TY - JOUR T1 - <sup>225</sup>Ac-DOTA-MC1RL, a potential radiotherapy for the treatment of uveal melanoma JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 316 LP - 316 VL - 59 IS - supplement 1 AU - Narges Tafreshi AU - Darpan Pandya AU - Michael Doligalski AU - Mikalai Budzevich AU - Mark McLaughlin AU - David Morse AU - Thad Wadas Y1 - 2018/05/01 UR - http://jnm.snmjournals.org/content/59/supplement_1/316.abstract N2 - 316Introduction: The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanomas, which has a poor median survival being less than one year because there are no effective therapies for metastatic disease (1). We have developed a MC1R specific ligand (MC1RL), demonstrated its high selectivity for MC1R expressing tumors in mice, and its rapid systemic clearance (2). This work describes the preclinical evaluation of the targeted alpha particle therapy, 225Ac-DOTA-MC1RL for the treatment of uveal melanoma. Methods: 225Ac-DOTA-MC1RL was prepared using 225Ac(NO3)3, and stability studies were conducted in human serum for 10 days at 37ÂșC. In vitro cytotoxicity assays were performed with several cell lines demonstrating high and low MC1R expression. Acute biodistribution studies were performed in SCID mice bearing MC1R expressing human A375 subcutaneous xenograft tumors. Maximum tolerated dose studies were performed in normal mice. Mice received 0, 9, 18, 28, 37, 56, 74 or 148 kBq of 225Ac-DOTA-MC1RL and were then monitored for 120 days before being euthanized. Histopathology was performed on all mouse tissues. Using the MTD, in vivo efficacy studies were performed in SCID mice bearing MC1R expressing human A375 subcutaneous xenograft tumors. Results: 225Ac-DOTA-MC1RL was more than 90% intact after 10 days in serum at physiological temperature, while in vitro cytotoxicity assays showed significant cell death in uveal and cutaneous cell lines in an MC1R dependent manner. Biodistribution studies showed tumor selectivity and a combination of renal and hepatic clearance with minimal retention in other normal tissues. Toxicity studies revealed no signs of altered behavior among the groups. The group that received the highest dosage had a slightly but significantly lower increase in body weight over the course of the study, suggesting that 225Ac-DOTA-MC1RL is tolerated extremely well. Blood work and organ pathology did not show any significant deleterious effects even at the highest dose. In vivo efficacy studies showed excellent tumor growth control relative to control cohorts. Conclusions: We have demonstrated the radiosynthesis of 225Ac-DOTA-MC1RL, and observed its robust stability in human serum. In vitro studies demonstrated MC1R dependent cytotoxicity in uveal melanoma cells. In vivo studies demonstrated favorable biodistribution and significant antitumor efficacy. This data suggests that 225Ac-DOTA-MC1RL is worthy of further study as a therapeutic radiopharmaceutical for the treatment of uveal melanoma and its associated metastases. ER -