@article {Rayjnumed.120.256388, author = {Sangeeta Ray and Ala Lisok and IL Minn and Anders Josefsson and Vivek Kumar and Mary Brummet and Srikanth Boinapally and Cory Brayton and Ronnie C Mease and George Sgouros and Robert F Hobbs and Martin G. Pomper}, title = {Preclinical evaluation of 213Bi-/225Ac-labeled low-molecular-weight compounds for radiopharmaceutical therapy of prostate cancer}, elocation-id = {jnumed.120.256388}, year = {2020}, doi = {10.2967/jnumed.120.256388}, publisher = {Society of Nuclear Medicine}, abstract = {Prostate-specific membrane antigen (PSMA) targeted radiopharmaceutical therapy is a new treatment option for patients with advanced prostate cancer refractory to other treatments. Previously we synthesized a β-particle-emitting low-molecular-weight compound, 177Lu-L1, which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, 213Bi-L1, and 225Ac-L1 to evaluate their safety and cell kill effect in PSMA+ xenograft models. Methods: Radiochemical synthesis, cell uptake, cell kill effect, and biodistribution of 213Bi-L1 and 225Ac-L1 were evaluated. The efficacy of 225Ac-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 weeks and chronic toxicity at one year after administration were evaluated for 225Ac-L1. Radiation absorbed dose of 225Ac-L1 was determined using the biodistribution data and α-camera imaging. Results: 213Bi-/225Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. Biodistribution of 213Bi-L1 and 225Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of 225Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. 225Ac-L1 also showed an increased survival benefit in the micrometastatic model compared to 177Lu-L1. Activity-escalated acute and chronic toxicity studies of 225Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was ~1 MBq/kg. α-camera imaging of 225Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Conclusion: 225Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity issues. 225Ac-L1 is a promising therapeutic for further clinical evaluation.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/early/2020/12/04/jnumed.120.256388}, eprint = {https://jnm.snmjournals.org/content/early/2020/12/04/jnumed.120.256388.full.pdf}, journal = {Journal of Nuclear Medicine} }