TY - JOUR T1 - A Single Dose of <sup>225</sup>Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 649 LP - 655 DO - 10.2967/jnumed.118.219592 VL - 60 IS - 5 AU - James M. Kelly AU - Alejandro Amor-Coarasa AU - Shashikanth Ponnala AU - Anastasia Nikolopoulou AU - Clarence Williams, Jr. AU - Nikki A. Thiele AU - David Schlyer AU - Justin J. Wilson AU - Stephen G. DiMagno AU - John W. Babich Y1 - 2019/05/01 UR - http://jnm.snmjournals.org/content/60/5/649.abstract N2 - Promising biochemical responses to 225Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to β-particle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods: 225Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of 225Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mm3. Results: 225Ac-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (&gt;10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-to-kidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. Conclusion: A single dose of 148 kBq of 225Ac-RPS-074 induced a complete response in 86% of tumors, with tumor–to–normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic. ER -