Comparison of PSMA-TO-1 and PSMA-617 labeled with gallium-68, lutetium-177 and actinium-225

BACKGROUND: PSMA-TO-1 (“Tumor-Optimized-1”) is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with (68)Ga and (177)Lu, and the survival after treatment with (225)Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of (177)Lu-PSMA-TO1/-617 in prostate cancer patients. METHODS: First, PET images of (68)Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of (177)Lu-PSMA-617 or (177)Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of (225)Ac-PSMA-617, (225)Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of (177)Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations. RESULTS: Tumor uptake measured by PET imaging of (68)Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. (177)Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle (225)Ac-PSMA-TO-1 survived longer than those treated with (225)Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p < 0.0001). Kidney, salivary gland, bone marrow and mean ± SD tumor dose coefficients (Gy/GBq) for (177)Lu-PSMA-TO-1 in patients #01/#02/#03 were 2.5/2.4/3.0, 1.0/2.5/2.3, 0.14/0.11/0.10 and 0.42 ± 0.03/4.45 ± 0.07/1.8 ± 0.57, respectively. CONCLUSIONS: PSMA-TO-1 tumor uptake tended to be greater than that of PSMA-617 in both preclinical and clinical settings. Mice treated with (225)Ac-PSMA-TO-1 conferred a significant survival benefit compared to (225)Ac-PSMA-617 despite the accompanying increased kidney uptake. In humans, PSMA-TO-1 dosimetry estimates suggest increased tumor absorbed doses; however, the kidneys, salivary glands and bone marrow are also exposed to higher radiation doses. Thus, additional preclinical studies are needed before further clinical use. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-022-00935-6.