a promising treatment for prostate cancer (PCa) patients1,2. However, xerostomia has been identified as a dose-limiting side-effect for PSMA-TRT3,4. Xerostomia results from salivary gland irradiation due to PSMA mediated accumulation of PSMA-TRT and can cause severe symptoms which affect patients qualify of life5,6,7. Even though PSMA has been studied extensively for developing imaging and therapy agents, little is known about why it is physiologically expressed in the salivary glands and its role in the salivary function, including whether PSMA-targeted agent is excreted in the saliva8. Information on the excretion of these agents via saliva can help design better strategies to prevent dose-limiting toxicity of PSMA-TRT. Thus, with an intent to learn more about the fate of PSMA targeted agents, data from patients administered with the PSMA targeted PET agent [18F]DCFPyL were prospectively collected, and radioactivity in saliva were measured over-time. METHOD: Five patients with prostate cancer were enrolled in a prospective prostate cancer PET imaging clinical trial using [18F]DCFPyL. Patients were intravenously administered with 6.20-6.59 mCi of [18F]DCFPyL. Saliva samples were collected at baseline (prior to administration of [18F]DCFPyL) and 15, 30, 60, and 120 min post-injection of [18F]DCFPyL. Radioactivity in saliva was measured using the gamma counter and the percentage injected dose/gram (%ID/g) of saliva was calculated. PET images were obtained 2 h after administration of the radioactive agent. Images were reconstructed and SUV was drawn to determine radioactivity in the salivary glands. All the studies were conducted following the IRB protocol. Results: Five enrolled prostate cancer patients were intravenously injected with an average of 6.48 mCi of [18F]DCFPyL. The amount of radioactivity in the saliva, increased over 120 min, with the max radioactivity (2.04E-03-2.70E-03 %ID/g of saliva) in the saliva for each patient recorded at this time-point. At 15 min and 30 min, the radioactivity (% ID/g of saliva) in the saliva ranged between 3.95E-05 to 9.98E-05 and 3.33E-04 to 6.12E-04 respectively. Compared to 60 min, at 120 min, an average of 169.2 % increase in radioactivity was observed in the saliva. SUV of the salivary gland of these five patients were typical of images obtained with [18F]DCFPyL, and the radioactivity in the saliva could be qualitatively visualized in the gravity-dependent pocket of the oral cavity. CONCLUSION: The results indicate that after administration of [18F]DCFPyL the amount of radioactivity in the saliva increased over 120 min in all the patients (5/5). Moreover, radioactivity in the saliva was also observed on the PET images. This finding helps expand our knowledge about the fate of PSMA-targeted agents in the salivary glands and may help researchers design more-effective strategies to prevent xerostomia. However, it will be interesting to identify if the radioactivity in the saliva is contributed by intact [18F]DCPyL or its metabolite. We intend to characterize the radioactive content in the saliva in the future studies.